Pharmaceutical compositions and methods for fabrication of solid masses comprising polypeptides and/or proteins

Abstract

Embodiments of the invention provide shaped masses (SM) comprising one or more drugs such as proteins or polypeptides and methods for forming and delivering such SM's. One embodiment provides a SM comprising a drug e.g., a protein or polypeptide having a biological activity in the body of a mammal. The SM is formed by compression of a precursor material (PM) comprising the drug wherein an amount of biologically active drug in the SM is a minimum level to that in the PM. Drugs which may be incorporated into the SM include insulin, incretins and immunoglobulins e.g., interleukin neutralizing antibodies or TNF-α-inhibiting antibodies. Embodiments of the invention are particularly useful for the oral delivery of drugs which would be degraded within the GI tract, wherein the SM containing the drug is formed as or incorporated into a tissue penetrating member which is inserted into the intestinal wall after oral ingestion.

Claims

1. A method of delivering a drug to a patient in need thereof, the method comprising: inserting into an intestinal wall of the patient a shaped mass administered orally to patient, the shaped mass comprising a drug portion and a layer of drug sequestering water swellable (DSWS) polymer at least partially surrounding the drug portion, the drug portion comprising the drug, the shaped mass formed by compression of a precursor material comprising the drug, the biological activity of the drug in the shaped mass being at least 50% by weight to that in the precursor material, wherein the biological activity is degraded in the presence of secretions of the GI tract of the patient, the shaped mass configured to release the drug into wall tissue or adjacent tissue of the GI tract when the shaped mass is positioned in or adjacent said tissue following oral administration, thereby delivering the drug such that the biological activity of the drug is substantially preserved; wherein the DSWS polymer comprises a hydrogel and swells in the presence of fluids in the intestinal wall or adjacent tissue to form a barrier structure which sequesters the drug within the barrier structure so as to slow a release rate of the drug from the shaped mass into the intestinal wall or adjacent tissue.

2. The method of claim 1, wherein the reduction of the release rate of the drug is in a range of about 50 to 250%.

3. The method of claim 1, wherein the shaped mass is contained or incorporated into a tissue penetrating member which is inserted into the patient's intestinal wall or adjacent tissue, said adjacent tissue including peritoneal tissue.

4. The method of claim 3, wherein the tissue penetrating member is carried by a swallowable capsule that protects the shaped mass from degradation in a stomach, small intestine or other lumen of the GI tract.

5. The method of claim 1, wherein the barrier structure is degraded in the intestinal wall or adjacent tissue such that the release rate of the drug is increased.

6. The method of claim 1, wherein an amount of biologically active drug in the shaped mass is at least about 80% by weight to that in the precursor material.

7. The method of claim 1, wherein the drug comprises a protein or polypeptide.

8. The method of claim 7, wherein the drug comprises a therapeutically effective dose of insulin for treatment of diabetes or other glucose regulation disorder.

9. The method of claim 8, wherein the shaped mass comprises between about 0.2 mg to about 0.8 mg of insulin.

10. The shaped mass of claim 7, wherein the drug comprises a therapeutically effective dose of an incretin for treatment of diabetes or other glucose regulation disorder.

11. The shaped mass of claim 10, wherein the incretin comprises exenatide.

12. The shaped mass of claim 11, wherein the shaped mass comprises between about 1 mg to about 5 mg of exenatide.

13. The method of claim 1, wherein the drug comprises an immunoglobulin.

14. The method of claim 13, the immunoglobulin comprises TNF-α inhibiting antibody (TNFIA).

15. The method of claim 14, wherein the TNFIA comprises adalimumab.

16. The method of claim 13, wherein the immunoglobulin comprises an interleukin neutralizing antibody.

17. The method of claim 16, wherein the interleukin neutralized by the interleukin neutralizing antibody comprises an interleukin from the interleukin-17 family of interleukins.

18. The method of claim 16, wherein the immunoglobulin comprises secukinumab.

19. The method of claim 18, wherein the immunoglobulin comprises a therapeutically effective dose of secukinumab for the treatment of plaque psoriasis.

20. The method of claim 19, wherein a dose of secukinumab in the shaped mass is about 3 mg to 10 mg of secukinumab.

21. The method of claim 16, wherein the immunoglobulin comprises broadalumab.

22. The method of claim 21, wherein the immunoglobulin comprises a therapeutically effective dose of broadalumab for the treatment of psoriatic arthritis.

23. The method of claim 22, wherein a dose of broadalumab in the shaped mass is about 10 mg to 20 mg of broadalumab.

24. The method of claim 16 the immunoglobulin comprises ixekizumab.

25. The method of claim 24, the immunoglobulin comprises a therapeutically effective dose of ixekizumab for the treatment of psoriatic Arthritis.

26. The method of claim 25, wherein a dose of ixekizumab in the shaped mass is about 2 mg to 6 mg of ixekizumab.

27. A method of delivering a drug to a patient in need thereof, the method comprising: inserting into an intestinal wall of the patient a shaped mass administered orally to the patient, the shaped mass comprising the drug and a drug sequestering water swellable (DSWS) polymer, the shaped mass formed by compression of a precursor material comprising the drug, the biological activity of the drug in the shaped mass being at least 50% by weight to that in the precursor material, wherein the biological activity is degraded in the presence of secretions of the GI tract of the patient, the shaped mass configured to release the drug into wall tissue of the GI tract when the shaped mass is positioned in or adjacent said tissue, thereby delivering the drug such that the biological activity of the drug is substantially preserved, wherein the DSWS polymer comprises one or more of a cyclic oligosaccharide and a cyclodextrin, and non-covalently interacts with the drug in the presence of aqueous fluids in the intestinal wall or adjacent tissue so as to slow a release rate of the drug from the shaped mass into the intestinal wall or adjacent tissue were the DSWS polymer is not present.

28. The method of claim 27, wherein the wall tissue is the wall tissue of a small intestine or a peritoneum.

29. The method of claim 27, wherein the DSWS polymer interacts with drug by at least one of acid, hydrophobic, hydrogen bonding, or solvophobic interactions.

30. The method of claim 27, wherein the DSWS polymer includes a hydrophobic cavity which interacts with the drug in the presence of fluid of the wall of the GI tract or adjacent tissue.

31. The method of claim 30, wherein a reversible inclusion complex forms between the hydrophobic cavity and the drug in the presence of fluids of the wall of the GI tract.

32. The method of claim 31, wherein the inclusion complex is reversed based on at least one of a change in the pH or dilution of the complex in the tissue fluid adjacent the shaped mass.

33. The method of claim 32, wherein the inclusion complex is reversed based on at least one of an increase in the pH or dilution of the complex in the tissue fluid adjacent the shaped mass.

34. The method of claim 27, wherein the DSWS polymer comprises a cyclic oligosaccharide.

35. The method of claim 27, wherein the DSWS polymer comprises a β-cyclodextrin.

36. The method of claim 27, wherein the DSWS polymer surrounds the drug.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1A is a lateral cross-sectional view showing an embodiment of the shaped mass having a cylindrical shape.

(2) FIG. 1B is a perspective view of the embodiment of FIG. 1A.

(3) FIG. 1C is cross-sectional view showing of the shaped mass including a drug sequestering polymer.

(4) FIG. 2 is a lateral view showing an embodiment of the shaped mass having a cubical shape.

(5) FIG. 3 is a lateral view showing an embodiment of the shaped mass having a hotdog/capsule like shape.

(6) FIG. 4 is a lateral view showing an embodiment of the shaped mass having a tablet shape.

(7) FIG. 5 is a perspective view showing an embodiment of the shaped mass having a spherical shape.

(8) FIG. 6 is a lateral view showing an embodiment of the shaped mass having a hemispherical shape.

(9) FIG. 7 is a lateral view showing an embodiment of the shaped mass having a pyramidal shape.

(10) FIG. 8 is a lateral view showing an embodiment of the shaped mass having an arrow-head shape.

(11) FIG. 9 is a perspective view showing an embodiment of the shaped mass having a conical shape.

(12) FIG. 10 is a perspective view showing an embodiment of the shaped mass having a rectangular shape.

(13) FIG. 11 is a perspective view showing an embodiment of the shaped mass having a dog boned shape.

(14) FIGS. 12A-12D are lateral views illustrating use of swellable polymers to create a barrier structure to contain the release of a drug or other therapeutic compound delivered by embodiments of the tissue penetrating member.

(15) FIG. 13 shows the chemical structure of a cyclodextrin molecule.

(16) FIG. 14A-14C shows embodiments of the chemical structure of various cyclodextrins molecules including alfa (FIG. 14A), beta (FIG. 14B) and gamma (FIG. 14C) cyclodextrins

(17) FIGS. 15A and 15B show the chemical and three dimensional structure of a cyclodextrin molecule.

(18) FIGS. 16A-16C are schematic views showing the formation of an inclusion complex (or inclusion compound) between a cyclodextrin molecule and a drug. FIG. 16A depicts the drug and cyclodextrin molecule prior to complex formation, FIG. 16B shows the drug sifting in the cyclodextrin cavity complexed with the cyclodextrin and FIG. 16C shows the drug released or decomplexed from the cyclodextrin.

(19) FIG. 17A-17B are schematic views showing formation of a inclusion complex wherein the drug is singly (FIG. 17A) or doubly complexed (FIG. 17B) with a cyclodextrin molecule.

DETAILED DESCRIPTION OF THE INVENTION

(20) With reference now to FIGS. 1-12, various embodiments of the invention provide pharmaceutical compositions in the form of solid shaped masses comprising one more drugs and methods for forming solid shaped masses comprising one or more drugs or other therapeutic agents. According to one or more embodiments, the drug may comprise one or more polypeptides and proteins such as various immunoglobulins proteins (e.g., an antibody) which have a biological activity (e.g., a binding affinity and/or neutralizing ability for an antigen, a glucose regulating ability, hormonal property, chemotherapeutic property, antiviral property and the like) which may be decreased by conventional solid pharmaceutical formulation processes (e.g., such as various compression processes used to form pills, tablets etc.) as such processes tend to degrade or otherwise damage the molecular structure of the protein or peptide. One embodiment of the shaped mass 10 is shown in FIGS. 1A and 1B comprises a therapeutic composition 20 which can include one or more drugs or other therapeutic agents 25; an excipient 30 and a material 40 which is incorporated with and or surrounds the drug. In some embodiments (e.g., that shown in FIG. 1B) material 40 may correspond to one which degrades within a target delivery site in the body (e.g., the wall of the small intestine) or otherwise interacts with tissue to release drug 25. Such materials may include which (polyethylene, various sugars, lactic acid polymer, PGLA and the like. In other embodiments, shown in FIG. 1C, material 40 may correspond to and/or include a drug sequestering polymer (ds-polymer) 41 described herein, which is configured to slow and otherwise control the release rate of drug 25 into the tissue site TS, (e.g., intestinal wall tissue in wall) where the shaped mass 10 is positioned. Ds-polymer 41 may also be incorporated into the therapeutic composition 20 along with drug 25 such that it can readily interact with the drug upon exposure to tissue fluids at the tissue site (e.g., interstitial fluid in the wall of the small intestine or peritoneal wall). Ds-polymer may correspond to various water swellable polymers such as various hydrogels, and also polymers such as various cyclodextrins. In embodiments where it comprises a water swellable polymer it can encase the drug so as to readily swell to form a barrier structure 50 as shown in FIGS. 12A and 12B.

(21) According to many embodiments drug or other therapeutic 25 comprises a chemical compound which is degraded by secretions of the gastric tract (e.g., such as those in the stomach and small intestine) so as to lose its biological activity within the body of human or other mammal. Such drugs 25 may correspond to various polypeptides and proteins including, without limitations, various antibodies or other immunoglobulins such as tnf-α inhibiting antibodies or interleukin neutralizing antibodies; various glucose regulating compounds such as insulin and various incretins; various hormones such as thyroid hormone, parathyroid hormone, gonadotropin releasing hormone, growth hormone, testosterone, estrogen, pro-estrogen, luteinizing hormone, follicle stimulating hormone; and variants, derivatives and fragments thereof.

(22) The shaped mass 10 can be formed from a variety of shaping processes known in the pharmaceutical arts. Typically, the shaped mass 10 will be formed by a compression process such as compression molding. The drug may comprise a protein, peptide or antibody. According to one or more embodiments, the biological activity of the protein or peptide in the mass is at least about 70% to that prior to compression, more preferably, at least 80% to that prior to compression, still more preferably about 90% to that prior to compression and still more preferably at least 95% prior to compression. (Note, as used herein, the term “about” refers a number within 10% of the stated value of the biological or other parameter (e.g., various pharmacokinetic parameters described herein)). These numbers may also correspond to a percentage (e.g. by weight) of the drug in the shaped mass relative to that prior to formation. In these and related embodiments, the shaped mass can have a density in a range of about 0.80 to about 1.15 mg/mm.sup.3, more preferably in a range from about 0.90 to about 1.10 mg/mm.sup.3, still more preferably in a range of about 1.02 to 1.06 mg/mm.sup.3 and still more preferably in a range from about 1.03 to 1.05 mg/mm.sup.3. The shape will typically comprise a pellet shape but may also have a tablet, conical, cylindrical, cube, sphere or other like shape. Also in these or alternative embodiments the particle size (e.g., diameter or widest dimension) of the powder used to make the shape mass may be in the range of 50 to 450 μm, more preferably between 100 to 400 μm and still more preferably between 200 to 400 μm.

(23) According to various embodiments, the shaped mass 10 can be formed in part from a material that is configured to slow or otherwise control the release the drug into the intestinal wall and/or surrounding tissue (or other tissue site) after the shaped mass is inserted there (e.g., using various embodiments of a capsule or other swallowable/oral drug delivery devices such as those described in U.S. Pat. No. 9,149,617) with the effect in some embodiments being reversible. In various embodiments, the slowed release and subsequent reversed slowed release of drug can occur by interactions of the material, and/or drug with the adjacent tissue. Such interactions can include one or more of dissolution, pH, hydrophilic hydrophobic or hydrogen bonding interactions. In preferred embodiments, the material is configured to dissolve or other otherwise degrade in tissue the wall of the intestine such as the small intestine (or another tissue site, e.g., an intramuscular site) so as to release the drug into the intestinal wall where it diffuses or otherwise is transported into the capillary bed of the intestinal wall and then is carried by the circulatory system throughout the body. As used herein, the term “degrade” includes one more of the processes of biodegradation, dissolving or disintegration due to contact with a biological fluid (e.g., blood, interstitial fluid, lymph etc.) and/or tissue. Also the terms degrade(ation) can be used interchangeably. Suitable degradable materials include various sugars such as maltose, mannitol, cyclodextran and sucrose, various lactic acids polymers such as polyglycolic acid (PGA), polylactic acid (PLA); polyglycolic lactic acid (PGLA); various polyethylenes such as high density, low density and linear low density PE and PEO (polyethylene oxide), various cellulose polymers such as HPMC (hydroxypropyl methyl cellulose), CMC (carboxy methyl cellulose), MC (methyl cellulose), methacrylic acid—ethyl acrylate copolymer, methacrylic acid—methyl methacrylate copolymer PVOH (polyvinyl alcohol), silicone rubber. and other biodegradable polymers known in the art. The material and other properties of the degradable polymer and shaped mass can be selected to produce selectable rates of degradation in the intestinal wall. According to one or more embodiments, the rates of degradation can be selected to achieve various pharmacokinetic parameters such as t.sub.max, C.sub.max, t½, etc. In one or more specific embodiments, the materials properties of the shaped mass (e.g., its chemical composition, solubility in interstitial fluids, size and shape) can be selected so as to have the shaped mass degrade within the intestinal wall to achieve a C.sub.max for the selected drug(s) in a shorter time period than a time period to achieve a C.sub.max for an extravascularly injected dose of the drug.

(24) Embodiments of Methods For Fabricating Drug Containing Shaped Masses. A description will now be provided of the fabrication process used to make various embodiments of the drug containing shaped masses described herein. The process includes a process for fabricating a powder containing one or more drugs and a shaped mass formation process for forming the powder into micro-tablets or other shaped masses comprising one or more drugs. For ease of discussion, the shaped masses will now be referred to as micro-tablets; however it should be appreciated that other forms and/or shaped for the shaped masses are equally applicable. It should also be appreciated that this process is exemplary and other processes are also considered.

(25) Drug Powder Formation Process. The process for formulation of a powder comprising the drug will now be described. Typically, it includes three steps. The first step is to prepare an aqueous solution of the drug and then add then add the desired excipients for the particular application. According to one more embodiments, the excipients can include a lubricant, a binder and a bulking agent. The lubricant is added to facilitate both micro-tablet formation and ejection from a mold. The lubricant may correspond to polyethylene glycol 3350 and in one or more embodiments may be added in proportion of approximately 10% w/w of the total batch mass. The bulking agent may correspond to mannitol and the binder may correspond to povidone. Other excipients which may be added include binders, fillers, disintegrants, stabilizers, buffers and antimicrobials. The proportions of the different ingredients, active and non-active, in the powder mixture are taken into consideration during the formulation process so as to achieve a desired therapeutic dose of the drug in the resulting micro-tablet.

(26) The second step is to evaporate the aqueous mixture. The gently-mixed solution containing the drug and the excipients is then placed in a flexible and flat plate (for example, silicone plate) inside of a vacuum chamber containing desiccant. The chamber is then placed inside of a refrigerator or cold room and is connected to a vacuum line or pump. The solution is left under vacuum and low temperature, above 0° C., until it dries out completely.

(27) The third step comprises milling the evaporated mixture to produce a fine powder. The evaporated mixture is placed in a low-protein-binding tube along with a single high-density milling ball, preferably, made of stainless steel or yttrium-stabilized zirconium. The milling is done using a rotator at max speed containing the tube film-wrapped to avoid moisture absorption or contamination. An ice pack is desirably placed on top of the tube to keep it cold. The room temperature can be controlled in a range for example from 60 to 64° F. The size of the milling tube, mass of the milling ball and duration of mixing may be selected to produce particular powder grain sizes, grain size homogeneity and powder density. For example, for the production of a 40 mg to 100 mg batch capacity, the use of a bottom-rounded 2 mL tube, a milling ball having a 0.44 g mass and a milling duration of 3 hours resulted in fine and consistent grain sizes, achieving more homogeneous and reliable density values.

(28) Micro-tablet Fabrication Process. The process is desirably done in a clean and temperature-controlled room where the temperature is kept between 60-64° F. The micro-tablet formation is typically done via compression using a compression mold or other fixture to apply a compressive force to the powder including the drug. Two types of compression fixtures may be used, a semiautomatic one or a fully automatic version. For fabrication using the semiautomatic fixture, the micro-tablets are fabricated over a base which consists of two metal sheets connected to a force gauge stand by four cylinders, four springs and four vibration mounting stoppers. The top sheet has a cavity with a hole on it for a mold or well to slide in. The mold used for the compression has a 45 degree funnel ending in a well with required diameter and length to accommodate the powder for compression. A pin is attached to a pin holder and connected to the force gauge which can be moved up and down by a controlled motor operated by a 3-way switch.

(29) The semiautomatic fabrication procedure can include the following steps: 1) positioning of a stopper, 2) placing a tablet mold on top of the stopper and a pin into the holder, 3) loading the powder required for the micro-tablet and letting it sink/settle into the mold hole, 4) compressing the powder into the mold by advancing a motorized pin (which is connected to force gauge) into the mold until a desired force is reach (i.e. compression force) and holding it in position with the applied force for a set time period (i.e. hold time), 6) removing the tablet metal stopper and place a dish to collect the tablet, and 7) lowering the pin with the motor switch until the micro-tablet exits the mold and collect the micro-tablet in a dish. The combination of compression force and hold time will determine the mechanical structure of the micro-tablet as well as the decrease in the bioactivity of the drug.

(30) For the process using the automatic fixture, the processes of drug sinking, compression and ejection are fully automated. The mold rests in a base and is restrained by a mold holder by three screws. The mold bottom is in contact with a piece of metal referred to as a “gate” which can be move by the action of an air cylinder. The gate will stop the powder from falling down during loading and compression and will open during the ejection. An air cylinder is attached to the force gauge stand by a cylinder holder. This top air cylinder has a pin holder attached to its piston rod with a pin in it, which has the diameter required to be inserted into the mold hole and compress the powder. In general, a diameter of 0.0005″ less than the diameter of the mold hole would be enough to have a tight fit between pin and mold hole. The top air cylinder connected to the pin extends to produce the powder compression and the ejection of the micro-tablet. A reed switch is connected to this cylinder to know the position of the piston rod. The stand also has a pneumatic vibrator with an air filter to vibrate the system and force the powder to move inside of the mold hole during loading. The three pneumatic components, gate air cylinder, compression/ejection top air cylinder and vibrator, are controlled by an electro-pneumatic system. This system consists of a power supply, programmable logic controller (PLC), four solenoids valves, reed switch, foot-switch pedal and a control panel that includes four regulators, four pressure gauges, micro-graphic panel and power switch.

(31) In an automatic fashion, the controlling system is built and programed in a way for the user to complete the following sequence: 1) user loads the powder; 2) user press pedal for initiation and hold it until the end of the sequence; 3) vibration starts (vibration duration and pressure can be modified at control panel); 4) powder is compressed by the pin due to the extension of the top cylinder (compression duration and pressure can be modified at control panel) followed by the retraction of the cylinder after compression; 5) gate is opened by the retraction gate air cylinder (gate pressure can be modified at control panel as well as the time for opening and closing the gate); 6) the micro-tablet is ejected by the new extension of top air cylinder (ejection duration and pressure can be modified at control panel) followed by the retraction of the cylinder after ejection; finally 7) the gate closes ending the sequence.

(32) After the micro-tablet is fabricated, the length, weight, density and bioactivity of the drug in the pellet are measured. The bioactivity of the drug in the micro-tablet may be assayed using an Enzyme-linked immunosorbent assay (ELISA) or other immune assay known in the art. According to one or more embodiments, a separate compound, herein a bioactivity marker compound (herein bioactivity marker), may be included in at some batches, wherein the herein bioactivity marker has a molecular structure which has the same response (in terms of preservation of molecular structure and/or bioactivity) to compressive force used in the fabrication process as the drug included in the micro-pellet. The bioactivity marker however can be selected so that a bioactive amount of biomarker compound present in the micro-tablet and/or at any step in the fabrication process can be determined using a simple analytical test such as a colorometric and/or turbidity test.

(33) Embodiments of Shaped Masses Comprising Insulin. According to one or more embodiments of the pharmaceutical compositions described herein, the drug contained in the micro-tablet or other shaped mass comprises insulin or like molecule for the treatment of diabetes or other glucose regulation disorder. The insulin may be obtained from any suitable source e.g. human insulin and/or that generated using recombinant DNA methods known in the art. It may also correspond to basal or fast acting insulin (the type taken after eating a meal also known as meal time insulin) or a combination of both. Suitable basal insulins may include NP, Glargine and Detemir. Suitable fast-acting insulins may include aspart, glulisine, lispro, and regular. The specific dose of the insulin contained in the mass can be selected based on one more of the weight, age and/or other parameter of the patient. In specific embodiments, the micro-tablet may comprise between about 0.2 to about 0.8 mgrams of insulin. In various embodiments of the shaped mass comprising insulin, the shaped mass may also include one or more excipients comprising salts (e.g., sodium chloride, potassium chloride, etc.) and/or acids (e.g., citric acid) which are selected so as to control or adjust the drug or drug depot that is formed within the wall of intestine once the shaped mass is inserted into the wall of the small intestine or other delivery site. Such properties may correspond to the pH of the drug and/or drug depot. Control of the pH in turn can be used to control the elution/release profile of the insulin or other drug from the shaped mass (e.g., an incretin). For example in the case of insulin and its analogues, at low pH, insulin forms multimers (one example including a hexo-polymer structure) which aggregate together and then disassociate in vivo (as the pH comes back to neutral levels) back to insulin monomers to release the insulin into its physiologically active form that acts on the body. Thus in one or more embodiments, acid salts such as citrates (e.g., citric acid) can be incorporated into the micro-tablet or other shaped mass along with insulin (or other like molecule) so as to slow the release rate of insulin into the interstitial fluids of the intestinal wall (or other target tissue site) and in turn into the blood stream.

(34) The shaped mass may be formed according to one more methods described herein including compression forming methods/processes such as those described in the examples as well as 3D printing methods known in the art and also described herein. In these and related embodiments, the compression forming method is configured to preserve the biological activity of the insulin in the micro-tablet so as to be able to allow the drug to treat diabetes or other glucose regulation disorder once released into the body of a patient. The compression force use in such compression methods may be in the range of about of 0.5 to 4 pounds of force and more preferably in a range of about 1.5 to 3 about pounds of force. The weight percent of the insulin in the mass can range from about 10 to 95%, more preferably from about 20 to 95%, still more preferably from about 25 to 95% and still more preferably from about 80 to 95%. The biological activity and/or weight percentage of the insulin in the shaped mass may be in a range from about 88 to 99.8% to that prior to formation (e.g. from a powder used to form the micro-tablet). The density of the micro-tablet in such embodiments can range from about 0.95 to about 1.15 mg/mm.sup.3, more preferably from about 1.0 to about 1.10 mg/mm.sup.3. In preferred embodiments, the biological activity of the insulin in the shaped mass may comprise 99.2 to 99.8% of that prior to formation. The density of the micro-tablet in such embodiments can range from about 1.08 to 1.10 mg/mm.sup.3. Measurement of the biological activity of the insulin in the shaped mass can be performed using assays known in the art, including ELISA or other immuno-assay methods.

(35) According to one or more embodiments, the insulin containing shaped mass may also comprise one or more excipients including, for example, a lubricant, a bulking agent, a binding agent or binder and an acid salt as described herein. The lubricant is selected to reduce the amount of force required to eject drug containing shaped masses from a mold and may correspond to polyethylene glycol (PEG) an example including PEG 3350. The bulking agent may correspond to mannitol and the binder may correspond to povidone. The weight percent of the insulin in the mass can range from about 10 to 95%, more preferably from about 20 to 95%, still more preferably from about 25 to 95% and still more preferably from about 80 to 95%. The weight percent of PEG can range from about 1 to 10% with a specific embodiment of 5%. The weight percent of Mannitol can range from about 4 to 70% with a specific embodiment of 5%. The weight percent of Povidone can range from about 1 to 5% with a specific embodiment of 1%.

(36) Embodiments of Shaped Masses Comprising Incretin. According to one or more embodiments of the pharmaceutical compositions described herein, the drug contained in the micro-tablet or other shaped mass comprises an incretin such as exenatide for the treatment of a glucose regulation disorder such as diabetes. Other incretins are also contemplated. The shaped mass may be formed according to one more methods described herein including compression forming methods such as those described in the examples for insulin. As described above for insulin the compression forming method is configured to preserve the biological activity of the incretin in the micro-tablet so as to be able to allow the drug to treat diabetes or other glucose regulation disorder once released into the body of a patient. The specific dose of the exenatide or other incretin contained in the mass can be selected based on one more of the weight, age and other parameter of the patient. In specific embodiments, the micro-tablet may comprise between about 0.2 to about 1 to 5 mgms of exenatide. The density of the mass containing the incretin can be in the range of 1.04±0.10 mg.

(37) Embodiments of Shaped Masses Comprising TNF Inhibiting Antibody. According to one or more embodiments of the pharmaceutical compositions described herein, the drug contained in the micro-tablet or other shaped mass comprises an antibody from the TNF (Tumor Necrosis Factor) inhibitor class of antibodies (e.g., adalimumab) for the treatment of various autoimmune disorders (e.g. rheumatoid arthritis) which are characterized by the over production of tissue necrosis factor. In these and related embodiments, the compression and other aspects of the forming process used to fabricate the micro-tablet or other shaped mass is configured to preserve the biological activity of the TNF inhibiting antibody so as to be able to treat one or more autoimmune disorders. In specific embodiments, the TNF inhibiting antibody contained in the micro-tablet or other shaped mass may correspond to one or more of adalimumab (Humira), infliximab (Remicade), certolizumab pegol (Cimzia) or golimumab (Simponi), or etanercept (Enbrel). Further description of adalimumab may found at en.wikipedia.org/wiki/Adalimumab.

(38) As various embodiments of the shaped masses described herein comprise TNF antibodies, a brief discussion will now be presented on the TNF inhibitor class of antibodies, the conditions they treat and the mechanism of treatment. Tumor necrosis factor (herein TNF, or TNF-α) is a cytokine involved in systemic inflammation. The primary role of TNF is in the regulation of immune cells. TNF, being an endogenous pyrogen, is able to induce fever, to induce apoptotic cell death, to induce sepsis (through IL1 & IL6 production), to induce cachexia, induce inflammation, and to inhibit tumorigenesis and viral replication. TNF promotes inflammatory response, which in turn causes many of the clinical problems associated with autoimmune disorders such as rheumatoid arthritis, spondylitis, Crohn's disease, psoriasis, hidradenitis suppurativa and refractory asthma. Antibodies that can therapeutically achieve inhibition of TNF-α come under this TNF α (Tumor Necrosis Factor α) inhibitor class of antibodies. All antibodies including this TNFα inhibitory class of antibodies are characterized by having the structure of antibody, which is described as containing two fragments, Fab and Fc, joined together by disulphide bonds to form a Y-shaped molecule. Examples for TNFα inhibitory class of antibodies are: Infliximab (Remicade) is mouse Fab-human Fc chimeric antibody (˜150 kda), Adalimumab (Humira©)˜148 kda fully humanized antibody, Etanercept (Enbrel) is 150 kda, p75 TNF-receptor domain-Fc (IgG1) fusion protein, Certolizumab pegol (Cimzia) has human mab (Fab) linked to PEG. The most labile part of an antibody including TNFα inhibitory class of antibodies is the disulphide bonds at the junction of the Y-shape. As shown by the examples herein, the inventors have demonstrated (by virtue ELISA data showing that antibody molecule remains structurally intact and retains its bioactivity) that these disulphide bonds are preserved for various antibodies incorporated into a micro-tablet fabricated using the compression formation methods described herein. Therefore, one skilled in the art will appreciate that embodiments of the compression formation methods described herein would be expected to preserve the structure and bioactivity of antibody (including the TNF inhibitory class of antibodies) which has disulphide bonds at the junction of its Y-shaped molecule.

(39) A description of the formation process for a micro-tablet or other shaped mass comprising adalimumab (herein HUMIRA), will now be provided; however it should be appreciated that this process is applicable to any antibody and in particular to any antibody in the TNF inhibitory class of antibodies (e.g., infliximab or etanercept, etc.). The compression force used to fabricate a micro-tablet containing HUMIRA may be in the range of 1.0 to 4 pounds of force, with a specific embodiment of 3 lbs. The weight percent of the HUMIRA in the mass can be in a range from about 60 to 95%, more preferably from about 80 to 95%, with a specific embodiment of about 95%. The biological activity of the HUMIRA in the shaped mass may be in a range from about 67 to 99% to that prior to formation (e.g. from a powder used to form the micro-tablet). The density of the micro-tablet in such embodiments can range from about 0.86 to 1.05 mg/mm.sup.3, more preferably from about 0.88 to about 1.03 mg/mm.sup.3. In preferred embodiments, the biological activity of the HUMIRA in the shaped mass may comprise about 86 to 99% of that prior to formation. The density of the micro-tablet in such embodiments can range from about 1.09 to 1.17 mg/mm.sup.3. Measurement of the biological activity of the HUMIRA in shaped mass can be performed using assays known in the art, including ELISA or other immuno-assay methods.

(40) According to one or more embodiments, the HUMIRA containing shaped mass may also comprise one or more excipients including, for example, a lubricant, a bulking agent and a binding agent or binder. The lubricant is selected to reduce the amount of force required to eject drug containing shaped masses from a mold and may correspond to polyethylene glycol (PEG) an example including PEG 3350. The bulking agent may correspond to mannitol and the binder may correspond to povidone. The weight percent of PEG can range from about 1 to 15% with a specific embodiment of 10%.

(41) Embodiments of Shaped Masses Comprising Interleukin Inhibiting Antibody. According to one or more embodiments of the pharmaceutical compositions described herein, the drug contained in the micro-tablet or other shaped mass comprises an interleukin neutralizing antibody or other interleukin neutralizing immunoglobulin or protein wherein the interleukin neutralizing antibody is capable of neutralizing and/or inhibiting the biologic effects of one more of interleukins 1-36 by preventing or diminishing the ability of the selected interleukin from binding to a receptor for that interleukin. Such a neutralizing effect can be achieved by selecting the interleukin neutralizing antibody which binds to the selected interleukin or a receptor for that particular interleukin so as to prevent the interleukin from activating the receptor and in turn causing one or more biologic effects. Related embodiments provide methods of preparing a shaped mass comprising a drug wherein the drug comprises an antibody that neutralizes the biological/biochemical effects of interleukins including interleukins 1-36 wherein the biological activity of the anti-body (e.g., its binding affinity to a selected antigen and/or neutralizing ability of the selected antigen) is preserved after formation of the shaped mass in amounts of 70, 80, 90 or 95% relative to that of a precursor material prior to formation such amounts considered to comprise substantial preservation of the biological activity of the antibody. Accordingly, as used herein, the term “substantially preserved” in reference to the biological activity of an antibody or other therapeutic agents referred to herein means preservation of the biological activity of the particular therapeutic agent in an amount equal to or greater than 70% to that prior to fabrication of the shaped mass and/or prior to insertion of the shaped mass into tissue e.g., intestinal wall or adjacent tissue.

(42) Many embodiments provide shaped masses comprising antibodies which neutralize the biological effects of the interleukin 17 family of interleukins with particular embodiments comprising one or more of the antibodies Secukinumab, Brodalumab, and Ixekizumab. For example, according to one embodiment, the shaped mass can include a therapeutically effective dose of Seckinumab for the treatment of plaque psoriasis which may correspond to a dose in the range of about 3 to 10 mg. In another embodiment, the shaped mass can include a therapeutically effective dose of Brodalumab for the treatment of psoriatic arthritis which may correspond to a dose of about 10 to 20 mg of Brodalumab. In another embodiment, the shaped mass can include a therapeutically effective dose of Ixekizumab for the treatment of psoriatic arthritis which may correspond to a dose of about 2 to 6 mg of Ixekizumab.

(43) Embodiments of Shaped Masses Produced Using 3D Printing Methods. Various embodiments of the invention also provide methods of preparing a shaped mass comprising a drug (which may comprise a protein or polypeptide) wherein an outer coating(s) and/jacket of materials is formed over the drug using 3-D printing methods so as to form a selectively shaped micro-micro tablet or other shaped mass. The coating or jacket may comprise one more biodegradable materials described herein. According to one or more embodiments, the 3-D printing methods can be configured to deposit the coating or jacket as a single layer or as multilayer coating. In the latter case, different layers can be applied which have different compositions, material properties, and thickness. In such multilayer applications allows for more precise control of one or more properties of the shaped including for example the rates of biodegradation of the shaped mass. For example according to one embodiment, a relatively fast degrading layer can be deposited over a drug layer, which is in turn positioned over a more slowly degrading layer that in turn is positioned over a core mass of drug. In use, such embodiments provide for bio-modal form of release with a rapid release (e.g., a bolus release) of drug under the first layer and a more slow release of drug under the second layer.

(44) Use of 3-D printing methods allow the shaped mass to be formed with minimal or no pressure applied to the mass and in turn the underlying drug. In use, such methods improve the yield of the drug in the final shaped mass due to decreased protein denaturation and/or other degradative effects on the drug. This in turn improves the bioactivity of the drug in the final shaped mass. Use of 3-D printing also allows a variety of shapes to be produced without use of a mold or other related device reducing the potential for contamination and improving sterility. Such shapes may include for example, an arrow head shape, rectangle, pyramidal, spherical, hemispherical, conical and others. 3 D printing methods also allow for rapid customization of the drug mass shape and size for individual patient parameters, for example one or more of a patient's weight, medical condition and particular medical regimen (e.g., taking of medication once day, twice etc.). In still other embodiments, 3-D printing methods can be used to produce shaped masses configured to have a bimodal form of delivery, e.g., fast release and slow release.

(45) Embodiments of Inventories of Shaped Masses Having Uniform Properties. Other embodiments of the invention provide an inventory of shaped masses comprising a drug such as a peptide, protein or immunoglobulin, wherein a property of a composition comprising the shaped mass, such as the biological activity of the drug post formation, is maintained within a selected range for substantially the entire inventory. In use, such embodiments help to ensure the uniformity of one or more of dosage, pharmacokinetic parameters (e.g. t.sub.1/2, t.sub.max, c.sub.1/2, c.sub.max, AUC, MRT etc) and resulting clinical effect for one or more selected drugs delivered using the shaped masses. For example, for embodiments of the shaped mass comprising insulin, the biological activity and/or weight percentage of the insulin post formation can be maintained in a range of about 99.2 to 99.8% to that prior to formation for substantially the entire inventory.

(46) Embodiments of Shapes for the Shaped Masses. In various embodiments the size and shape of the micro-tablet or other shaped mass can be configured to control and/or optimize one or more of the following parameters: the payload (e.g., mass) of drug, shape and size of the particular tissue penetrating member, size of the delivery capsule (containing and/or otherwise carrying the tissue penetrating member comprising the shaped mass), pharmacokinetic parameters (e.g., C.sub.max, C.sub.1/2, t.sub.max, t.sub.1/2) and the release rate of drug. According to one or more embodiments the micro-tablet can have a cylindrical, capsule (e.g., hot dog), rectangular, spherical, hemispherical, dogbone or triangular volumetric shape. In preferred embodiments, the micro-tablet has a cylindrical or like shape with a diameter in the range of about 0.5 to 1.5 mm and a length of about 1 to 4 mm. These and other shapes for the shapes for embodiments of the shaped masses 10 are shown in FIGS. 1-11.

(47) Embodiments of the Shaped Masses in the Form of Spherical Drug Beads. In various embodiments, the shaped mass can be in the form bead or micro-bead which is inserted or otherwise formulated into embodiments of a tissue penetrating member described herein. Multiple such beads may be formulated into the tissue penetrating member, with different beads formulated to have different drug release so as to achieve and/or comprising different drugs. In use, such embodiments allow for the simultaneous delivery of multiple drugs (e.g. such as those used to in a multidrug regimen to treat a particular condition such as AIDS, autoimmune disease (e.g., MS) as well as achieve a varied or release profile and release rate of drug. For example, in one or more embodiments, the beads cans be selected to achieve a bimodal release profile for a particular drug. For embodiments of beads having varied release rates, beads can be included in the tissue penetrating member which have a fast release period (e.g., minutes to hours) and a slower release profile (e.g., hours to days). In use, such fast and slow release drug bead embodiments allow for a rapid rise in plasma concentration of drug so as to quickly approach therapeutic levels for the drug and a slower release to keep the plasma concentration at the therapeutic level for extended periods of time (e.g., days to week) once the release from the faster releasing bead tails off. In related embodiments, additional beads can be included which have an intermediate release rate (e.g, in between the fast and slow release rate) so as to achieve a more constant drug concentration over an extended period of time, for example, over a period from a few hours to 14 or thirty days or more.

(48) Several different approaches are contemplated for achieving varied drug release rates and profiles for embodiments using drug beads. According to one or more embodiments, the varied release profiles can be achieved by formulating the beads with embodiments of water-soluble polymer and/or drug sequestering polymers described herein. According to other embodiments, the surface area of the bead can be used to control the release rate. Multiple smaller beads can be used to produce faster release rates and larger beads can be used to produce a slower though a longer lasting release of drug. The rates of drug release for particular bead sizes can be determined using the Noyes-Whitney equation (shown below) to calculate the rate of drug dissolution from the bead into the interstitial fluids of the intestinal wall or other target tissue site.

(49) $\frac{\mathrm{dW}}{\mathrm{dt}}=\frac{\mathrm{DA}\left(C_s-C\right)}{L}$
Where:

(50) $\frac{\mathrm{dW}}{\mathrm{dt}}$
is the rate of dissolution.

(51) A is the surface area of the solid.

(52) C is the concentration of the solid in the bulk dissolution medium.

(53) is the concentration of the solid in the diffusion layer surrounding the solid.

(54) D is the diffusion coefficient.

(55) L is the diffusion layer thickness.

(56) Applying this equation to an embodiment having three beads, two smaller and one larger bead having a radius of 1 mm, where the two smaller beads having the same total mass as the third larger bead, owing to their larger surface area, the two smaller beads are going to produce a release rate that is about 26% faster than the larger sphere. Other embodiments contemplate a variety of mixtures of smaller and larger beads so as to achieve a desired drug distribution profile e.g., biomodal, trimodal etc. over a selected time period for a particular drug or drugs. For example, in one embodiment, the shaped mass can include two 0.8 mm beads (for fast drug release), one 1 mm bead (for mid-rate release) and a third 2 mm bead for longer term release. Also according to one or more embodiments, the rate of release can be further increased (e.g., per the Noyes-Whitney equation) by texturing the surface of the bead (or other shaped mass) so as to increase its surface area relative to unshaped beads. Texturing of the bead surface can be achieved using a variety of known methods, e.g. by the use of textured molds and/or plasma treatment of the beads. In various embodiments, texturing of the bead surface can be done to increase its surface area from 5 to 300% or more, with specific embodiments, of 25, 50, 75, 100, 125, 150, 175, 200, and 250% increase in surface area.

(57) Embodiments of the Shaped Masses Including Salts. In various embodiments, the shaped mass can also comprise one or more salts which are selected for various properties which affect the shaped mass and/or the drug. In particular embodiments, the salts are selected to stabilize the drug molecule and adjust the pH of the shaped mass once positioned in situ in the wall of the small intestine or other location. Such pH adjustment can be used to control the elution profile of the drug. For example, for a drug such as long acting insulin, low pH can be used to promote the formation of multi-meric insulin micelles which slowly dissociate at the tissue boundary of the micelles to form monomers which comprise the bioactive form of the drug such as the monomer form of insulin. Suitable acids in salt form to be used into the shaped mass can include ascorbic acid, citrates, hydro chlorates, EDTA, sodium acetate and all like salts. Suitable bases in salt form to be used in the shaped mass can include hydroxides, chloride (sodium chloride, potassium chlorides), phosphates (potassium phosphates, sodium di-hydrogen phosphates) carbonates, bicarbonates, azides and all like molecule.

(58) Embodiments of the Shaped Mass Including Drug Sequestering Polymers. In various embodiments, in addition to the API, the shaped mass can also comprise one or more repeating chain complexes herein in drug sequestering polymers 41 also described as a ds-polymer 41 configured to trap or otherwise contain (e.g., by binding) the drug molecules (e.g., polypeptide, protein or other API) within the polymeric structure formed by the repeating chains.

(59) In various embodiments, the ds-polymer may correspond to one or more of water swellable polymers such as various hydrogels PEG (polyethylene glycol, of various molecular weights), dextrin, cyclodextrin, dextran, cyclo-dextran, mannitol and other complex sugars, cellulose, methyl-cellulose and other like molecules. One or more of the ds-molecules are mixed with the API into the shaped mass in ratios in a range from about 3:98 to about 98:2. For example, for embodiments of the micro-tablet comprising PEG and Immunoglobulin-gamma (IgG) or other antibody the weight ratio of PEG to the mass of an immunoglobulin can be in the range of about 1:2 to about 1:49. For embodiments of the micro-tablet comprising PEG and insulin (or other comparable protein), the weight ratio of PEG to the mass of insulin can be in the range of about 1:1 to about 1:19. For embodiments of the micro-tablet comprising Povidone and insulin, the weight ratio of Povidone to the mass of insulin can in be in the range of about 1:19 to about 1:99. For embodiments of the micro-tablet comprising mannitol and insulin, the ratio of the mass of mannitol to the mass of insulin can be in the range of about 1:1 to about 1:9.

(60) Embodiments of the Shaped Masses Including Drug Sequestering Water Swellable Polymers. In various embodiments, the shaped mass can include ds-polymers 41 which comprise one or more water swellable polymers 42 (herein ws polymers 42) such as various hydrogels which function to create a barrier structure 50 described herein. The function of an embodiment of such a barrier structure will now be described. Referring now to FIGS. 12A-12D, once the shaped mass 10 is inserted into a moist tissue environment such as that found in the wall W of the small intestine SI, the polymer chains of the ds-polymer may expand or otherwise, reshape or re-orient to form a three dimensional structure or barrier structure 50 as shown in FIGS. 12A and 12B, to further contain and control the release of the API 25. The barrier structure 50 is subsequently biodegraded (e.g., by hydrolysis) within the intestinal wall (or other location) as shown in FIGS. 12C and 12D which in turn causes the release of drug or API. FIG. 12C illustrate the degraded sections 51 of the barrier structure allowing tissue fluid to reach the API 25 allowing molecules 26 of the drug 25 to be absorbed or otherwise diffuse into tissue at the tissue site TS. FIG. 12D shows the barrier structure 50 completely degraded with only remnant sections 52 (which are further degraded or pass through the intestinal tract) allowing more significant amounts of diffusion or transport of the drug molecules 26 into the tissue site TS. In particular embodiments, when the barrier structure 50 is present, the API 25 can have a first rate of release and is it degrades it may have a second rate of release which typically will be faster than the first rate of release. In this way, one or more ds-polymers can be used to control the drug elution/release profile in a predetermined predictable fashion. In particular embodiments, based on the type and amount of the water swellable polymer 42 or other ds-molecule 41, the rate of release of the API can be slowed relative to an API release rate when the ds-polymer is not present in a range from about 10 to 300% or even higher such as 500 to 1000%. Narrower reduction range may include 20 to 300%, 20 to 250%, 20 to 150%, 20 to 100, 50 to 250% 50 to 150% and 50 to 100%. Specific embodiments for reduction of the release rate may include 20, 30, 50, 75, 100, 150, 200, 225, 250 and 275%. Slower release rates can be obtained for the use of three dimensionally structured ds-polymers such as various cyclical shaped ds-polymers (e.g., various) cyclodextrins, and/or ds-polymer having larger molecular weights. For example, using one more of these or other ds-polymers, the release rate of an API such as insulin, a TNF-alfa antibody or an interleukin neutralizing antibody can be slowed in the range of 1 mg/per minute to 1 mg per hour so that for a 5 mg dose of drug the release time can be extended from approximately five minutes to approximately 5 hours.

(61) The ws-polymers 42 are desirably formulated into the shaped mass in a dry state and then when exposed to the moisture in tissue (e.g., from interstitial fluids when the shaped mass is inserted into the intestinal wall) swell to form an in situ three dimensional structure also referred to herein as barrier structure which entraps or otherwise contains the drug (e.g., by intercalating with the drug molecules) to form a reservoir or depot of drug from which the drug elutes in a predictable, pre-determined time course, e.g., several hours to several days or longer. The water swellable polymer 42 can include those known in the art and in preferred embodiments comprise hydrogels. Suitable hydrogels can include both natural polymer and synthetic polymer hydrogels and combinations of both. They also may be in the superabsorbent and super-porous class of hydrogels or both. Further description of suitable hydrogels and their properties may be found in the paper by E Ahmed, entitled “Hydrogel: Preparation, characterization, and applications: A review” Journal of Advanced Research (2015) 6, 105-121 the contents of which are incorporated by reference herein for all purposes. After the hydrogel or other barrier structure 50 forms, it can be configured to subsequently biodegrade over a selected period at the tissue site so as to release the drug or other therapeutic agent as is shown in FIGS. 12C and 12D. The degradation can be by one or more of hydrolysis or other chemical reaction of various bonds of the water swellable polymer such as various cross links. Depending upon the hydrogel and its properties (e.g. molecular weight, degree of cross linking) and amount of hydrogel in the shaped mass, the period of degradation can be in the range of 4 hours 7 days, with specific embodiments of 6, 8, 12, 24, 36, 48, 72, 96, 120 and 144 hours.

(62) In various embodiments, the amount of hydrogel or other ws-polymer 42 can range from about 4 to 98% weight percent of the shaped mass 10 with specific embodiments of 10, 20, 30, 40, 50, 60 and 75 weight percent. The amount being selected to control one more of the degree of swelling and the selected period of release of the drug. According to various embodiments the hydrogel or other ws-polymer can be selected so as to swell between 10 to 100 times in volume of its dry form volume so as to cause the shape mass to swell in a similar amount in volume. According to some embodiments, the amount of swelling is sufficient to fix or anchor the shaped mass in place in the wall of the small intestine or other target tissue site. The amount of swelling to achieve such an anchoring function can be in the range of 3 to 50 times. In particular embodiments, the hydrogel or other ws-polymer can be configured to cause the shaped mass to swell from a length of 3 about mm and a diameter of about 0.7 mm to a length of 30 mm and a diameter of about 7 mm.

(63) Embodiments of the Shaped Mass Including Drug Sequestering CycloDextrins.

(64) Referring now to FIGS. 13-17, in various embodiments, the drug sequestering polymer 41 may comprise a polymer 43 which non-covalently and reversibly interacts with the drug so as to slow a release rate of the drug from the shaped mass into tissue surrounding the shaped mass such as intestinal wall and/or peritoneal wall tissue once the shaped mass 10 is placed there. Such reversible non-covalent interactions can comprise one or more of electrostatic Coulomb, dipole-dipole, van der Waals, solvophobic, hydrophobic, or hydrogen bonding interactions or other supramolecular chemical interactions. In many embodiments, such drug sequestering polymers 43 can include compounds having a cavity typically a hydrophobic cavity which reversibly interacts with the drug in the presence of aqueous tissue fluids (e.g., various interstitial fluids) surrounding the shaped mass 10 to form a reversible inclusion complex 70 comprising the drug 25 and the drug sequestering polymer 41. The complex also known as an inclusion compound 70 can be configured to be reversible based in part on a change in the chemical, fluidic or other physical property in the fluid dissolving or otherwise surrounding the host-guest complex. Such changes in the physical properties can include, for example, a change in the pH of the fluid (e.g. an increase in pH from about 7 to a neutral pH) and or a change in the concentration of the inclusion compound (e.g., a decrease in the concentration as inclusion compound diffuses down gradient and/or more dilute aqueous tissue fluids are drawn to the host guest complex by osmolar gradient, hydrophilic or other related forces).

(65) In the above and related embodiments, the drug sequestering polymer 41 may comprise cyclic oligosaccharides 60, including various cyclodextrins 61 comprising 5 or more α-D-glucopyranoside units 62. An example of the chemical structure of a cylodextrin one or more α-D-glucopyranoside units 62 is shown in FIG. 13. Cyclodextrins (also known as cycloamyloses) are a family of compounds made up of sugar molecules bound together in a ring (i.e., cyclic oligosaccharides). Cyclodextrins are produced from starch by means of enzymatic conversion. They are composed of 5 or more α-D-glucopyranoside units 61 linked 1.fwdarw.4, as in amylose (a fragment of starch). The largest well-characterized cyclodextrin contains 32 1,4-anhydroglucopyranoside units, at least 150-membered cyclic oligosaccharides are also known. Typical cyclodextrins contain a number of glucose monomers ranging from six to eight units in a ring, creating a cone shape. As shown in FIGS. 14A-14C, according to one or more embodiments, suitable six to eight unit cyclodextrins 61 may correspond to one of the following molecules: α (alpha)-cyclodextrin 63, a 6-membered sugar ring molecule; β (beta)-cyclodextrin 64, a 7-membered sugar ring molecule; and γ (gamma)-cyclodextrin 65, a 8-membered sugar ring molecule. Still other cyclodextrins are considered. In preferred embodiments the cyclodextrin comprises the β (beta)-cyclodextrin form as the cavity of this particular cyclodextrin has a size for accommodating a variety of drugs and other therapeutic agents such as various hormones and vitamins.

(66) Typically, cyclodextrins have a toroid shape with a hydrophobic cavity 66 and the secondary and primary faces 68 and 67 (which consist of what are known as the primary and secondary groups of exposed hydroxyl groups) which define two openings or apertures including a larger and smaller aperture 69s and 68p also known as the secondary (the larger) and primary apertures 69 as is shown in FIG. 15B. The hydrophobic cavity 66 is what interacts with one or more drugs 25 to form the inclusions compound 70 (by one or more super-molecular interactions, e.g., hydrophobic, hydrogen bonding interactions, etc.) and its size (e.g., the primary or secondary opening size) can selected to complex with specific drugs or other therapeutic agents.

(67) COMPLEXATION OF CYCLODEXTRINS (CD) WITH DRUG: Complexation of molecules to CDs occurs through a non-covalent interaction between the molecule and the CD cavity. This is a dynamic process whereby the guest molecule continuously associates and dissociates from the host CD. CDs are insoluble in most organic solvents; they are soluble in some polar, aprotic solvents. Although the solubility of CDs is higher in some organic solvents than in water, complexation may not occur readily in non-aqueous solvents because of the increased affinity of the guest for the solvent compared to its affinity for water. Also, CDs form complexes with lipophilic solvents, even with ethanol and methanol, and these complexes become contaminants in the final product. CDs glass transition occurs at about 225 to 250° C. The glass transition temperature varies with the degree of substitution. Thermal decomposition occurs at 308° C. Strong acids such as hydrochloric acid and sulfuric acid hydrolyze CDs. The rate of hydrolysis is dependent upon temperature and concentration of the acid. CDs are stable against bases. HP-CD can be hydrolyzed by some amylases at a very slow rate compared to the corresponding unsubstituted CD. The greater the degree of substitution, the less hydrolysis occurs. Substitution provides hindrance to the binding of CD to the active site of the enzyme; as a result, the extent of hydrolysis is reduced.

(68) THE MECHANISM OF DRUG RELEASE FROM CD COMPLEXES: Different mechanisms play a role in drug release from the drug-CD complex. Complexation of the drug (D) to CD occurs through a non-covalent interaction between the molecule and the CD cavity. This is a dynamic process whereby the drug molecule continuously associates and dissociates from the host CD. Assuming a 1:1 complexation, the interaction will be as follows:

(69) ##STR00001##
Two parameters, the complexation constant (K) and the lifetime of the complex factor into the drug release mechanism.

(70) Dilution.—Dissociation due to dilution appears to be a major release mechanism. The recent example reported for miconazole, a more strongly bound drug compared to prednisolone supports the probable role of dilution. Dilution is minimal when a drug-CD complex is administered ophthalmically. Efficient corneal absorption is further exacerbated by contact time.

(71) Competitive displacement.—Competitive displacement of drugs from their CD complexes probably plays a significant role in vivo. Addition of parabens to parenterals not only leads to decreased antimicrobial activities of the parabens, due to complexation, but also decreases the drug solubility due to its displacement from complexes. This showed that alcohol displaces 2-napthol from -CD complexes. It has been reported that the -CD complex of a poorly water-soluble drug, cinnarizine, was more soluble in vitro than cinnarizine alone. Oral administration of the complex showed less bioavailability than expected, based on the in vitro dissolution experiments. It was suggested that cinnarizine was too strongly bound to the CD so that complex dissociation was limiting oral bioavailability. Co-administration of phenylalanine, a displacing agent, improved the bioavailability of cinnarizine from the complex but not from conventional cinnarizine tablets.

(72) Protein binding.—Drug binding to plasma proteins may be an important mechanism by which the drug may be released from a drug-CD complex. It is evident that proteins may effectively compete with CDs for drug binding and thus facilitate the in vivo release of drugs from drug-CD complexes. Dilution alone may be effective in releasing free drugs from weak drug-CD complexes but when the strength of the binding between the drug and CD is increased, a mechanism such as competitive displacement is at work. Plasma and tissue protein binding may also play a significant role. Researchers studied the effect of HP-CD on the displacement of both naproxen and flurbiprofen from plasma binding sites in vivo. They found that tissue distribution of flurbiprofen and naproxen was higher when HP-CD-drug solution was administered compare to drug solution in plasma, 10 minutes after parenteral dose, meaning that more drug was free from CD solution to distribute to the tissues than from the plasma solution.

(73) Drug uptake by tissue.—A potential contributing mechanism for drug release from CD is preferential drug uptake by tissues. When the drug is lipophilic and has access to tissue, and is not available to the CD or the complex, the tissue then acts as a “sink”, causing dissociation of the complex based on simple mass action principles. This mechanism is more relevant for strongly bound drugs or when the complex is administered at a site where dilution is minimal, e.g., ocular, nasal, sublingual, pulmonary, dermal or rectal sites. For example, CD has been used in ophthalmic delivery of poorly water-soluble drugs to increase their solubility and/or stability in the tear fluid, and in some cases to decrease irritation.

(74) FIGS. 16A-16C illustrate the formation of the inclusion complex or compound 70. Once the drug 25 and cyclodextrin 61 are in the moist tissue environment such as that in the wall of the small intestine the cyclodextrin 61 interacts with the drug 25 in the presence of the aqueous solutions in the wall of the small intestine or other tissue site to have the drug be attracted and then complex with the cavity 66 to form the inclusion compound/complex 70. Then, when the pH or dilution of the inclusion compound changes the drug is release where it can then be release into tissue. As shown in FIGS. 17A and 17B according to various embodiments, the drug can be either singly or doubly complexed with cyclodextrin or the other related ds-molecule to form a 1:1 drug-CD (cyclodextrin) inclusion complex 71 or a 2:1 drug-CD (inclusion complex 72. The degree of complexing can be controlled by the ratio of Cyclodextrin to drug, for example a 2:1 ratio or greater.

(75) As indicated, cyclodextrins are capable of forming inclusion compounds 70 with a variety of drugs. The formation of the inclusion compounds greatly modifies the physical and chemical properties of the guest molecule, mostly in terms of water solubility. In particular inclusion compounds of cyclodextrins 70 with hydrophobic molecules are able to penetrate body tissues, these can be used to release biologically active compounds under specific conditions. In many embodiments, mechanism of controlled degradation of such complexes can be based on pH change of water solutions surrounding the inclusion compound 70, leading to the loss of hydrogen or ionic bonds between the host 61 and the guest molecules (the drug 25). In alternative embodiments, other means for the disruption of the complexes take advantage of body heat or action of enzymes added as excipients to shaped mass 10 and/or therapeutic preparation 20 which are able to cleave linkages between glucose monomers.

(76) The reversible interactions between the cyclodextrin 61 or other related drug sequestering polymer 41, 42 or 43 can be selected to slow or otherwise control the release of the drug into the tissue surrounding the shaped mass relative to the release rate of the drug were the drug sequestering polymer not there. In various embodiments, the ratio of the drug sequestering polymer to drug can be selected to decrease the release rate of the drug by selectable amounts (e.g., by 50, 100, 150, 200, 250, 500% etc.). In various embodiments, the ratio of drug sequestering polymer to drug can be in the range of 4:1 to 1:4 with narrower range of 2:1 to 1:2 and specific embodiments of 2:1, 3:2, 1:1, 2:3 and 1:2. The ratio can also be selected such that two or more drug sequestering polymer interact with each drug molecule (e.g., via a ratio of drug sequestering polymer to drug of 2:1).

(77) In additional or alternative embodiments, the cyclodextrin molecule 61 can be covalently copolymerized with one or more water soluble polymers such that the resulting copolymer contains multiple cyclodextrin groups which can each bind with a drug molecule. This allows for a single copolymer molecule containing the CD groups to bind to multiple drug molecules allowing for lower ratio of cyclodextrin containing drug sequestering molecule to drug molecule in the shaped mass. For example, various cyclodextrins can be co-polymerized with N-isopropylacrylamide (NIPAAM) as shown in a paper by Jiawen Zhou and Helmut Ritter entitled Cyclodextrin Jiawen Zhou Polym. Chem., 2010, 1, 1552-1559 which is incorporated by reference herein for all purposes so as to have multiple cylcodextrins attached to a single polymer chain.

(78) Routes of Delivery for the Shaped Masses. Embodiments of the micro-tablets or other shaped mass described herein, can be configured to be used in combination with any suitable drug delivery system to be administered via any appropriate route of administration. Such routes of administration can include without limitation, oral, sublingual parenteral, intravenous, intramuscular, subcutaneous, intra-ventricular, intra-cardiac, intra-cerebral. For example, according to one embodiment, insulin comprising micro-tablets can be taken orally and then have the drug be absorbed through the wall of the small intestine or delivered into the wall small intestine. In the latter case, this can be done using a drug delivery device which includes a biodegradable tissue penetrating member which contains or otherwise includes the micro-tablet. The tissue penetrating member may be advanced into the intestinal wall using an advancement means such as an inflatable balloon which directly or indirectly applies a force to the tissue penetrating member. In an alternative or additional embodiment, the micro-tablet can be delivered subcutaneously to an intramuscular or other subcutaneous tissue site. In specific embodiments, the micro-pellet can be configured to dissolve at a selectable rate or rates to achieve a C.sub.max or other desired pharmacokinetic parameter (e.g., t.sub.max etc.). Further, the composition and properties of the micro-tablet can be configured to have a dissolution rate configured to achieve the desired C.sub.max for the tissue at a given site (e.g., in the wall of the small intestine, vs an intramuscular site). In particular embodiments, the shaped mass can be inserted into a cavity in the tissue penetrating member which is then sealed up. The tissue penetrating member may comprise any number of biodegradable materials such as maltose, sucrose or other sugar, PGLA (Polyglycolic lactic acid), polyethylene and others as is described in more detail above.

EXAMPLES

(79) Various embodiments of the invention are further illustrated with reference to the following examples. It should be appreciated that these examples are presented for purposes of illustration only and that the invention is not to be limited to the information or the details therein.

Example 1: Micro-Tablets Comprising Human IgG and PEG

(80) Materials. Pure human IgG (Alpha Diagnostics Intl. Inc, Cat #20007-1-100), Poly Ethylene Glycol 3350 (PEG, Sigma-Aldrich, Cat #P4338-500G), Water, molecular biology reagent grade (Sigma-Aldrich, Cat #W4502).

(81) Methods. Human IgG and PEG 3350 in powder form were weighed out and mixed into a solution using molecular biology reagent grade water. The percentage of IgG and PEG are 90% and 10% respectively and the powders were dissolved in water at 40 mg/ml concentration. Batches using different IgG mass capacity were prepared: 100 mg (batch 6 and 7), 140 mg (batch 8) and 60 mg of IgG (batch 9). The aqueous solution was placed in a silicone plate and then evaporated in a vacuum chamber with desiccant inside of a refrigerator for a minimum of 19 hours (batch 6, 7 and 8) and up to 21 hours (batch 9) until full evaporation occurs. Data for batches 1-5 are not included because these batches were trial batches made using a different processes (e.g., different or no milling, evaporation, etc.) and micro-tablets were not fabricated for some of these batches as well

(82) The evaporated powder was collected into a low-bind conical 1.5 ml tube. Two small stainless steel balls (3.96 mm diameter, 0.5 g total mass) and a rotator (Roto-shake Genie) at max speed were used for milling. The milling duration was 1.75 hrs (batches 6 and 7) and 1.5 hours (batches 8 and 9). It was done at 64° F. room temperature with an ice pack surrounding the tube

(83) Once the powder was milled, micro-tablets were fabricated using a semiautomatic molding fixture. The molding parameter included a compressive force of approximately 2.5 to about 3.5 lbs of force and a compression hold time of approximately 3 sec. Measurements were made of the amount of intact (e.g., biological active) IgG that was recovered in the powder from before-milling, after-milling and in the formed micro-tablets. These measurements were made using IgG immunoassay (Alpha Diagnostics Inc.).

(84) Micro-tableting includes the steps of processing of the powder recovered from evaporation into fine homogenous powder and then forming it into a solid micro-tablet. The before-milling powder recovery is the starting point of the micro-tableting process and the percentage of IgG recovered using this manufacturing method was calculated by taking the before-milling protein recovery (e.g., the amount of biologically protein active recovered in the powder prior to milling) to be 100%. The micro-tablet data and IgG recovery values are detailed in Table 1. Densities were measured by measuring the mass and volume of the tablet. Average density was found to be between 1.02 and 1.06 mg/mm3 while the recovery of intact and bioactive IgG found in the micro-tablets was equal or higher than 94.2% in average.

(85) TABLE-US-00001 TABLE 1 Micro-tablet Data and IgG recoveries for IgG Micro-tablets comprising 90% IgG and 10% PEG 3350, Absolute Micro-tablet Micro-tablet Micro- IgG Batch Length Micro-tablet Density tablet IgG #* (mm) Weight (mg) (mg/mm.sup.3) Recovery 6 2.77 ± 0.07 1.16 ± 0.03 1.05 ± 0.01   87% ± 1.4% (N = 23) (N = 23) (N = 23) (N = 10) 7 3.17 ± 0.15 1.33 ± 0.06 1.06 ± 0.02 94.1% ± 0.9% (N = 15) (N = 15) (N = 15) (N = 5) 8 2.67 ± 0.09 1.11 ± 0.03 1.06 ± 0.02 89.2% ± 3.2% (N = 15) (N = 15) (N = 15) (N = 5) 9 2.85 ± 0.09 1.15 ± 0.02 1.02 ± 0.02 77.8% ± 1.6% (N = 13) (N = 13) (N = 13) (N = 4)

Example 2: Micro-Tablets Comprising Human IgG PEG and Other Excipients

(86) Materials. Pure human IgG (Alpha Diagnostics Intl. Inc, Cat #20007-1-100), Poly Ethylene Glycol 3350 (PEG, Sigma-Aldrich, Cat #P4338-500G), Water, molecular biology reagent grade (Sigma-Aldrich, Cat #W4502), sodium chloride (Sigma-Aldrich, Cat #59888), mannitol (Sigma-Aldrich, Cat #M8429-100G).

(87) Methods. Human IgG was dissolved along with lubricant PEG 3350 and principal excipients in HUMIRA pen (sodium chloride and mannitol) in the same percentage that in the pen solution. The powders were brought into solution using 0.94 ml of molecular biology reagent grade water. The evaporation process was done using the same procedure as used in a) above.

(88) TABLE-US-00002 TABLE 2 Micro-tablet Data and IgG recoveries in IgG Micro-tablet Formulation 67.8% IgG 7.5% PEG 3350 8.4% NaCl 16.3% Mannitol Total Ball Micro-tablet Micro-tablet Micro-tablet Absolute Milling Mass Length Weight Density Micro-tablet IgG Batch # Ball (grams) (mm) (mg) (mg/mm.sup.3) IgG Recovery 7 1 S. Steel 0.438 3.23 ± 0.15 1.25 ± 0.07 0.97 ± 0.01 89.3%   (N = 8) (N = 8) (N = 8) (N = 2) 8 1 S. Steel 0.438  2.5 ± 0.21  1.1 ± 0.07 1.12 ± 0.02 96% (N = 5) (N = 5) (N = 5) (N = 2) 9 1 Zirconium 0.4539 2.76 ± 0.14 1.29 ± 0.05 1.18 ± 0.01 94% (N = 5) (N = 5) (N = 5) (N = 2)

(89) The evaporated powder was then transferred to a low-bind round-bottom 2 ml tube. The milling process was slightly different for each batch. Batches 7 and 8 were milled using stainless steel ball having a mass of 0.438 with 3 hours of milling. Batch nine was made using an Yttrium-stabilized zirconium ball having a mass of 0.454 gr with a milling duration of 3 hours. The rotation method and temperature conditions were kept as used in example 1). Note: data for batches 1-6 are not included because they were made for milling optimization purposes only and micro-tablets were not fabricated for these batches. Approximate measurements were made of particle grain sizes (diameter or widest dimension) for cases 7, 8 and 9 using a hemocytometer. Particle size ranged from about 50 to about 450 μm for the three batches with specific data of 100, 200, 200, 400 and 400 for batch 7; 50, 200, 300 and 400 for batch 8; and 50, 100, 300 and 450 for Batch 9.

(90) After milling, micro-tablets were fabricated using an automatic fixture using compression forces 2.6 lbs. of compression force and a compression holding time of 3 sec. The intact IgG recovered from the stages of before-milling powder, after-milling powder and micro-tablets were tested using an IgG immunoassay (Alpha Diagnostics Inc.). The micro-tablet data and IgG recovery values are detailed in Table 2.

(91) Definitions for terms used in Tables: The definitions for the terms used in the tables below is provided below.

(92) Absolute protein recovery after micro-tableting (APRAMT): This is the percentage of active protein in the micro-tablet relative to that amount in the powder used to form the micro-tablet; it is determined using an ELISA assay of the selected protein in the micro-tablet. The formula for calculation of this value is shown below
APRAMT=(ELISA estimated protein content mass in the micro-tablet)/(total micro-tablet mass*protein mass percentage in total mass)

Example 3: Micro-Tablets Comprising HUMIRA and HUMIRA Pen Excipients

(93) Materials. HUMIRA pens (Abbott Laboratories) and Poly Ethylene Glycol 3350 (PEG, Sigma-Aldrich, Cat #P4338-500G).

(94) Methods. The solution contained in the HUMIRA pen was placed in a low-bind 1.5 ml tube where PEG 3350 amount was added and mixed with HUMIRA ingredients. The solution was evaporated following the same conditions as the ones described in example 1 a) and b).

(95) The milling conditions were the same as in example 1 a) where two balls were used with total mass of 0.5 grams and 1.5 hours (batch 1, 2 and 4) and 1.75 hours (batch 3) of milling duration. The same temperature conditions were kept as in example 1.

(96) After powder milling, micro-tablets were formed by using a semiautomatic fixture using approx. 3 lbs. of force for compression and a holding compression time of approx. 3 sec. The intact HUMIRA recovered in before-milling powder, after-milling powder and micro-tablets were tested using an HUMIRA immunoassay (Alpha Diagnostics Inc.). As in example 1), the before-milling powder recovery is the starting point of the micro-tableting process and the percentage of HUMIRA recovered using this manufacturing method was calculated using the before-milling powder recovery as 100%. The micro-tablet data and HUMIRA recovery values are detailed in Table 3.

(97) The average density ranged from about 0.88 up to about 1.05 mg/mm.sup.3 and the amount of bioactive HUMIRA recovered in the micro-tablets ranged from about 67 to about 80% to that prior to formation of the micro-tablet.

(98) TABLE-US-00003 TABLE 3 Micro-tablet Data and Adalimumab recoveries in Adalimumab Micro-tablet Formulation: 90% HUMRIA Preparation (Drug and Excipients) from HUMIRA Pen Adalimumab Micro-tablet Micro-tablet Absolute Amount PEG added Length Micro-tablet Density Micro-tablet Batch (mg) (mg) (mm) Weight (mg) (mg/mm.sup.3) Adalimumab Recovery 1 40 4.4 3.28 ± 0.16 1.33 ± 0.05 1.03 ± 0.02 79.3% ± 2.3% (N = 19) (N = 19) (N = 19) (N = 6) 2 40 4.4 4.12 ± 0.17 1.56 ± 0.08 0.96 ± 0.03 74% (N = 13) (N = 13) (N = 13) (N = 2) 3 40 4.4 3.15 ± 0.03 1.22 ± 0.02 0.98 ± 0.01 66.7%   (N = 23) (N = 23) (N = 23) (N = 2) 4 48 5.3 3.25 ± 0.10 1.13 ± 0.04 0.88 ± 0.02 76.2% ± 2%   (N = 23) (N = 23) (N = 23) (N = 9)

Example 4: Micro-Tablets Comprising Insulin-Biotin Complex

(99) Materials. Biotin-Human Insulin solution (Alpha Diagnostics, cat #INSL16-BTN-B) and Poly Ethylene Glycol 3350 (PEG, Spectrum, Cat #P0125-500G).

(100) Methods. Biotinylated insulin (that insulin with an attached biotin molecule) was purchased from Alpha Diagnostics and received in a liquid form containing 2 mg/ml Insulin in 1×PBS (12 mM KPO4, 2.7 mM KCl, and 137 mM NaCl, pH). Ovalbumin was added to the solution at 1% by supplier. The solution purchased was placed in a low-bind 1.5 ml tube where PEG 3350 was added and mixed into the solution. The constituency of the final formulation for bathes 4-7 was the following: 8.7% biotin-human insulin complex, 5% PEG 3350, 43.5% Ovalbumin and 42.7% salts from 1×PBS during dialysis. Note batches, 1-3, were not included here due to large difference in the excipients amounts from batches 4-5. The solution was evaporated following the same conditions as the ones described in example 1.

(101) Once the powder was fully dry, it was then transferred to a low-bind round-bottom 2 ml tube. The milling process used a single Yttrium-stabilized zirconium ball having a mass of 0.445 g for a duration of 1.5 hours. The rotation method and temperature conditions were the same as used in Example 1.

(102) After milling, micro-tablets were fabricated using an automatic fixture using 26 psi air pressure for compression, resulting in a compression force of about 1.8 lbs, and using a holding compression time of 3 sec. The air pressure for ejection was set at 28 psi (˜1.82 lbs ejection force). The Biotin-Human Insulin micro-tablets were tested using an Insulin-biotin ELISA immunoassay kit (Alpha Diagnostics Inc., Cat #0030-20-1). The micro-tablet data and Biotin-Human Insulin recovery values are listed in Table 4.

(103) TABLE-US-00004 TABLE 4 Micro-tablet Data and Biotin-Human Insulin Complex Recovery Data Formulation 8.7% Biotin- Human 5%PEG Insulin 3350 43.5% 42.7% Salts from 1X Complex Micro- Ovalbumin PBS during dialysis Micro-tablet tablet Micro-tablet Absolute Micro- Length Weight Density tablet Insulin Batch (mm) (mg) (mg/mm.sup.3) Recovery 4 3.40 ± 0.07 1.35 ± 0.08  1.0 ± 0.05 94.2% ± 3.6% (N = 4) (N = 4) (N = 4) (N = 3) 5 3.78 ± 0.04 1.35 ± 0.02 0.90 ± 0.01 69.9% ± 2.3% (N = 5) (N = 5) (N = 5) (N = 3)

Example 5: Micro-tablets Comprising Insulin

(104) Materials. Human Insulin (Imgenex, cat #IMR-232-250), Poly Ethylene Glycol 3350 (PEG, Spectrum, Cat #P0125-500G), Mannitol (Amresco, Cat #0122-500G), Povidone (ISP-Technologies, Plasdone C-30) and sterile water (APP Pharmaceutical, Cat #918510).

(105) Methods. Human insulin was mixed in solution with different excipients producing various batches for analysis. The formulation of each batch is detailed in Table 5. Batches 1-A, 2, 3B and 6B were not included due to different fabrication parameters. The excipients included PEG 3350 (lubricant), Mannitol (bulking agent) and Povidone (binder). These excipients and the API (human insulin) were dissolved in sterile water. The solution was evaporated using the same conditions as the ones described in example 1.

(106) The milling process and parameters were the same as in example 4, using a low-bind round-bottom 2 ml tube and a single Yttrium-stabilized zirconium ball (mass of approx. 0.45 g) for a duration of 1.5 hours. The rotation method and temperature conditions were kept as used in Example 1.

(107) After milling, micro-tablets were fabricated using an automatic fixture with 74.5 psi air pressure used for compression (resulting in a compression force of about 2.6 lbs) and a holding compression time of 3 sec. The air pressure for ejection was set at 80 psi (˜2.7 lbs ejection force) The human Insulin micro-tablets were tested using Human Insulin ELISA immunoassay kit (Alpha Diagnostics Inc., Cat #0030N). The micro-tablet data and Human Insulin recovery values are detailed in Table 6.

(108) TABLE-US-00005 TABLE 5 Formulation for Human Insulin Micro-tablets (weight %)* Human PEG Batch Insulin 3350 Mannitol Povidone 1B 25.8%   5% 69.2%   — 3A 23% 5% 72% — 4 89% 5%  6% — 5 89% 5%  4% 2% 6A 80% 5% 13% 2% 7 80% 5% 13% 2% *Note, the formulations are listed for Insulin batches 1b-7 because the composition in these batches changed from batch to batch, they did not do so for other batches.

(109) TABLE-US-00006 TABLE 6 Micro-tablet Data and Human Insulin Recovery Data Absolute Micro-tablet Micro-tablet Micro-tablet Micro-tablet Weight Density Insulin Batch Length (mm) (mg) (mg/mm.sup.3) Recovery 1B 2.10 ± 0.03 0.90 ± 0.01 1.08 ± 0.01 87.5% ± 0.8% (N = 22) (N = 22) (N = 22) (N = 5) 3A 2.32 ± 0.07 0.93 ± 0.02 1.01 ± 0.01 96.6% ± 2.6% (N = 6) (N = 6) (N = 6) (N = 3) 4 2.42 ± 0.11 0.97 ± 0.04 1.01 ± 0.01 81.1% ± 3.1% (N = 5) (N = 5) (N = 5) (N = 3) 5 2.42 ± 0.07 0.95 ± 0.02 0.99 ± 0.02 97.6% ± 1.6% (N = 9) (N = 9) (N = 9) (N = 6) 6A 1.95 ± 0.03 0.86 ± 0.01 1.12 ± 0.01 94.8% ± 3.5% (N = 15) (N = 15) (N = 15) (N = 3) 7 2.09 ± 0.02 0.91 ± 0.01 1.09 ± 0.01 99.5% ± 0.3% (N = 82) (N = 82) (N = 82) (N = 16)

CONCLUSION

(110) The foregoing description of various embodiments of the invention has been presented for purposes of illustration and description. It is not intended to limit the invention to the precise forms disclosed. Many modifications, variations and refinements will be apparent to practitioners skilled in the art. For example, embodiments of the shaped masses described herein may contain and be used to deliver any number of drugs not necessarily described herein including for example anti-biotics, anti-viral compounds, various chemo-therapeutic agents, nutritional supplements, clotting factors, anti-parasitic agents, birth-control agents, fertility agents, anti-seizure compounds, vaccines and the like. The shaped masses may also be adapted in one or more of shape, dosage and consistency for various pediatric and neonatal applications, as well as various veterinary applications in a variety of mammals including, without limitation, use for delivery of drugs in bovine, canines, equine, feline, ovine and porcine applications.

(111) Elements, characteristics, or acts from one embodiment can be readily recombined or substituted with one or more elements, characteristics or acts from other embodiments to form numerous additional embodiments within the scope of the invention. Moreover, elements that are shown or described as being combined with other elements, can, in various embodiments, exist as stand-alone elements. Further various embodiments expressly contemplate the negative recitation of any element that is shown or described in one or more embodiments. Hence, the scope of the present invention is not limited to the specifics of the described embodiments, but is instead limited solely by the appended claims.