DRUG DELIVERY SYSTEMS AND METHODS FOR PREPARATION THEREOF

Abstract

The invention provides a drug delivery system in which a drug or another active substance is delivered from the surface of an inactive, placebo carrier. The system uses a placebo tablet carrier having a concavity or multiple concavities in the top surface for receiving a drug. After manufacture of the placebo tablet carrier, a dosage of the drug in liquid or semisolid form is deposited in the concavity and solidifies as a dot or disk on the tablet surface. Thus, the drug is carried on the surface of the tablet and is not part of the tablet bulk. The drug delivery system is particularly useful for delivery of low dose (i.e. potent) drugs, for delivery of multiple doses of a drug, or for delivery of multiple types of drugs. Additionally, the invention provides methods for preparation of the inventive drug delivery systems.

Claims

1. A compressed, inactive tablet for carrying an active substance, the tablet comprising a concavity in a top surface configured for receiving the active substance.

2. The compressed, inactive tablet according to claim 1, formulated for immediate release of an active substance received in the concavity.

3. The compressed, inactive tablet according to claim 1, wherein the concavity is an indentation in the top surface to about 35% of a thickness of the tablet.

4. The compressed, inactive tablet according to claim 3, wherein the indentation is shaped to receive a predetermined volume of the active substance.

5. The compressed, inactive tablet according to claim 1, wherein the top surface of the tablet does not extend in height above edges of the concavity.

6. The compressed, inactive tablet according to claim 1, wherein the tablet has a diameter and the concavity has a diameter and the ratio of the tablet diameter to the concavity diameter is about 8:3.

7. A drug delivery system comprising: a compressed, inactive tablet having a concavity in a top surface for receiving an active substance; and an active substance deposited in the concavity.

8. The drug delivery system according to claim 7, wherein the active substance is a drug.

9. The drug delivery system according to claim 8, wherein the tablet is formulated for immediate release of the drug from the concavity.

10. The drug delivery system according to claim 8, wherein the drug is any one of a steroidal hormone, a synthetic hormone, and amlodipine besylate.

11. The drug delivery system according to claim 10, wherein the steroidal hormone is hydrocortisone and the synthetic hormone is levothyroxine.

12. The drug delivery system according to claim 8, wherein an amount of the drug deposited in the concavity ranges from about 1 to about 20 mg.

13. The drug delivery system according to claim 8, wherein an amount of the drug deposited in the concavity ranges from about 1 to about 5 mg.

14. The drug delivery system according to claim 8, wherein a concentration of the drug is about 33% w/v and could reach 50% or more.

15. The drug delivery system according to claim 8, wherein the tablet further comprises a pharmaceutically-acceptable coating for protecting the drug.

16. The drug delivery system according to claim 15, wherein the pharmaceutically-acceptable coating is one or more of hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), cellulose derivatives, starch derivatives, acrylates, acetates, gelatin, and shellac.

17. A method for preparing a drug delivery system, the method comprising: selecting a drug for delivery; selecting a polymer for dispersion of the drug; preparing a liquid or semi-solid drug dispersion by dispersing the drug in the polymer; and depositing a droplet of the drug dispersion in a concavity in a top surface of a compressed, inactive tablet such that the droplet solidifies to form a disc on the top surface of the tablet.

18. The method according to claim 17, further comprising selecting a temperature at which to deposit the droplet of the drug dispersion.

19. The method according to claim 17, wherein the selected drug has a therapeutic dose of 25 mg or less.

20. The method according to claim 17, wherein the selected polymer for dispersion is polyethylene glycol (PEG) or similar polymer with fatty or hydrophobic character.

21. The method according to claim 17, wherein the dispersing includes dispersing the drug in the polymer in an amount from about 1 mcg to about 10 mg.

22. The method according to claim 17, wherein the dispersing includes dispersing the drug in the polymer in an amount from about 1 mcg to about 5 mg.

23. The method according to claim 17, wherein volume of the droplet deposited ranges from about 0.25 l to about 10 l.

24. The method according to claim 17, further comprising coating the tablet with a pharmaceutically-acceptable coating to protect the drug.

25. The method according to claim 24, wherein the pharmaceutically-acceptable coating is one or more of hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), cellulose derivatives, starch derivatives, acrylates, acetates, gelatin, and shellac.

26. The method according to claim 17, wherein the drug selected is any one of a steroidal hormone, a synthetic hormone, and amlodipine besylate.

27. The method according to claim 26, wherein the steroidal hormone selected is hydrocortisone and the synthetic hormone selected is levothyroxine.

28. A drug delivery system prepared according to the method of claim 17, wherein the drug is any one of hydrocortisone, levothyroxine, and amlodipine besylate.

29. A compressed, inactive tablet for carrying at least one active substance, the tablet comprising: a concavity in a top surface configured for receiving the at least one active substance; and a plurality of concavities spaced apart and embedded within the concavity in the top surface, each of the plurality of concavities configured for receiving an active substance.

30. The compressed, inactive tablet according to claim 29, wherein the plurality of concavities includes three concavities.

31. The compressed, inactive tablet according to claim 29, wherein the tablet has a semi-solid formulation.

32. The compressed, inactive tablet according to claim 29, further comprising an identifier for facilitating detection.

33. The compressed, inactive tablet according to claim 32, wherein the identifier is ink or is embedded in ink.

34. The compressed, inactive tablet according to claim 29, wherein in the concavity in the top surface is an indentation in the top surface to about 35% of a thickness of the tablet.

35. The compressed, inactive tablet according to claim 33, wherein the top surface does not extend in height above edges of the concavity.

36. The compressed, inactive tablet according to claim 29, wherein the tablet has a diameter of about 8 mm and the concavity in the top surface has a diameter of about 3 mm.

37. The compressed, inactive tablet according to claim 29, wherein the tablet is shaped as a bullet having at least one curved end and an indentation for the concavity in the curved end or in a flat side.

38. The compressed, inactive tablet according to claim 29, wherein the tablet has a diameter and the concavity has a diameter and the ratio of the tablet diameter to the concavity diameter is about 8:3.

39. A drug delivery system comprising: a compressed tablet having a concavity in a top surface for receiving at least one active sub stance; a plurality of concavities spaced apart and embedded within the concavity in the top surface; and an active substance deposited in the concavity in the top surface or an active substance deposited in at least one of the plurality of concavities.

40. The drug delivery system according to claim 39, wherein the active substance is a drug.

41. The drug delivery system according to claim 39, wherein the tablet has a semi-solid formulation.

42. The drug delivery system according to claim 40, wherein the drug is any one of a steroidal hormone, a synthetic hormone, and amlodipine besylate.

43. The drug delivery system according to claim 42, wherein the steroidal hormone is a cortisone derivative such as hydrocortisone and the synthetic hormone is levothyroxine.

44. The drug delivery system according to claim 40, wherein the tablet further comprises a pharmaceutically-acceptable coating for protecting the drug.

45. The drug delivery system according to claim 44, wherein the pharmaceutically-acceptable coating is one or more of hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), cellulose derivatives, starch derivatives, acrylates, acetates, gelatin, and shellac.

46. The drug delivery system according to claim 39, wherein the tablet is inactive.

47. The drug delivery system according to claim 46, wherein the active substance is deposited in the concavity in the top surface and each of the plurality of concavities is configured to support the active substance deposited in the concavity in the top surface.

48. The drug delivery system according to claim 47, wherein the tablet is formulated for immediate release of the active substance deposited in the concavity in the top surface.

49. The drug delivery system according to claim 39, wherein the active substance is a drug deposited in at least one of the plurality of concavities.

50. The drug delivery system according to claim 49, wherein the drug is formulated as a solid, a semi-solid, an emulsion, a suspension, a solution, a gel, or a fatty depot.

51. The drug delivery system according to claim 50, wherein the drug is a water-soluble drug or a water-insoluble drug.

52. The drug delivery system according to claim 51, wherein volume of the drug ranges from about 0.5 l to about 500 l.

53. The drug delivery system according to claim 39, wherein the plurality of concavities includes three concavities spaced apart from each other.

54. The drug delivery system according to claim 53, wherein an active substance is deposited in each of the three concavities.

55. The drug delivery system according to claim 54, wherein the active substance deposited in each of the three concavities is a drug.

56. The drug delivery system according to claim 55, wherein each of the three concavities includes a different dosage of the same drug.

57. The drug delivery system according to claim 55, wherein each of the three concavities includes a different drug.

58. The drug delivery system according to claim 39, wherein the tablet is formulated to include at least one active substance.

59. The drug delivery system according to claim 58, wherein the at least one active substance is a drug.

60. The drug delivery system according to claim 59, wherein the drug is levothryroxine and an active substance deposited in the concavity in the top surface is liothyronine.

61. The drug delivery system according to claim 59, wherein the drug is levothryroxine and an active substance deposited in each of the three concavities is liothyronine in different dosages.

62. A tablet for a drug delivery system comprising an active substance and/or an identifier embedded on a surface of the tablet.

63. The tablet according to claim 62, wherein the active substance is a drug embedded on the surface of the tablet.

64. The tablet according to claim 62, wherein the identifier is embedded in ink imprinted on the surface of the tablet.

65. A method for delivering at least one active substance to a subject in need thereof from a surface of a tablet carrier, the method comprising: providing a compressed tablet having a concavity in a top surface for receiving at least one active substance and at least one active substance deposited in the concavity; and administering the tablet to the subject in need thereof.

66. The method according to claim 65, wherein the providing includes providing a compressed, inactive tablet.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0062] A more complete understanding of the present invention may be obtained by references to the accompanying drawings when considered in conjunction with the subsequent detailed description. The embodiments illustrated in the drawings are intended only to exemplify the invention and should not be construed as limiting the invention to the illustrated embodiments.

[0063] FIG. 1A shows one embodiment of the placebo tablet carrier of the drug delivery system. The arrow points to the concavity for receiving an active substance, such as a drug, in the top surface of the tablet.

[0064] FIG. 1B shows the placebo tablet carrier of FIG. 1A having a drug or other active substance deposited in the concavity.

[0065] FIG. 2A is an infrared spectra obtained using Fourier Transform Infrared Spectroscopy (FTIR) of hydrocortisone embedded in polyethylene glycol (PEG) as deposited in the concavity of a placebo tablet carrier.

[0066] FIG. 2B is an FTIR spectra of polyethylene glycol (PEG) alone deposited in the concavity of a placebo tablet carrier for comparison with the spectra shown in FIG. 2A.

[0067] FIG. 2C is an FTIR spectra of pure hydrocortisone for comparison with the spectra shown in FIGS. 2A and 2B.

[0068] FIG. 3A is an infrared spectra obtained using Fourier Transform Infrared Spectroscopy (FTIR) of amlodipine besylate embedded in polyethylene glycol (PEG) as deposited in the concavity of a placebo tablet carrier.

[0069] FIG. 3B is an FTIR spectra of polyethylene glycol (PEG) alone deposited in the concavity of a placebo tablet carrier for comparison with the spectra shown in FIG. 3A.

[0070] FIG. 3C is an FTIR spectra of the polyethylene glycol (PEG) blend (unmelted) for comparison with the spectra shown in FIGS. 3A and 3B.

[0071] FIG. 4 is an infrared spectra obtained using Fourier Transform Infrared Spectroscopy (FTIR) of levothyroxine embedded in polyethylene glycol (PEG) as deposited in the concavity of a placebo tablet carrier. This spectra is superimposed with the FTIR spectra of polyethylene glycol (PEG) alone deposited in the concavity of a placebo tablet carrier (FIG. 5B). The region of 1550 to 1900 cm.sup.1 and the peak at 2400 cm.sup.1 could be used for Process Analytical Technology (PAT) detection in a manufacturing plant.

[0072] FIGS. 5A-E are sketches showing multiple views of an alternative embodiment of the placebo tablet carrier of the drug delivery system. This embodiment is a round tablet having a main concavity in the top surface and three smaller concavities spaced apart and embedded within the main concavity. FIGS. 5A-B show views of the top surface of the tablet including the concavities; FIG. 5C shows a side view of the tablet; and FIGS. 5D-E show views of the bottom surface of the tablet showing an embossed brand logo or other identification marking the tablet.

[0073] FIG. 6A is a sketch showing a side view of the placebo tablet carrier of FIG. 1A. The indentation represents the concavity in the center of the top surface of the tablet.

[0074] FIG. 6B is a sketch showing a top view of the placebo tablet carrier of FIG. 6A FIG. 6C is a sketch showing a side view of another embodiment of the placebo tablet carrier having a bullet-like shape with a rounded end and a flat end. In this embodiment of the tablet, a concavity can be embedded in the curved surface of the top end or in a flat side surface.

[0075] FIG. 7 is a sketch showing top and side views with various dimensions identified, including the diameter of the tablet (D) and the diameter of the indentation or concavity (d). A preferred ratio of D to d is 8:3.

DETAILED DESCRIPTION OF THE INVENTION

[0076] For the purpose of promoting an understanding of the principles of the invention, reference will now be made to embodiments illustrated herein and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of the invention is thereby intended. Any alterations and further modification in the described drug delivery systems, compositions, tablets, formulations, and methods and any further application of the principles of the invention as described herein, are contemplated as would normally occur to one skilled in the art to which the invention relates.

[0077] In one embodiment, the drug delivery system described herein represents a new dosage form having a placebo tablet that carries the load of active drug in a specific spot on the surface such that the active drug is delivered from the surface of the tablet. The spot is identified by a concavity on the upper or top surface of the tablet that serves to accommodate the drug load in the form of a semi-solid droplet or disk. In an industrial setting, tablet manufacturing of potent or low dose drugs (i.e. steroids) is simplified in this manner as the core tablets are made as placebo tablets. The active ingredient/substance or drug is added in liquid form at the end of the manufacturing process to the core tablet. The active substance/ingredient adheres to the surface of the tablet and is not formulated as part of the bulk of the tablet. Thus, the same core tablet formulation may be used with many different drugs and/or other active substances (e.g. vitamins).

[0078] Additionally, this drug delivery minimizes cleaning steps and change overs during tablet processing. Modern liquid technologies allow for the delivery of precise micro-volumes which help design drug delivery systems of low dose drugs with high accuracy and precision.

[0079] Conventional processing of solid drugs includes steps for granulation, sifting, mixing, and milling followed by compression into tablets. These solid form processing steps create drug powder containment problems and represent an environmental and occupational safety hazard as the processing room and environmental air become contaminated with particulate matter. The inventive manufacturing process helps contain the drug as it will be processed in a liquid phase and not in the solid state. The active ingredient/substance or drug would be transferred from the raw material stage directly to the wet phase containing the dispersant polymer.

[0080] The inventive manufacturing process includes dispersing the active ingredient/substance or drug in a suitable polymer or a blend thereof. The solubility of the drug in water determines the choice of molecular weight polymers that are used for the polymer blend. Polyethylene glycol (PEG) is commonly used. For polymers that require heat, the drug should be dispersed in the melted polymer at a temperature that will not affect the drug. The goal is to engulf the drug with melted polymer which will cool and solidify rapidly when placed in the concavity of the tablet which serves to hold the droplet of the dispersion while in the liquid phase. The dispersion solidifies as a disc or dot and adheres to the tablet with enough strength to tolerate average handling. The solidified dispersion and the placebo tablets should be stored at room temperatures below 25 C. to prevent melting. Polymers of higher melting points may be used to make the final product more tolerant to warm environments and may not require refrigeration for storage.

[0081] The drug-loaded tablet may be coated with a compatible polymer such as hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), cellulose derivatives, starch derivatives, acrylates, acetates, gelatin, shellac, and other pharmaceutically-acceptable coatings to add physical protection to the drug dispersion.

[0082] Formulations of steroidal hormones, synthetic hormones, and other low dose drugs, i.e. lower than 25 mg, are ideal for the inventive method as exemplified in the examples presented below.

Example 1

Droplet Composition and Formulation of Hydrocortisone

[0083] Hydrocortisone is a steroidal hormone. Due to its similarity in molecular structure with other hormones, it (hydrocortisone) can be used as a model for all steroidal drug hormones available in the market and potentially usable in the inventive drug delivery system.

[0084] A dispersion of hydrocortisone USP was prepared using a concentrated dispersion of the drug in a polyethylene glycol (PEG) blend. PEG of various molecular weights may be used in the PEG mix/blend. One (1) gram of drug was dispersed in 2 ml of melted PEG mix/blend to provide a 33% load of the drug in the dispersion. Various concentration ratios and drug loads can be used according to purpose. An optimum amount of 1 to 5 mg per tablet was achieved with a top load of 10 mg without affecting the quality of the tablet. Deposition of the droplets at different temperatures affect the density of the droplet and the load per volume. A range of active droplet volumes may be added to each tablet. A range of 0.25 to 10 uL is considered optimum for a volume of drug dispersion to be deposited, using a drug concentration of 33% (w/v).

[0085] Exemplary drug delivery systems of this embodiment include tablets formulated with 1 mg hydrocortisone (designation drop 3.1 mg; total table weight 247.4 mg) and tablets formulated with 3.9 mg hydrocortisone (designation drop 11.6 mg; total table weight 257.8 mg). The designation drop is the amount of melted polymer added.

[0086] An infrared spectra obtained using Fourier Transform Infrared Spectroscopy (FTIR) of hydrocortisone embedded in polyethylene glycol (PEG) as deposited in the concavity of a placebo tablet carrier is shown in FIG. 2A. An FTIR spectra of polyethylene glycol (PEG) alone deposited in the concavity of a placebo tablet carrier for comparison to the infrared spectra of hydrocortisone embedded in PEG is shown in FIG. 2B. From the similarity of these two spectra, it appears that the instrument detects only the polymer. The drug, i.e. hydrocortisone, is embedded within the polymer structure. An FTIR spectra of pure hydrocortisone for comparison (with the spectra shown in FIGS. 2A and 2B) is shown in FIG. 2C.

Example 2

Droplet Composition and Formulation of Amlodipine Besylate

[0087] Amlodipine besylate is another representative example of a group of drugs that may be formulated in the inventive drug delivery system. It can be prepared in semi-solid form using a polymer blend of two or more polyethylene glycol (PEG) polymers of different molecular weights. Amlodipine besylate was prepared as above in Example 1. The dispersion can be diluted or concentrated further to facilitate deposition onto the tablet or to achieve a desired concentration of drug or to adjust the drug content per droplet.

[0088] An exemplary mixture/blend of PEG 400, PEG 8000, and Polysorbate 80 can be used to dissolve the drug in the melted phase. Other polymeric materials such as, but not limited to, fatty bases can also be used.

[0089] A PEG/drug droplet placed on top of the placebo tablet forms a mini-disk or dot upon drying or solidifying. The PEG/drug droplet changes color from beige to yellow depending on the time it is heated.

[0090] Exemplary drug delivery systems of this embodiment include tablets formulated with amlodipine besylate in amounts of 0.8 mg, 5.33 mg, and 6 mg (total polymer-drug solidified disks weigh 2.4 mg, 16 mg, and 18 mg, respectively; total tablet weight 240 mg).

[0091] An infrared spectra obtained using Fourier Transform Infrared Spectroscopy (FTIR) of amlodipine besylate embedded in polyethylene glycol (PEG) as deposited in the concavity of a placebo tablet carrier is shown in FIG. 3A. An FTIR spectra of polyethylene glycol (PEG) alone deposited in the concavity of a placebo tablet carrier for comparison with the spectra of amlodipine besylate embedded in polyethylene glycol (PEG) is shown in FIG. 3B. The amlodipine besylate spectra versus the PEG placebo spectra shows some differentiation which can be employed for Process Analytical Technology (PAT) detection in a manufacturing plant. An FTIR spectra of the polyethylene glycol (PEG) blend, un-melted, for comparison (with the spectra shown in FIGS. 3A and 3B) is shown in FIG. 3C.

Example 3

Droplet Composition and Formulation of Levothyroxine

[0092] Levothyroxine is a synthetic hormone used in the form of tablets to treat thyroid deficiency. The dose ranges from 25 mcg to 300 mcg per tablet and is commercially-available in 12 different strengths. The inventive formulation allows the drug to be engulfed by a liquid polymer prior to its deposition onto a tablet. This way the molecules are not subject to the forces involved in the manufacture of tablets which can improve consistency of dose and stability. Levothyroxine was prepared as above in Example 1. All 12 strengths of levothyroxine can be formulated for the inventive drug delivery system.

[0093] An infrared spectra obtained using Fourier Transform Infrared Spectroscopy (FTIR) of levothyroxine embedded in polyethylene glycol (PEG) as deposited in the concavity of a placebo tablet carrier is shown in FIG. 4. This spectra is superimposed with the FTIR spectra of polyethylene glycol (PEG) alone deposited in the concavity of a placebo tablet carrier (FIG. 3C). The region of 1550 to 1900 cm.sup.1 and the peak at 2400 cm.sup.1 could be used for Process Analytical Technology (PAT) detection in a manufacturing plant.

Example 4

Multi-Dosage Drug/Multi-Drug Delivery System

[0094] CarreTab Multi-Disk Technology or CTMD is the intended commercial name for the embodiment of the inventive drug delivery system involving multiple drug dosages and/or multiple drugs. Aspects of this embodiment encompass: 1) delivery of three different doses of a drug from the surface of a carrier tablet, and 2) delivery of three different drugs from the surface of a carrier tablet. There is no contact between the drug dosages/drugs on the surface of the tablet. Thus, physico-chemical interactions within the dosage forms/different drugs is minimized.

[0095] The dosage form is prepared as two separate and distinct phases or forms; i.e. a core tablet and the semi-solid minidisks with drug that fill the concavities in the core tablet (FIGS. 5A-E). The different phases are joined together as one dosage form of two or more compartments where one compartment (core tablet) serves as the main carrier (placebo portion) and the other compartment (semi-solid) serves as the active (drug-containing) portion.

[0096] Minidisks containing the drugs are located in three or more concavities that themselves are embedded within a main bigger concavity on the surface of the carrier/core tablets (FIGS. 5A-E). The minidisks have a volume that ranges from a few microliters (l) to close to (but not limited to) approximately 500 microliters. The concavities are functional since they support and hold drugs (minidisks) properly formulated for this type of delivery application. Further, other functionalities of the concavities include: serving as base to strengthen the bond between drug formulation and core tablet, separating the different doses of a drug or different active ingredients, serving as ornamentation and/or decoration, and serving as an indicator or identifier of a specific tablet. The drug-containing concavities could be coated with polymer or suitable pharmaceutical agents to add stability to the dosage form. This CTMD technology allows for multiple detection of different drugs simultaneously by remote spectrophotometry at line since each drug is separately concentrated in a specific spot on the surface of the tablet main concavity.

Core Tablet as an Inactive, Placebo Carrier

[0097] The core tablet is prepared, as described above, in a traditional way via direct compression, dry granulation or wet granulation methods, and formulated as a placebo. The core tablet is prepared with a hole or main concavity on the surface specifically designed to carry a dose of a drug in the form of mini disks or semi-solid depots. Within this concavity there are three or more mini-concavities that hold the mini-disks in place. Or alternatively, the mini-concavities serve as footing to hold a larger disk or depot in the whole main concavity. The core tablet is preferably prepared as a compressed tablet, but may be prepared as any pharmaceutical table suitable, for example, but not limited to a molded tablet. The drug depot (semi-solid mini-disks) would be prepared separately from the core tablet and placed in the selected spot on the surface of a tablet to combine or fuse the two phases.

Tooling Design of the Core/Carrier Tablets

[0098] A logo can be embossed on one side of the tooling (lower punch) and indentations for making the concavities on the other side of the tooling (upper punch). See FIGS. 5A-E. Tapered dies can be used to relieve pressure during compression cycles.

[0099] The ratios of diameters are important to the tablet design to minimize breaking the tooling during processing and (the ratios) also provide desired concavity and mechanical strength to the finished tablets. If a capsule or bullet shape is used instead of a tablet design, the diameter could be referred to as width, regardless of whether a circular cross-section is present.

[0100] Regarding relative measurements for tooling design, Fibonacci ratios (0.610-0.67) can be used as starting point or guideline between main concavity diameter and tablet diameter, between small concavities and main concavity, and between thickness of the concavities and thickness of the tablet, but these ratios may vary beyond the region specified above. See FIG. 7 in which D refers to the tablet diameter; d refers to the concavity diameter; R refers to the radius of curvature of the tablet; r refers to the radius of curvature of the concavity; W.sub.1 refers to the depth of the crown of the tablet; and W.sub.2 refers to the depth of the concavity. For example, a core tablet with a diameter of 8 mm would have a main concavity diameter of 3 mm (which would leave a difference of 5 mm from the inner circle to the edge of the tablet (these three numbers follow the Fibonacci sequence in the series (e.g. 1, 1, 2, 3, 5, 8, etc.). Similarly, if the thickness of the tablet is 4 mm, the depth of the concavities should not exceed 1.5 mm to maintain the Fibonacci ratios as much as possible even though 1.5 and 4 are not Fibonacci numbers.

Preparation of Drug/Active Disks

[0101] The active minidisks or semisolid formulations may be prepared as described above.

[0102] The minidisks or drug depot can be formulated as an emulsion or suspension (with particle sizes in the nano-meter and micro-meter levels), as a solution, gel, fatty depot, semi-solid, or solid. This allows formulation of both water soluble and water insoluble drugs.

[0103] With semi-solid and solid formulations, the drug is prepared in high concentration in a hydrophobic melt (made of PEG mixtures, fatty base or similar) and placed on the core tablet surface as a drop or spray depot where it will solidify at room temperature. The volume of the depot is in the microliter range.

[0104] With emulsions, suspensions, and solutions, the drug is formulated in a very high concentration and the solvent is allowed to evaporate during application of the depot via spraying or similar solvent evaporation method.

Core Tablet as an Active Tablet

[0105] In addition to drugs on the surface, the core tablet may contain a drug to produce a combination product. In this aspect, the core tablet is prepared in the traditional way as above but further includes an active drug. It would be used in the inventive systems when the administration of two drugs or more is desired. This tablet can be used to accommodate one drug in two or more doses, or two or more drugs in one dosage form. It can be used to deliver two doses of the same drug with different release properties, to deliver two different drugs (one in the bulk tablet and the other on the surface as a semi-solid), or more than two drugs (for example more than one drug depot may be placed on the core tablet). This way the drugs are located in different compartments in the same system and thus could be formulated differently. Further, the system may contain two drugs inside the core tablet and a third drug on the surface semi-solid portion.

Versatility of the Multi-Dosage Drug/Multi-Drug Delivery System

[0106] The CTMD system is a drug delivery system that allows three or more different drugs or formulations of the same drug in the same system separated by different compartments to minimize physical contact and eliminate the potential of chemical interaction within the dosage form. The formulations in the CTMD can differ in drug identity, molecular size, dose, amount, concentration, composition, excipients, release profiles (dissolution and absorption), and methods of manufacture. The CTMD system may contain more than two drugs without interacting due to the separation of compartments and technologies in the same tablet device.

[0107] The drugs in the CTMD system may be identifiable by analytical instruments for PAT (Process Analytical Technologies) applications. If desired, instead of a drug, an identifier (a secret chemical) may be used instead of a drug to provide brand identification against a potential counterfit product. This identification may be done without destroying the tablet. The CTMD system can then be coated if desired to provide a barrier against the environment. The concept applies to capsules as well (CarreKap is the intended commercial name for this embodiment).

[0108] The CTMD system can be used either for immediate release tablets or for sustained or controlled release tablets. It is very useful to handle potent (low dose) drugs. The drugs in the surface can be colored to identify the different dose strengths. All low dose drugs (less than 10 mg) are good candidates for the surface portion of the CTMD. For example, steroidal hormones such as testosterone, progesterone, and cortisone derivatives are good candidates. Synthetic hormones such as levothyroxine, which is present in more than 10 tablets strengths in the market, is also a good candidate. For example, levothyroxine can be formulated in the core tablet and the metabolite, liothyronine could be formulated in the mini-disks in different strengths.

Benefits of the Multi-Dosage Drug/Multi-Drug Delivery System

[0109] The benefits of the multi-dosage/multi-drug delivery system are similar to the benefits of using a core tablet having a single concavity. The CTMD has the added benefits of enhancing the bonding between drug semisolid formulation and core tablet, and of allowing several doses or drugs in the same dosage forms without being in physical contact. This minimizes drug incompatibilities in the dosage form.

[0110] Benefit for the Patient (improve patient adherence): the system will provide a smaller dosage form to patients who take several drugs and have trouble adhering to the therapy. The CarreDisk allows for multidrug administration in tiny disks within one tablet, thus minimizing the number of tablets a patient has to take. For example, a patient that takes 4 drugs two times a day, could take two CTMDs instead of eight tablets in a day.

[0111] Improved Manufacturing Costs (cost reduction via cycle time reductions): for a one drug delivery, the system will reduce dramatically the cost of producing a tablet since the majority of core tablets will be placebo tablets and the cleaning validation efforts as well as the potential for contamination will be greatly minimized. This will reduce processing cycle times for producing the core placebo tablet which will help reduce the cost of the producing the medicine. Since the drug will be formulated in the liquid form, there is no drug powder in the solids processing rooms (powder blending, tablet compression or encapsulation) and thus, no need for in-process testing for drug content during the tableting process.

[0112] Improved Quality Compliance (PAT Application, PAT Enabled Dosage Form):

The drug spot(s) will be identifiable by the naked eye and by analytical instruments which will allow the implementation of Process Analytical Technologies (PAT) at line; potentially enabling 100% of the tablets produced to be inspected by PAT for drug identification and possibly drug content; suitable for IR measurements (infrared spectroscopy).

Example 5

Embossed Tablets

[0113] In another aspect, the inventive drug delivery system includes a molded tablet having a design embossed thereon rather than concavities. See FIGS. 5A-E. The active ingredient or drug is formulated with the design material and applied to the tablet with application of the design; i.e. drug in print.

CONCLUSION

[0114] The invention described and exemplified herein represents a new concept of tablet formulation/drug delivery system for delivery of low dose (i.e. potent) drugs, for delivery of multiple doses of a drug, or for delivery of multiple types of drugs. This concept leads to an overall improvement in quality in both the drug itself and in the manufacturing process.

[0115] All patents and publications mentioned in this specification are indicative of the levels of those skilled in the art to which the invention pertains. All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. It is to be understood that while a certain form of the invention is illustrated, it is not intended to be limited to the specific form or arrangement herein described and shown. It will be apparent to those skilled in the art that various changes may be made without departing from the scope of the invention and the invention is not to be considered limited to what is shown and described in the specification. One skilled in the art will readily appreciate that the present invention is well adapted to carry out the objectives and obtain the ends and advantages mentioned, as well as those inherent therein. The tablets, drug delivery systems, methods, procedures, and techniques described herein are presently representative of the preferred embodiments, are intended to be exemplary and are not intended as limitations on the scope. Changes therein and other uses will occur to those skilled in the art which are encompassed within the spirit of the invention. Although the invention has been described in connection with specific, preferred embodiments, it should be understood that the invention as ultimately claimed should not be unduly limited to such specific embodiments. Indeed various modifications of the described modes for carrying out the invention which are obvious to those skilled in the art are intended to be within the scope of the invention.