Polymeric compositions containing ambient-temperature stable biopharmaceuticals and methods for formulation thereof
11260024 · 2022-03-01
Assignee
Inventors
Cpc classification
A61K9/0021
HUMAN NECESSITIES
Y02A50/30
GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
International classification
Abstract
Biopharmaceuticals, such as vaccine agents and probiotics, are encapsulated in carbohydrate-glass particles and embedded in an amorphous polymer substrate to produce polymeric compositions containing ambient-temperature stable biopharmaceuticals for syringeless administration to patients such as via dissolvable films, micro-needle patches and similar medical delivery devices. The amorphous polymer substrate is soluble in both water and a volatile organic solvent, yet the carbohydrate-glass particles are insoluble in the volatile organic solvent.
Claims
1. A composition, comprising: an amorphous substrate including: a polymeric excipient and a plasticizer; and carbohydrate-encapsulated biopharmaceuticals embedded within said amorphous substrate; characterized in that: said polymeric excipient is soluble in both water and an organic solvent; and said carbohydrate-encapsulated biopharmaceuticals are not soluble in said organic solvent; wherein the carbohydrate-encapsulated biopharmaceuticals are encapsulated in carbohydrate-glass particles.
2. The composition of claim 1, wherein the polymeric excipient comprises: hydroxypropyl cellulose and/or cellulose acetate.
3. The composition of claim 1, wherein the plasticizer comprises one or more from the group consisting of: polyethylene glycol, propylene glycol, triacetin, and poloxamer 407.
4. The composition of claim 1, wherein the carbohydrate-encapsulated biopharmaceuticals comprise one or more vaccine agents and/or probiotics.
5. The composition of claim 4, wherein said carbohydrate-glass particles comprise a particle size less than 50 microns.
6. The composition of claim 5, wherein said carbohydrate-glass particles comprise a particle size between 10 microns and 30 microns.
7. The composition of claim 1, wherein said carbohydrate glass particles consist essentially of: non-reducing sugars and/or derivatives thereof.
8. A composition, comprising: an amorphous substrate comprising between: 70 to 95 percent by weight hydroxypropyl cellulose and 5 to 30 percent by weight triacetin; and carbohydrate-encapsulated biopharmaceuticals embedded in said amorphous substrate, wherein the carbohydrate-encapsulated biopharmaceuticals are encapsulated in carbohydrate-glass particles.
9. The composition of claim 8, wherein said carbohydrate-encapsulated biopharmaceuticals comprise a vaccine agent and/or a probiotic.
10. The composition of claim 8, wherein said carbohydrate-glass particles comprise non-reducing sugars and/or derivatives thereof.
11. A medical delivery device for delivery of biopharmaceuticals to a patient, the medical delivery device comprising: a vaccine agent and/or a probiotic encapsulated in carbohydrate-glass particles; said carbohydrate-glass particles embedded in an amorphous polymer substrate; wherein said amorphous polymer substrate is soluble in both water and an organic solvent; and wherein said carbohydrate-glass particles are not soluble in the organic solvent.
12. The medical delivery device of claim 11, wherein said amorphous polymer substrate comprises hydroxypropyl cellulose.
13. The medical delivery device of claim 12, said amorphous polymer substrate further comprises a plasticizer selected from the group consisting of: polyethylene glycol, propylene glycol, triacetin, and poloxamer 407.
14. The medical delivery device of claim 13, said device comprising a dissolvable film.
15. The medical delivery device of claim 13, said device comprising a patch.
16. The medical delivery device of claim 15, said device comprising a micro-needle patch.
Description
BRIEF DESCRIPTION OF DRAWINGS
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
DESCRIPTION OF EMBODIMENTS
Definitions
(9) For purposes of this invention, the term “biopharmaceuticals” is used herein to describe encapsulated sensitive biopharmaceuticals including (i) vaccine agents, such as but no limited to: killed micro-organisms, including: rabies, influenza, cholera, bubonic plague, polio, hepatitis A, and HIV; live attenuated microorganisms, including: yellow fever, measles, rubella, mumps, typhoid, influenza, RSV, H5N1, cholera, bubonic plague, polio, hepatitis A; inactivated toxic compounds, including: tetanus, and dipthera; and subunit proteins, including: surface proteins of hepatitis B virus, and viral major capsid protein, and the hemagglutinin and neuraminidase subunits of influenza virus, and (ii) probiotics, such as but not limited to: L. rhamnosus; L. jensenii; and L. crispatus.
(10) The term “ambient-temperature stable” is used herein to describe the stability of sensitive biopharmaceuticals at ambient temperature. In the scope of this application we will consider any temperature between −20° C. and +40° C. as an ambient temperature. We will call a formulation of biopharmaceutical ambient temperature stable if the biopharmaceutical will have less than 0.5 logs (or 66%) of the activity loss after storage above 37° C. during a period of at least two months storage at 25° C. (room temperature) or lower ambient temperatures during a period of at least two years. Normally stability of biopharmaceuticals immobilized inside carbohydrate glasses increases with decreasing storage temperature. For this reason, it is difficult to achieve required stability at 25° C. and 37° C. Accordingly, ambient temperature stable biopharmaceuticals also are often referred to as “thermostable” biopharmaceuticals. In the scope of this application we will consider thermostable and ambient temperature stable biopharmaceuticals to be interchangeable.
(11) The term “micronized” is used herein to describe a substance which is milled or otherwise processed to yield particles having a size of 50 microns or less, such particles in plurality forming a micronized powder.
(12) The term “biocompatible” is used herein to describe the quality of not having toxic or injurious effects on biological systems.
(13) The term “polymeric excipient” is used herein to describe a polymer formulated alongside the active ingredient of a pharmaceutical composition.
(14) The term “bi-soluble” is used herein to describe solubility in both water (aqueous solution) and a volatile organic solvent.
(15) The term “plasticizer” is used herein to describe additives that increase the plasticity of the polymer in the solid state.
(16) The term “organic solvent” is used herein to describe carbon-based substances that are capable of dissolving the polymer.
(17) The term “polymer solution” is used herein to describe one or more polymers, plasticizers, and other materials dissolved in a liquid solvent medium.
(18) The term “foam drying” is a general term used herein to describe various drying techniques for obtaining preserved biopharmaceuticals, including “preservation by foam formulation (PFF)” as described in U.S. Pat. No. 5,766,520; and “preservation by vaporization (PBV)” as described in WO 2005/117962
(19) The term “preservation by vaporization (PBV)” describes the current state of the art method for preserving sensitive biological.
(20) The term “carbohydrate-glass” is used herein to describe an amorphous solid carbohydrate matrix including one or more carbohydrates, generally sugars. The matrix may further include amino acids, salts, surfactants and polymers that were dissolved in preservation solutions before drying.
(21) The term “amorphous polymer substrate” is used herein to describe a polymer substrate that lacks the long-range order characteristic of a crystal.
(22) The term “water-soluble film” or “dissolvable film” is used herein to describe a solid comprising one or more thin layers of a water soluble polymeric composition. Typically the thickness of the dissolvable films used to deliver biopharmaceuticals is between 1 and 100 microns.
(23) The term “micro-needle patch” is used herein to describe a solid polymeric patch containing micro needles that pierce into the skin upon application similar to that of a regular bandage. The micro needles dissolve in the skin, release and deliver the therapeutic.
(24) The term “delivery device” is a general term used herein to describe a device for delivering a therapeutic. For example, dissolvable films and patches are the delivery devices.
(25) In accordance with aspects of the invention, it is a primary objective to form a water-soluble polymeric composition containing ambient-temperature stable biopharmaceuticals for administration to a patient. The composition can be manufactured in different forms including dissolvable films, micro-needle patches, or similar medical delivery devices. However, it is important that during manufacture of such devices, the contained ambient-temperature stable biopharmaceuticals, such as carbohydrate-glass vaccine powders or probiotic powders, must not be dissolved or activity thereof should not be destroyed. Accordingly, because carbohydrate-glass powders are soluble in water, an organic solvent is preferred to be used when making a polymer solution. In this regard, the carbohydrate-glass powder can be mixed into a suspension with the anhydrous polymer solution in which the powder remains in solid phase such that sensitive biological agents remain protected in an encapsulating particle.
(26) To achieve this goal, and to effectively formulate dissolvable films and micro-needle patches containing dry vaccine powders, novel mixtures are suggested herein comprising a bi-soluble polymer such as, for example, hydroxypropyl cellulose (HPC) with a plasticizer such as, for example, triacetin, dissolved in an organic solvent such as, for example, acetone. Because the bi-soluble polymer is soluble in both water and organic solvent, an organic solvent can be used to dissolve the polymer and plasticizer to form a polymer solution and the carbohydrate-glass powder can be suspended therein without harm to the encapsulated biopharmaceuticals. Upon evaporation of the organic solvent, the resulting polymeric composition contains carbohydrate-glass powder and protected biopharmaceuticals therein, which can be used to manufacture a delivery device, such as a dissolvable film or micro-needle patch.
(27) Although various examples are given, it should be generally understood that any polymer that is biocompatible and bi-soluble, or soluble in both water and volatile organic solvent, can be used, along with any suitable plasticizer known to those having skill in the art, with the same or similar methods as described herein to achieve similar results. The claimed invention is not intended to be limited by the express examples herein. Rather, these examples are being offered in order to illustrate one preferred embodiment.
(28) Now turning to the drawings,
(29) Using the composition derived from the general method above, one or more optional processing steps may include: producing a dissolvable film; or producing a micro-needle patch. The manufacture of both dissolvable films and micro-needle patches from aqueous solutions by water casting are known in the art, and the manufacture of these from anhydrous polymeric suspensions would be similar, however using a novel polymer composition containing ambient-temperature stable biopharmaceuticals as described herein.
(30) In addition to these delivery devices, the composition can also be used as a coating for an off the shelf personal medical device, such as a bandage, a tampon, or a vaginal ring, among others.
(31) It should be noted that there were many unsuccessful attempts obtaining ambient-temperature stable biopharmaceuticals via conventional drying processes, such as freeze drying and spray drying. In many studies it was shown that foam drying provide activity and stability superior to that which could be obtained by freeze-drying and spay dying. Foam drying, such as preservation by foam formulation (PFF), or preservation by vaporization (PBV), is preferred. And more particularly, PBV is preferred due to the enhanced bioactivity stabilization that has been shown using this process. However, if successful any process which preserves sensitive biopharmaceuticals can be used to obtain the ambient-temperature stable biopharmaceutical powders used in the embodiments herein.
(32) If needed, a milling process, such as by using a jet mill or ball milling, can be implemented to powders for micronizing to the desired particle size.
(33)
(34)
(35)
(36)
(37) To further describe a preferred embodiment, the following examples are provided:
Example 1 Thermostabilization of Probiotic Bacteria Using PBV
(38) In this example, “Thermostable Vaginal Probiotic Microbicides” were formulated. One goal was to investigate the application of live probiotic bacterial microbicides against sexually transmitted diseases. The strategy was to use probiotics to occupy the vaginal epithelium and provide a long lasting protective environment against HIV, BV, and other STIs. Another goal of this work is formulation of potent multi strain thermostable probiotic vaginal topical microbicides (TPVM) that can be delivered using conventional thin film technology. It was first demonstrated that PBV preserved vaginal bacterial probiotics could be stable for at least 11 months 37° C. and 1 hour at 70° C. (see Table 1.1). This allowed effective encapsulation of these bacteria in thin polymeric films for delivery to vaginal (cervical) epithelium.
(39) TABLE-US-00001 TABLE 1.1 Survival of PBV bacteria (10.sup.8 CFU/ml) at 37° C. and 70° C. Activity of Activity Activity of Treatment L. rhamnosus of L. jensenii L. crispatus Before drying Form. 1 139 ± 17 118 ± 12 95 ± 28 Form. 2 — 137 ± 12 94 ± 9 Form. 3 150 ± 15 119 ± 14 93 ± 14 After drying Form. 1 93 ± 1.5 110 ± 15 70 ± 12 Form. 2 77 ± 8 106 ± 12 65 ± 13 Form. 3 103 ± 14 126 ± 22 67 ± 8 After 1 hour at 70° C. Form. 1 81 ± 6 101 ± 8 67 ± 8 Form. 2 56 ± 21 85 ± 11 50 ± 3 Form. 3 109 ± 3 104 ± 19 56 ± 9 After 3 months at 37° C. Form. 1 78 ± 6 116 ± 20 52 ± 9 Form. 2 69 ± 3 49 ± 29 37 ± 6 Form. 3 15 ± 6 54 ± 9 53 ± 15 After 6 months at 37° C. Form. 1 49 ± 7 31 ± 7 52 ± 12 Form. 2 31 ± 8 47 ± 3 25 ± 3 Form. 3 3.4 ± 0.6 23 ± 4 40 ± 7 After 11 months at 37° C. Form. 1 76 ± 7 42 ± 3 33 ± 5 Form. 2 2.4 ± 1.7 31 ± 3 0 Form. 3 1 ± 0.4 4.5 ± 1 0 After 11 months at RT Form. 1 113 ± 10 86 ± 15 55 ± 19 Form. 2 100 ± 16 86 ± 10 36 ± 11 Form. 3 68 ± 6 94 ± 16 2.5 ± 2.5
(40) Here, three preservation solutions (PS) were formulated to protect bacteria during PBV drying and subsequent storage at ambient temperatures. PS 1: comprised of 30% sucrose and 10% methylglucoside; PS 2: comprised of 30% sucrose and 10% mannitol; PS 3: comprised of 30% sucrose and 10% isomalt.
(41) A gentle PBV drying protocol was developed to stabilize probiotic bacteria (L. crispatus, L. jensenii and L. rhamnosus) at ambient temperatures.
(42) For all three bacteria, it was demonstrated that: more than 70% of the bacteria survived after drying; more than 70% of the bacteria survived after 60 minutes of post-drying equilibration at 70° C.; more than 50% of the bacteria survived after 3 months of storage at 37° C.; more than 50% of the bacteria survived after 11 months of storage at room temperature; and more than 30% of the bacteria survived after 11 months of storage at 37° C. in the formulation containing methylglycoside (PS1). See Table 1.1.
(43) It was also demonstrated that micronization of dry preserved bacteria using FPS Jet Mill at injector pressure of 60 psi did not damage bacteria and allows decreasing size of dry sugar particles to about 20μ or less as is seen from
(44) These thermostable micronized probiotic powders for development of dissolvable films containing the probiotics (see below).
Example 2. Solubility of Different Polymers and Plasticizers in Acetone
(45) Studies were performed to determine compatibility between many organic solvents and plasticizers with the carbohydrate-coated lactobacilli and other PVB preserved biologics. Solvents looked at included acetone, ethanol, dichloromethane, and ethyl acetate, all of which are commonly used as volatile solvents for preparation of polymeric water-dissolvable films and other devices. Acetone was chosen as the preferred organic solvent for use in film or patches formulation development due to its compatibility with carbohydrate-glass particles and low toxicity. It was found that PBV-preserved bacteria could be kept in acetone at 37° C. for >24 hours with no loss in bacterial activity. The same was found to be valid for triacetin, a reason for which it could be a preferred acetone-soluble plasticizer in these formulations (see table. 2.1). It was also found that of the many potential polymers that could be used to produce patched and films, hydroxypropyl cellulose (HPC) was the only one that dissolved in acetone (Table 2.2).
(46) TABLE-US-00002 TABLE 2.1 Solubility study results for different plasticizers in commonly used organic solvents Con- centration Ethyl Plasticizer (w/v) Acetone Ethanol Dichloromethane acetate PEG 400 1% + + + + 3% + + + + Sorbital 1% − − − − 3% − − − − Propylene 1% + + + + Glycol 3% + + + + Glycerin 1% − + − − 3% − + − − Triacetin 1% + + + + 3% + + + + Pluronic 1% + + + + F127 6% + P + + PEG 4000 1% + P + + 6% + P + P “+” means dissolved; “−” means not dissolved; “P” means the excipient precipitated out when placed overnight at room temperature after solubilization with the help of 3 h sonication.
(47) TABLE-US-00003 TABLE 2.2 Solubility study results for different polymers in commonly used organic solvents Polymer Concentration (w/v) Acetone PVP K90 1% − 6% − Pullulan 1% − 6% − HPMC E5 1% − 6% − HPC 1% + 6% + HEC 1% − 6% − Methyl Cellulose 1% − 6% − CMC-Na 1% − 6% − PVA 1% − 6% − “+” means dissolved; “−” means not dissolved;
Example 3. Placebo Film Formulation Development
(48) The acetone-based polymer solution was used as the film base to prepare several film prototypes (Table 3.1). The film prototypes were manufactured by creating a uniform polymer solution which was cast onto a glass substrate attached to the hot surface of an automatic film applicator (ELCOMETER® 4340) using the mini-applicator doctor blade. None of the evaluated prototypes tested resulted in acceptable film properties including manufacturability, mechanical strength, and appearance. Manufacturing parameters were modified with respect to casting substrate used, drying time, and temperature. It was found that “Formulation 4” with modified manufacturing parameters could be used to achieve an acceptable film platform. Once the optimal placebo formulation was established, the bacteria were loaded into the film.
(49) TABLE-US-00004 TABLE 3.1 The tested formulations during the optimization of placebo films. Formulation Formulation 1 2 Formulation 3 HPC 0.8 g HPC 0.8 g HPC 0.8 g PEG400 0.2 g PEG400 0.4 g PEG400 0.6 g Acetone 10 ml Acetone 10 ml Acetone 10 ml Formulation Formulation 4 5 Formulation 6 HPC 0.8 g HPC 0.8 g HPC 0.8 g Triacetin 0.2 g Triacetin 0.4 g Triacetin 0.6 g Acetone 10 ml Acetone 10 ml Acetone 10 ml Formulation Formulation 7 8 Formulation 9 HPC 0.8 g HPC 0.8 g HPC 0.8 g PEG 4000 0.2 g PEG 4000 0.4 g PEG 4000 0.6 g Acetone 10 ml Acetone 10 ml Acetone 10 ml Formulation Formulation 10 11 Formulation 12 HPC 0.8 g HPC 0.8 g HPC 0.8 g F127 0.2 g F127 0.4 g F127 0.6 g Acetone 10 ml Acetone 10 ml Acetone 10 ml
Example 4. Preparation of the HPC Film Containing Micronized Probiotic Powder
(50) The films, as shown in
(51) TABLE-US-00005 TABLE 4.1 Activity of L. jensenii bacteria after the solvent casting film preparations. Treatment Activity of L. jensenii (10.sup.8 CFU/ml) Before PBV drying with PS3 119 ± 14 After PBV drying with PS3 126 ± 22 After casting on a thin film 119 ± 5 applicator onto a substrate (A) After drying in a vacuum oven 142 ± 13 at 70° C. (C)
Example 5: Placebo Film Formulation Development by Hot Melt Extrusion Technique
(52) As a second manufacturing option in order to limit exposure of the bacteria to aqueous medium, the use of Hot Melt Extrusion (HME) technique was evaluated. Initial studies have focused on development of a placebo prototype which could be manufactured with limited exposure to excessive high temperature. To this end Polyethylene oxide (PEO) was identified as the polymer of choice for initial prototype development work. The plasticizers PEG 400 or Glycerin were also used. Prototype formulations to date are listed in Table 5.1. For these initial formulations HME (MiniLab HAAKE®) parameters were maintained constant for the six formulations. The temperature was set to 90° C., the screw rate to 180 rpm, feeding time was 15 min and mixing time was 15 min. The polymer and the plasticizer were hand fed into the HME throughout the 15 min period. The mixture was constantly mixed until the gate was opened and was released in a ribbon form. The ribbon was immediately transferred to the roller to form the desired film shape. Optimization of film appearance and manufacturability is ongoing.
(53) TABLE-US-00006 TABLE 5.1 The tested formulations during the optimization of placebo films. Formulation 1 Formulation 2 Formulation 3 PEO 4.5 g PEO 3.6 g PEO 4.5 g PEG400 1.5 g PEG400 2.4 g Glycerin 1.5 g Ratio 3:1 Ratio 3:2 Ratio 3:1 Formulation 4 Formulation 5 Formulation 6 PEO 3.6 g PEO 4.5 g PEO 3.6 g Glycerin 2.4 g PEG300 1.5 g PEG300 2.4 g Ratio 3:2 Ratio 3:1 Ratio 3:2
Example 6: Development of Bacteria-Loaded Films by Hot Melt Extrusion Technique
(54) The film containing thermostable bacteria (up to 70° C.) requires a relatively low humidity environment during the manufacturing and storage process in order to protect the sugar coating of the bacteria. To limit the aqueous contents in the thin film, hot melt extrusion (HME) manufacturing technique was evaluated in this study. Commonly used polymers with different melting points and thermal behaviors were chosen for study in this evaluation and are shown in Table 6.1.
(55) TABLE-US-00007 TABLE 6.1 The commonly used polymers with different melting points and thermal behaviors Polymer Melting point (° C.) Description Hydroxypropylmethyl 190-200 Browns at 190° C. and chars at 200° C. cellulose (HPMC) Hydroxyethyl 135-140, 280 Softens at 135-140° C., decomposes at cellulose (HEC) 280° C. Sodium carboxymethyl cellulose 227, 252 Browns at 227° C. and chars at 252° C. (NaCMC) Polyvinyl alcohol 228, 180-190 228° C. (fully hydrated grade), (PVA) 180-190° C. (partially hydrated grade) Polyvinyl pyrrolidone (PVP-K90) 150 Softens at 150° C. Hydroxypropyl cellulose (HPC) 260-270 Soften at 130° C. Polyethylene oxide (PEO) Hot Melt 65-70 Soften at 60° C. Extrusion (HME) technique
(56) Due to the low melting point of polyethylene oxide (PEO) it was chosen as the film forming polymer for the development of the placebo formulation. PEG 400 and glycerin were selected as the plasticizers in the formulation. HME (MiniLab HAAKE®) parameters remained constant for all trials. The temperature was maintained as 90° C., and the speed of screws was set at 180 rpm. Additionally, the feeding time was controlled within 15 min and the mixing time fixed at 15 min. The polymer and the plasticizer were hand fed into the HME, and the mixture was allowed to mix until the gate was open. Then, the mixture was extruded through a die in a ribbon form. The ribbon was immediately transferred to a roller to make a film. The results of the 3 formulations are presented in Table 6.2 and Table 6.3.
(57) TABLE-US-00008 TABLE 6.2 Development of placebo film formulations using HME Formulation 1 Formulation 2 Formulation 3 PEO 4.5 g PEO 3.6 g PEO 4.5 g PEG400 1.5 g PEG400 2.4 g Glycerin 1.5 g Ratio 3:1 Ratio 3:2 Ratio 3:1
(58) TABLE-US-00009 TABLE 6.3 The performance of each formulation Formulation Parameter setting Commentary 1 90° C.; 180 rpm; 15 min 1.32 g yield. Film is softer compared to 100% PEO. 2 90° C.; 180 rpm; 15 min 1.86 g yield. Film is softer compared to 100% PEO. However, the film was found to be very oily. 3 90° C.; 180 rpm; 15 min 1.66 g yield. Inadequate mixing of PEO and glycerin. The film was very soft.
(59) Continuous optimization studies were conducted to improve the texture properties of the film and to reduce the heat during the manufacturing process. The temperature was decreased to 70° C., and the speed of screws was set at 180 rpm. Feeding time was 15 min and mixing time was 10 min. The polymer and the plasticizer were hand fed into the HME, and the mixture was allowed to mix until the gate was open. Then, the mixture was extruded through a die in a ribbon form. The ribbon was immediately transferred to a roller to make a film. The results of three formulations are presented in Table 6.4 and Table 6.5.
(60) TABLE-US-00010 TABLE 6.4 Development of placebo film formulations using HME Formulation 4 Formulation 5 Formulation 6 PEO 3.0 g PEO 3.0 g PEO 3.0 g PEG4000 2.0 g PEG4000 2.0 g PEG4000 2.0 g PEG400 1 g Vitamin E 1.0 g PEG400 0.5 g Total 6 g Total 6 g Vitamin E 0.2 g Total 5.7
(61) TABLE-US-00011 TABLE 6.5 The performance of each formulation Formulation Parameter setting Commentary 4 70° C.; 180 rpm; 15 min 3.1126 g yield. Film was very soft and oily. 5 70° C.; 180 rpm; 15 min 2.3095 g yield. Mixture was too soft to make a film. 6 70° C.; 180 rpm; 15 min 1.4419 g yield. Film was soft and not oily. However manufacturing difficulty was experienced.
(62) After the development of these prototype formulations, thermostable bacteria were incorporated into the film shown in
Example 7: Preparation of the HPC Micro-Needle Patches Containing a Micronized Vaccine Powder Using Anhydrous Solvent Casting Method
(63) For preparation of formulations for micro-needle patch formation, “formulation 4” of example 3 (0.8 g HPC, 0.2 g triacetin, 10 mL acetone), above, was chosen for testing and mixed with micronized PBV-preserved vaccine powders. The acetone was then partially evaporated to obtain a viscous (syrup) mixture containing 20% to 70% of acetone with the vaccine powders inside. The mixture was pressed inside an inverse micro-needle mold and remaining acetone was evaporated under vacuum at temperatures below 80° C. This resulted in a solid HPC micro-needle patch containing micronized PBV-preserved vaccine particle incorporated inside the patch for transdermal delivery. It should be noted that the temperature at which the patch can be formulated depends on the concentration and type of plasticizer used in the mixture. Any plasticizer that is dissolvable in acetone and not harmful to the dry vaccine powder could be used. It is also not absolutely necessary to use vacuum to remove the remaining acetone.
Example 8: Preparation of the HPC Micro-Needle Patches Containing a Micronized Vaccine Powder Using Heat Melted Mixtures
(64) This method is similar to the one described in the Example 7 with one important difference. No acetone or other solvent were used. The mixture of vaccine particles with PEO and plasticizer was transformed by heating into a liquid viscous state containing suspended vaccine particles. The mixture was then filled into a mold, and solidified into micro-needles upon cooling.
INDUSTRIAL APPLICABILITY
(65) The invention applies to the manufacture of compositions used for delivery of sensitive biopharmaceuticals in regions where cold chain storage and/or clean water are not readily available.
(66) In addition, the invention can be used for alternative delivery platforms, such as the manufacture of dissolvable films and micro-needle patches, which aid in the reduction of problems associated with needle-delivery.
REFERENCE SIGNS LIST
(67) dissolvable film (100) first layer of polymeric composition (101) second layer of polymeric composition (102) carbohydrate-glass particle (110) carbohydrate-glass matrix (111) biopharmaceutical (112) micro-needle patch (120) first layer of patch (121) second layer of patch (122) micro needles (125)