Radiation sterilization of ultra-compacted polymer dosage forms

Abstract

A sterile pharmaceutical dosage form comprising an ester-terminated lactide polymer, a glycolide polymer, or a lactide-co-glycolide polymer super-compressed with an active pharmaceutical ingredient, wherein the sterile pharmaceutical dosage form has been sterilized using an electron beam; and a method of making the sterile pharmaceutical dosage form.

Description

Field of the Invention

[0001] The present invention relates to the field of sterilization of active pharmaceutical ingredients (API) dispersed in a biocompatible polymeric material that has been super-compacted (densified) to form a controlled release drug formulation. Background of the Invention

[0003] It is known that super-compression (densification) biocompatible lactide polymers, ethylene glycol lactide or lactide-ethylene glycol lactide copolymers containing API. For many applications of these products, it is desirable to utilize radiation to sterilize these products before being applied to or implanted in a patient. However, when sterilized with radiation, these super-compression polymers or copolymers are susceptible to degradation. When API is a heat-labile substance such as a polypeptide or protein, radiation sterilization must be used because those solid preparations can only be sterilized by radiation, since it is not feasible to produce these products under a sterile environment by a processing method. Applicants have observed that when applying gamma radiation to manufacture a sterile product based on a polymeric material comprising lactide polymers, ethylene glycol lactide or lactide-ethylene glycol lactide copolymers, these polymeric materials and any polypeptide or protein present may degrade or denature. This may result in a product that the API cannot reach efficacy regulatory standards.

[0004] Ionizing radiation is known to interact with the electrons of polymer molecules, resulting in energy transfer, ion generation, and the emission of secondary electrons. Depending on the kinetic energy level of the secondary electrons, other nearby molecules can be further ionized and excited. Exposure to ionizing radiation, such as gamma radiation, results in the formation of various energetic species, such as trapped radicals, electrons, and ions. The decay of these energetic species leads to fragmentation and the generation of free radicals. These conditions can destabilize (chain scission) or stabilize (crosslinking) polymeric materials and / or APIs.

[0005] An important factor influencing the interaction between reactive species of degradable peptides and proteins is their proximity to one another. Because hypercompression brings reactive species closer together, hypercompression can actually promote further degradation, leading to reduced product potency and a more unstable product with a shorter shelf life.

[0006] Current pharmaceutical regulations in the United States and Europe limit the amount of substances related to active pharmaceutical ingredients in a drug to no more than 1.0% by weight or 5 μg TDI (total daily intake), whichever is lower, with a maximum daily dose of 1.0 mg. These substances have been detected at levels in radiation-sterilized drug products containing polymers or copolymers that render the product useless for therapeutic purposes.

[0007] It has been found that when ultra-compacted dexamethasone / PLGA products are sterilized by gamma irradiation, the results show high levels of radiation-induced degradation byproducts (2.35% with acid-terminated PLGA and 2.16% with ester-terminated PLGA). When ester-terminated PLGA is sterilized using electron beam irradiation, the radiation-induced degradation byproducts are significantly reduced (ranging from 0.89% to 1.03%).

[0008] The present invention is based on the discovery that the use of electron beam sterilization technology avoids the degradation problem of ultra-compacted drug controlled-release products made from ester-terminated lactide polymers, ester-terminated glycolide polymers, or ester-terminated lactide-glycolide copolymers under gamma radiation sterilization. Summary of the Invention

[0009] The present invention provides a sterile pharmaceutical dosage form comprising an ester-terminated lactide polymer, an ester-terminated glycolide polymer, or an ester-terminated lactide-glycolide copolymer super-compressed with an active pharmaceutical ingredient, wherein the sterile pharmaceutical dosage form has been sterilized using an electron beam.

[0010] The present invention also includes a method for preparing a sterile super-compacted pharmaceutical dosage form of an ester-terminated lactide polymer, an ester-terminated glycolide polymer, or an ester-terminated lactide-glycolide copolymer, the method comprising:

[0011] (a) combining an active pharmaceutical ingredient with an ester-terminated lactide polymer, an ester-terminated glycolide polymer, or an ester-terminated lactide-glycolide copolymer to form a powdered product;

[0012] (b) compressing the powdered product of step (a) to form a super-compacted dosage form; and

[0013] (c) exposing the super-compacted dosage form of step (b) to a sterilizing amount of an electron beam radiation source to form a sterilized product.

[0014] The method of the present invention allows the use of room temperature during sterilization of polypeptide or protein APIs in ultra-compacted, controlled-release ester-terminated lactide polymer, ester-terminated glycolide polymer, or ester-terminated lactide-co-glycolide pharmaceutical formulations by using electron beam sterilization.

[0015] Therefore, the object of the present invention is to provide novel sterile pharmaceutical formulations comprising a polypeptide or protein API in a sterile ultra-compressed controlled release ester-terminated lactide polymer or ester-terminated glycolide polymer or ester-terminated lactide-glycolide copolymer pharmaceutical formulation.

[0016] The present invention also aims to provide a method for sterilizing a polymeric material and / or a polypeptide or protein API comprising an ester-terminated lactide polymer, an ester-terminated glycolide or an ester-terminated lactide-glycolide copolymer in an ultra-compressed controlled-release lactide polymer or glycolide polymer or lactide-glycolide copolymer pharmaceutical formulation.

[0017] Another object of the present invention is to provide a method for administering a sterile ocular therapeutic agent comprising a polypeptide or protein API in an ultra-compacted ocular insert of an ester-terminated lactide polymer, an ester-terminated glycolide polymer, or an ester-terminated lactide-glycolide copolymer, wherein the ocular therapeutic agent is in the form of microparticles or nanoparticles. Detailed Description of the Invention

[0019] Biodegradable polymers such as poly-(L-lactide) (PLLA) and poly-(lactide-co-glycolide) (PLGA) have been used in biomedical and pharmaceutical applications. Due to their splendid toxicological properties and adjustable biodegradability, they have been formulated as nanoparticles, micron particles, injectable reservoirs, films, supports and the overall implants for drug delivery. These controlled drug delivery systems are obtaining actual importance because they improve treatment and patient compliance, provide the drug concentration optimized at the site in the extended period, and reduce undesirable drug side effects.

[0020] Drug delivery devices formulated with PLGA, PLA, and other polymers have been investigated for the treatment of diseases of the eye and other sites, and their hydrolytic degradation, drug release properties, and mechanical integrity have been optimized for various applications.

[0021] The present invention utilizes an ester-terminated lactide polymer, an ester-terminated glycolide polymer, or an ester-terminated lactide-glycolide copolymer.

[0022] PLGA synthesis can be performed by the following methods: (i) direct polycondensation between lactic acid and glycolic acid monomers to produce lower molecular weight copolymers, 1,2 or (ii) ring-opening polymerization of cyclic dimers of lactic acid and glycolic acid to produce higher molecular weight copolymers. 3,4,5,6 Typical reaction conditions for this type of bulk polymerization are at temperatures ranging from 175°C for 2 to 6 hours in the presence of an initiator such as lauryl alcohol. Ester-terminated PLGAs are more stable than acid-terminated PLGAs, as shown by their higher resistance to degradation. 8,9

[0023] Ester-terminated polymers can be prepared by esterifying or transesterifying PLA (polylactic acid), PGY (polyglycolic acid), or PGLA polymers or copolymers using polycaprolactone. Ester-terminated polymers are commercially available, or they can be prepared according to well-known procedures. Gamma and electron beam irradiation are among the most popular and established methods for sterilizing polymer-based medical devices. However, it has long been known that these techniques can cause significant changes in the treated materials. High-energy radiation produces ionization and free radicals within the polymer molecules. These energy-rich species sequentially undergo dissociation, extraction, and addition reactions, leading to chemical instability. Destabilization processes that can occur during, immediately after, or even days, weeks, or months after irradiation often result in physical and chemical crosslinking or chain scission. Resulting physical changes include embrittlement, discoloration, odor development, hardening, softening, increased or decreased chemical resistance, and increased or decreased melting temperature.

[0024] Gamma irradiation causes radiolytic degradation of APIs containing peptides or proteins. This alters the biological properties of these substances by changing or disrupting their molecular structure. The extent to which these substances are affected depends on the delivered surface dose. By controlling the electron beam energy, the penetration depth of the beam in ultra-compacted dosage forms can be manipulated; lower energies produce shallower penetration depths and thus avoid altering or disrupting the molecular structure of the peptide or protein.

[0025] Electron beam (E-beam) processing, or electrons, involves the use of high-energy electrons to treat objects for various purposes. This can occur at high temperatures and under a nitrogen atmosphere. Uses for E-beam processing include sterilization and cross-linking polymers.

[0026] The principles of electron beam technology are similar to those of cathode ray tubes in television receivers. An electron beam accelerator generates an electron beam approximately 4 inches in diameter and excites it at speeds close to the speed of light. The beam passes through a scanning chamber, where a high-powered electromagnetic system sweeps it back and forth at 200 Hz, creating an electron curtain approximately 4 feet high. A high-speed conveyor carries totes or cartons containing the products to be sterilized by electron beam, where a precisely predetermined dose of radiation is delivered to the products.

[0027] The electron energy depends on the desired penetration depth and typically ranges from keV to MeV. The radiation dose is usually measured in kilograys (kGy).

[0028] NUTEK has a dual electron beam configuration system (see below) whereby as the sample travels through the electron beam storage on a tote carrier, the product is exposed to two electron beam (10 MeV, 8 KW) accelerators on opposite sides of the conveyor.

[0029] The basic components of a typical electron beam processing device are: an electron gun (consisting of a cathode, grid, and anode) is used to generate and accelerate the primary beam. A magneto-optical (focusing and deflection) system is used to control the path of the electron beam as it impinges on the material being processed (the "workpiece"). In operation, the gun cathode is the source of thermally emitted electrons, which are accelerated and shaped into a collimated beam by the electrostatic field geometry established by the configuration of the gun electrodes (grid and anode). The electron beam then exits the gun assembly through an exit aperture in the grounded anode at an energy equal to the value of the negative high voltage applied to the cathode (the gun operating voltage). This use of direct high voltage to generate a high-energy electron beam allows for conversion of input AC power into beam power with an efficiency exceeding 95%, making electron beam material processing a highly energy-efficient technology. After leaving the gun, the beam passes through a system of electromagnetic lenses and deflection coils. Lenses are used to produce a focused or defocused beam spot on the workpiece, while deflection coils are used to position the beam spot at a fixed position or provide some form of oscillatory motion.

[0030] Electron beam processing involves irradiating (treating) the product using a high-energy electron beam accelerator. Electron beam accelerators utilize on-off technology and have a common design similar to that of cathode ray televisions.

[0031] It has been unexpectedly discovered that electron beam radiation energy can be used to sterilize ultra-compacted pharmaceutical compositions without degrading the ester-terminated lactide polymers, ester-terminated glycolide polymers, or ester-terminated lactide-glycolide copolymers to an extent that such polymers would be useless in pharmaceutical formulations due to the production of unacceptable levels of degradation products.

[0032] However, one factor that hinders the constant rate release of drugs from PLGA and PLLA is that they undergo bulk degradation. The bulk degradation of these polymers is not a predictable phenomenon.

[0033] The ultra-compressible device of the present invention may comprise an ester-terminated lactide polymer, an ester-terminated glycolide polymer, or an ester-terminated lactide-co-glycolide polymer combined with an API and ultra-compressed to form a controlled-release dispensing unit. The API that may be mixed with the polymer may include hydrophilic or preferably hydrophobic drugs, such as antifungals, antibacterials, antibiotics, anti-inflammatory drugs, immunosuppressants, tissue growth factors, dentin desensitizers, antioxidants, nutrients, vitamins, and deodorants. Specific examples include steroids, nonsteroidal anti-inflammatory drugs, antihistamines, antibiotics, mydriatics, beta-adrenergic antagonists, anesthetics, alpha-2-beta adrenergic agonists, mast cell stabilizers, prostaglandin analogs, sympathomimetics, parasympathomimetics, antiproliferative agents, agents that reduce angiogenesis and revascularization, vasoconstrictors, and combinations thereof, as well as any other agent designed to treat a disease, such as: anti-tumor agents such as bevacizumab, ranibizumab, polynucleotides, or peptides or proteins (including recombinant protein analogs); angiogenesis inhibitors such as endostatin or thalidomide; 5-fluorouracil, paclitaxel, minocycline, timolol hemihydrate, recombinant human growth hormone (rhHGH), bleomycin, ganciclovir, huperzine, tamoxifen, piroxicam, levonorgestrel, cyclosporine, etc.

[0034] Other agents include, but are not limited to, specific steroids, but include steroids such as prednisone, methylprednisolone, dexamethasone; antibiotics including neomycin, tobramycin, aminoglycosides, fluoroquinolones, polymyxins, sulfacetamide; agents such as pilocarpine, isopilocarpine, physostigmine, decanediamine phenyl ester, phosphocholine and acetylcholine and their salts; mydriatics and cycloplegics including agents such as atropine, phenylephrine, hydroxyamphetamine, cyclopentolate, homatropine, scopolamine, tropicamide and their salts; anesthetics including lidocaine, proparacaine, tetracaine, phenacaine and the like; beta-blockers such as dapoxetine, benzocaine, benzodiazepine, benzophenone ... such as timolol, carteolol, betaxolol, nadolol, and levobunolol; carbonic anhydrase inhibitors such as dorzolamide and acetaminophen; prostaglandin analogs such as latanoprost, unoprostone, bimatoprost, or travoprost; recombinant proteins, including factor VIII, insulin, erythropoietin, vascular endothelial growth factor, fibroblast growth factor, and glucocerebrosidase; therapeutic antibodies, including abciximab, bevacizumab, protumumab, ocrelizumab, infliximab, and sarrelizumab; immunotoxins, including denileukin-toxin conjugates, moxetumomab-paxol, and sarilumab. pasudotox), LMB-2, oportuzumab monatox, HuM195-gelontoxin, A-dmDT390, and bisFv (UCHT1); cytokines, including granulocyte colony-stimulating factor, interferon, tumor necrosis factor, interleukin, and transforming growth factor-β; and ECM proteins, including elastin, collagen, fibronectin, and picococcus.

[0035] Generally, a peptide or protein will have a weight average molecular weight of about 5,000 to 250,000.

[0036] Prior to supercompression, the lactide polymer, glycolide polymer, or lactide-glycolide polymer or copolymer and the active drug can be formed into microparticles known as microspheres or microcapsules. The size of the microparticles typically ranges from about 2 microns to about 50 microns in diameter, preferably from about 2 to about 25 microns, and more preferably from about 5 to about 20 microns. The term "microsphere" is used to describe a generally uniform structure obtained by mixing the active drug with a suitable solvent and polymer, such that the finished product contains the drug uniformly dispersed in a polymer matrix formed into microspheres. Depending on the size range of the microparticles selected, the term "nanoparticle" is used to describe structures ranging in size from 1 to 1000 nanometers. A nanometer (nm) is one billionth of a meter, or the size of approximately 10 hydrogen atoms. Currently, nanoparticle drug carriers, i.e., polymeric materials, primarily consist of biodegradable solid particles ranging in size from 50 to 500 nm. Generally speaking, the particle size should be selected so that the particles can be easily measured and transferred when necessary, with the goal of placing the particles in a suitable press to apply supercompression forces to form a compressed dosage form.

[0037] Nanoparticles can be formed, for example, by sonicating a solution of a polylactide polymer in chloroform containing a 2% (weight / weight) polyvinyl alcohol solution in the presence of a therapeutic agent, such as an ocular therapeutic agent, using a sonicator (Misonix XL-2020, power output 50-55 W) for up to 10 minutes. Thereafter, the emulsion is stirred overnight at 4°C to evaporate the chloroform and obtain nanoparticles of the polymer and the therapeutic agent. Drug-containing nanoparticles can easily enter the interior of living cells and provide an unusual opportunity to enhance local drug therapy.

[0038] Microcapsules can also be used to form the compressed dosage forms of the present invention. The term "microcapsule" is used to describe dosage forms that are preferably non-spherical and have a polymer shell disposed around a core containing the active drug and any added excipients, and are within the size ranges described above. In general, microcapsules can be manufactured using one of the following techniques:

[0039] (1) Phase separation method, including aqueous and organic phase separation process, melt dispersion and spray drying;

[0040] (2) interfacial reactions, including interfacial polymerization, in situ polymerization, and chemical vapor deposition;

[0041] (3) physical methods, including fluidized bed spraying, electrostatic coating, and physical vapor deposition; and

[0042] (4) Solvent evaporation method, or use of an emulsion with an antisolvent.

[0043] Generally speaking, the microparticles contain, per 100 parts by weight of the total weight of the therapeutic agent and polymer, from about 0.00001 to about 50 parts by weight of the therapeutic agent and also contain from about 50 to about 99.9 parts by weight of the polymer. Preferred ranges are 1 to 50, 5 to 40, and 20 to 30 parts by weight of the therapeutic agent, with the remainder consisting of the polymer. If desired, 1 to 5% by weight of a binder such as polyvinylpyrrolidone may be uniformly mixed with the microparticles prior to the compression step.

[0044] The amount of drug present in the implanted super-compressed dosage form can vary, but generally 0.5-20% of the usual oral or intravenous dose of the drug can be used, but can vary widely depending on solubility, the area of implantation, the patient and condition to be treated. Microspheres can be formed by solvent evaporation techniques in typical emulsions as described herein.

[0045] In order to provide a biodegradable polymer matrix for a controlled release dosage form suitable for placement at a location where a therapeutic agent can be released to treat a condition, the polymer can be selected from ester-terminated poly(L-lactide), poly(dl-lactide), polyglycolide, poly(glycolide-co-lactide), poly(glycolide-co-dl-lactide), block polymers of polyglycolide, trimethylene carbonate, and polyethylene oxide, or mixtures of any of the foregoing. The synthesized polymer can be a polylactide or poly(lactide-co-glycolide) of any MW (weight average molecular weight) or MW polydispersity, all ratios between lactic acid (LA) and glycolic acid (GA), and all degrees of crystallinity. Generally, the MW ranges from about 500 to about 10,000,000 Da, preferably from about 2,000 to about 1,000,000 Da, and more preferably from about 500 to about 5,000 Da. p(LGA) having an LA:GA ratio of about 75:25 to about 85:15 (mol:mol) and a MW of about 5,000 to about 500,000 can be used. Lactide / glycolide polymers are bulk-eroding polymers (not surface-eroding polymers) and, when formed into a microparticle matrix, will hydrolyze as water enters the matrix and the polymer molecular weight decreases. By increasing the polymer molecular weight, using L-polymers, and reducing the surface area (increasing the size of the microparticles or the size of the dosage form), it is possible to shift the resorption curve to a longer time. Lactide / glycolide copolymers with intrinsic viscosities as high as 6.5 dl / g and as low as 0.15 dl / g are available. For the present invention, lower molecular weight copolymers are preferred. It has been found that a 50:50 molar ratio of glycolide to lactide results in the most rapid degradation and corresponding drug release. By increasing the ratio of lactide in the polymer backbone from about 50 mol% to 100%, the release rate can be reduced to provide prolonged therapeutic efficacy from a single dosage unit.

[0046] The preferred polymer for forming the capsule is poly(glycolide-co-dl-lactide) terminated with an ester, which can be formed with linear or branched aliphatic alcohols or by other means. The ester-terminated polymeric material that serves as the preferred controlled release delivery system for the dispensing device is structurally similar to absorbable polyglycolic acid and polyglycolic acid / polylactic acid suture materials. The polymer carrier serves as a sustained release delivery system for the therapeutic agent. The polymer undergoes biodegradation through a process whereby its ester bonds are hydrolyzed to form normal metabolic compounds, lactic acid and glycolic acid, and allows the release of the therapeutic agent.

[0047] The differences in degradation rates of copolymers composed of different ratios of lactic acid and glycolic acid have been studied. It is known that the biodegradation rate depends on the ratio of lactic acid to glycolic acid in the copolymer, and that a 50:50 copolymer degrades most rapidly. Selecting a biodegradable polymer system avoids the need and associated trauma to remove spent non-biodegradable structures from the eye.

[0048] Ester endcapping of the lactic and glycolic acid polymers or lactide-glycolide copolymers does not substantially affect the release rate of drugs formulated in these copolymers compared to non-ester endcapped lactic and glycolic acid copolymers.

[0049] After the microspheres are prepared, they are compressed at very high forces to form the dispensing device of the present invention. Supercompression can be performed in an apparatus capable of or allowing a pressure of 50,000 to 350,000 psi (hereinafter, "K" is used instead of "1,000"), or 100 Kpsi to 300 Kpsi, or 200 Kpsi to 300 Kpsi, or 50 or 60 Kpsi to 160 or 170 Kpsi, or particularly 60 Kpsi to 170 Kpsi, to be applied to the microparticles or nanoparticles. The term "psi (pounds per square inch)" is determined by taking the force in pounds applied to a particular dosage form and measuring or calculating the top area of the dosage form or mold in square inches, so that a conversion can be made to express the pressure applied to the dosage form in psi.

[0050] The ultra-compression dispensing device can be a perfect sphere, but preferably is a deformed sphere, such as a flat disk, a rod, or a pellet with rounded or smooth edges, which is small enough to be placed under the skin at a location such as a bone and its joints, including knuckles, toes, knees, hips, and shoulders; a gland, such as the pituitary, thyroid, prostate, ovary, or pancreas; or an organ, such as the liver, brain, heart, and kidney. More specifically, the dispensing device of the present invention can be used to treat pathological conditions by implanting the device at or near the site of the pathology, or in a manner that will affect the pathology, such as any part of the body, including humans, animals, fish, or other living species. Such parts can include the contents of cells, any part of the head, neck, back, chest, abdomen, perineum, upper or lower limbs. Any part of the skeleton, including but not limited to the spine; skull; chest bones, including the sternum or ribs; facial bones; upper limb bones, such as the clavicle, scapula, or humerus; hand bones, such as the wrist bones; lower limb bones, such as the ilium or femur; foot bones, such as the tarsal bones; joints or ligaments; muscles and fascia; cardiovascular system, such as the heart, arteries, veins, or capillaries or blood; lymphatic system, such as the thoracic duct, thymus, or spleen; central or peripheral nervous system; sensory organs, such as the eyes, ears, and nose; skin; respiratory system, such as the lungs, larynx, trachea, and bronchi; digestive system, such as the esophagus, stomach, or liver; genitourinary system, such as the bladder, prostate, or ovaries; endocrine glands, such as the thyroid, parathyroid, or adrenal glands.

[0051] A recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biological activity of human vascular endothelial growth factor (VEGF) is an approved agent for the treatment of age-related macular degeneration (AMD). Bevacizumab contains human framework regions and the complementarity-determining regions of a murine antibody that binds to VEGF. Bevacizumab is produced in a Chinese hamster ovary mammalian cell expression system in culture medium containing the antibiotic gentamicin and has a molecular weight of approximately 149 kilodaltons.

[0052] Example 1

[0053] Ultra-compressed PLGA / dexamethasone particles were prepared from acid-terminated PLGA (Purasorb PDLG5002, with an intrinsic viscosity of 0.16-0.24 dl / g in chloroform at 25°C, 1.0 g / dl, and a lactide to glycolide weight ratio of 50:50) by dissolving PLGA in dichloromethane to produce a total of 5 ml of PLGA / MeCl2 solution with 0.23% by weight dexamethasone. The solvent was evaporated, and 250.12 mg of the particles were compressed in a 7.87 mm diameter mold using a pressure of 200 kpsi to form pellets weighing 242.14 mg with a thickness of 3.76 mm. The pellets thus obtained were irradiated with gamma rays (a total of 25 kGy as a single dose), and the formulation was analyzed by HPLC, which showed the presence of up to 2.35% by weight of dexamethasone RS, and 0.37% by weight RS without any radiation, as described in the table.

[0054] Ultra-compacted PLGA particles containing 0.23% dexamethasone by weight were prepared from ester-terminated PLGA (Resomer RG755S, with an intrinsic viscosity of 0.5-0.7 dl / g at 0.1% by weight in chloroform at 25°C and a lactide to glycolide weight ratio of 75:25) in the same manner as the acid-terminated PLGA (Purasorb 5022) formulation. This formulation was irradiated with electron beam radiation (25 kGy total, as two equal doses of 12.5 kGy) and analyzed by HPLC. The results showed the presence of two major dexamethasone RS species (0.33% and 0.56%, respectively). Similarly, the same formulation was irradiated with electron beam radiation (25 kGy total, as a single dose) and analyzed by HPLC, which showed the presence of three major dexamethasone RS species (0.1%, 0.36%, and 0.57%, respectively). The same ultra-compacted PLGA / dexamethasone particles prepared from the same ester-terminated PLGA (Resomer RG755S) showed the presence of 2.16% dexamethasone after gamma irradiation and 0.4 wt% RS without any irradiation, as set forth in the table.

[0055] Ultra-compacted granules were sterilized by gamma irradiation or electron beam, and the API dexamethasone was used as a control. The results are summarized in the table below.

[0056] surface

[0057]

[0058] - The FDA guidance for industry Q3B (R2) impurities in new drug products and the European Medicines Agency guidance note on impurities in new drug products (CPMP / ICH / 2738 / 99) stipulate that the acceptance threshold for degradation products (i.e., RS) in new drug products is "1.0% or 5 μg TDI (total daily intake), whichever is lower, with a maximum daily dose of < 1 mg." Because ultra-compacted microparticles are a controlled-release system specifically designed for highly focused and extended release of drug at very small doses, the amount of drug released per day is expected to be well within the range of < 100 μg (well below the maximum permissible daily dose of < 1 mg specified in the official guidance); therefore, the above data indicate that the levels of identifiable RS (and unidentified RS) are expected to be well below the allowed maximum permissible TDI dose of 5 μg. Additional restrictions on RS are considered unnecessary.

[0059] For gamma sterilization, the parameters are as follows:

[0060] -Prescribed dose: 22.5 kGy to 27.5 kGy (i.e., 25 kGy ± 10%)

[0061] -Delivered dose: 24.2 kGy to 25.8 kGy

[0062] -Exposure time: 299 minutes

[0063] Electron beam irradiation was performed at room temperature, humidity, and in the absence of oxygen in a nitrogen atmosphere at doses of 12.5 kGy and 25 kGy in an electron beam accelerator at an accelerating voltage in kV. These radiation doses were chosen because previous studies have shown that polymers irradiated at these doses exhibit moderate (5 Mrad) to large (20 Mrad) increases in their degradation rates, which would cause pseudo-surface degradation of 20-5 to 0 MRad multilayer film constructions.

Claims

1. A sterile pharmaceutical dosage form comprising an ester-terminated lactide polymer, an ester-terminated glycolide polymer, or an ester-terminated lactide-co-glycolide polymer supercompressed with an active pharmaceutical ingredient using a compressive force of 50,000 to 350,000 psi, wherein the sterile pharmaceutical dosage form has been sterilized using an electron beam.

2. A sterile pharmaceutical dosage form as defined in claim 1, wherein the active pharmaceutical ingredient is selected from the group consisting of: steroids, nonsteroidal anti-inflammatory drugs, antihistamines, antibiotics, mydriatics, beta-adrenergic antagonists, anesthetics, alpha-2-beta adrenergic agonists, mast cell stabilizers, sympathomimetics, parasympathomimetics, antiproliferative agents, agents that reduce ocular angiogenesis and revascularization, vasoconstrictors, anti-tumor agents, polynucleotides, recombinant proteins, angiogenesis inhibitors, and combinations thereof.

3. A sterile pharmaceutical dosage form as defined in claim 1, wherein the polymer is selected from the group consisting of ester-terminated poly(dl-lactide), ester-terminated polyglycolide, ester-terminated poly(glycolide-co-lactide), and ester-terminated poly(glycolide-co-dl-lactide), or a mixture of any of the foregoing.

4. A sterile pharmaceutical dosage form as defined in claim 3, wherein the dosage form has been compressed by applying 100 Kpsi to 300 Kpsi.

5. A sterile pharmaceutical dosage form as defined in claim 4, wherein the dosage form has been compressed by applying 200 Kpsi to 300 Kpsi.

6. A sterile pharmaceutical dosage form as defined in claim 2, wherein the active pharmaceutical ingredient is a steroid.

7. A method for preparing a sterile super-compressed pharmaceutical dosage form of an ester-terminated lactide polymer, an ester-terminated glycolide polymer, or an ester-terminated lactide-glycolide copolymer, the method comprising: (a) combining an active pharmaceutical ingredient with an ester-terminated lactide polymer, an ester-terminated glycolide polymer, or an ester-terminated lactide-glycolide copolymer to form a powdered product; (b) compressing the powdered product of step (a) using a compression force of 50,000 to 350,000 psi to form an ultra-compressed dosage form; and (c) exposing the ultra-compacted dosage form of step (b) to an electron beam radiation source to form a sterilized product.

8. The method of claim 7, wherein the active pharmaceutical ingredient is selected from the group consisting of a steroid, a nonsteroidal anti-inflammatory drug, an antihistamine, an antibiotic, a mydriatic, a beta-adrenergic antagonist, an anesthetic, an alpha-2-beta adrenergic agonist, a mast cell stabilizer, a sympathomimetic, a parasympathomimetic, an antiproliferative agent, an agent that reduces ocular angiogenesis and revascularization, a vasoconstrictor, an antineoplastic agent, a polynucleotide, a recombinant protein, an angiogenesis inhibitor, and combinations thereof.

9. A method of preparing a sterile super-compressed pharmaceutical dosage form according to claim 7, wherein the dosage form has been compressed by applying 100 Kpsi to 300 Kpsi.

10. A method of preparing a sterile super-compressed pharmaceutical dosage form according to claim 7, wherein the dosage form has been compressed by applying 200 Kpsi to 300 Kpsi.

11. The method for preparing a sterile ultra-compacted pharmaceutical dosage form according to claim 7, wherein the active pharmaceutical ingredient is selected from the group consisting of peptides and proteins.

12. A sterile pharmaceutical dosage form as defined in claim 1, wherein the active pharmaceutical ingredient is selected from the group consisting of dexamethasone, prednisone, methylprednisolone, latanoprost, unoprostone, bimatoprost, travoprost, timolol, carteolol, betaxolol, nadolol, levobunolol, dorzolamide, and acetacetamide, wherein the sterile pharmaceutical dosage form has been sterilized using an electron beam.

13. A sterile pharmaceutical dosage form as defined in claim 12, wherein the dosage form has been compressed by applying 100 Kpsi to 300 Kpsi.

14. A sterile pharmaceutical dosage form as defined in claim 13, wherein the dosage form has been compressed by applying 200 Kpsi to 300 Kpsi.

15. The method of claim 7, wherein the active pharmaceutical ingredient is selected from the group consisting of dexamethasone, prednisone, methylprednisolone, latanoprost, unoprostone, bimatoprost, travoprost, timolol, carteolol, betaxolol, nadolol, levobunolol, dorzolamide, and acetacetamide.

16. A method of preparing a sterile super-compressed pharmaceutical dosage form according to claim 15, wherein the dosage form has been compressed by applying 100 Kpsi to 300 Kpsi.

17. A method of preparing a sterile super-compressed pharmaceutical dosage form according to claim 15, wherein the dosage form has been compressed by applying 200 Kpsi to 300 Kpsi.

18. A sterile pharmaceutical dosage form as defined in claim 6, wherein the active pharmaceutical ingredient is dexamethasone.

19. A sterile pharmaceutical dosage form as defined in claim 6, wherein the active pharmaceutical ingredient is prednisone.

20. A sterile pharmaceutical dosage form as defined in claim 6, wherein the active pharmaceutical ingredient is methylprednisolone.

21. A sterile pharmaceutical dosage form as defined in claim 6, wherein the active pharmaceutical ingredient is latanoprost.

22. A sterile pharmaceutical dosage form as defined in claim 6, wherein the active pharmaceutical ingredient is timolol.

23. A sterile pharmaceutical dosage form as defined in claim 6, wherein the active pharmaceutical ingredient is dorzolamide.

24. A sterile pharmaceutical dosage form as defined in claim 6, wherein the active pharmaceutical ingredient is acetacetamide.

25. A sterile pharmaceutical dosage form as defined in claim 6, wherein the active pharmaceutical ingredient is bimatoprost.

26. A sterile pharmaceutical dosage form as defined in claim 6, wherein the active pharmaceutical ingredient is betaxolol.

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