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WO2000074709A2 - Microspheres de polyester biodegradables modifiees pour la stabilisation et l'amelioration du profil de liberation de medicaments encapsules dans ces microspheres - Google Patents

Microspheres de polyester biodegradables modifiees pour la stabilisation et l'amelioration du profil de liberation de medicaments encapsules dans ces microspheres Download PDF

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Publication number
WO2000074709A2
WO2000074709A2 PCT/US2000/014875 US0014875W WO0074709A2 WO 2000074709 A2 WO2000074709 A2 WO 2000074709A2 US 0014875 W US0014875 W US 0014875W WO 0074709 A2 WO0074709 A2 WO 0074709A2
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Prior art keywords
microspheres
microsphere
insulin
drug
polymer
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Ceased
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PCT/US2000/014875
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English (en)
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WO2000074709A3 (fr
Inventor
Leonard C. Bailey
Pushpa G. Shao
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Rutgers State University of New Jersey
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Rutgers State University of New Jersey
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Priority to AU53055/00A priority Critical patent/AU5305500A/en
Publication of WO2000074709A2 publication Critical patent/WO2000074709A2/fr
Anticipated expiration legal-status Critical
Publication of WO2000074709A3 publication Critical patent/WO2000074709A3/fr
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1611—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)

Definitions

  • microencapsulated proteins in injectable biodegradable polymer microspheres (Furr, B.J.A. and Hutchinson, F.G. J. Contr. Rel . 1992 21:117-128). As the polymer degrades, the protein diffuses out in a sustained manner through the enlarged pore channels over the desired period of time.
  • These microencapsulated proteins can be self- administered parenterally, i.e. subcutaneously or intramuscularly, via a syringe.
  • poly(L- lactic acid) and its copolymers with D-lactic acid or glycolic acid provide a wide range of degradabilities from months to years depending on their composition and molecular weight (Lewis, D.D. Controlled release of bioactive agents from lactide/glycolide polymer. In M. Chasin and R. Langer (ed.) Biodegradable Polymers as Drug Delivery Systems, Marcel Dekker, New York, 1990, pp:l-41) .
  • These polymers are known to be biocompatible and to cause minimal tissue reaction when implanted for long periods of time when used as surgical suture material .
  • An object of the present invention is to provide modified biodegradable microspheres for encapsulation of a drug which comprise a biodegradable polymer and a basic excipient .
  • Another object of the present invention is to provide a method of improving the release profile of a drug encapsulated within a biodegradable microsphere which comprises incorporating a basic excipient into the biodegradable polymer to form a biodegradable polymer microsphere and encapsulating the drug within the microsphere .
  • Another object of the present invention is to provide a method of delivering a drug to a patient which comprises encapsulating the drug in a biodegradable polymer microsphere comprising a biodegradable polymer and a basic excipient and administering the encapsulated drug to the patient.
  • the present invention relates to modified biodegradable microspheres which minimize the degradation of drugs, and in particular proteins or peptides, encapsulated within the microsphere, by maintaining a near neutral pH environment within the degrading microsphere throughout its in vivo lifetime.
  • a stabilization technique has now been established wherein a basic excipient such as sodium bicarbonate is incorporated into a polymer microsphere. This technique results in a significant reduction in the covalent dimerization of an unreleased protein drug and an improved in vi tro release profile for the drug.
  • porcine insulin encapsulated microspheres prepared from 50:50 DL-PLGA and L-PLA using both a Double-Emulsion-Solvent-Evaporation and Emulsion- - Solvent -Evaporation technique were subjected to in vi tro release studies.
  • the cumulative percent insulin released after a 30 -day incubation period from various polyester microsphere formulations is shown in Table 1.
  • the cumulative % released depicted in Table 1 represents the average value from replicate in vi tro release studies.
  • the in vi tro release profiles obtained from these studies exhibited an incomplete release of porcine insulin from all microsphere formulations over the time period investigated.
  • Polyester microspheres degrade via random chain scission of ester linkage in the polymer backbone. The degradation process generates water soluble oligomers that leach out of the microspheres and contribute to a decrease in medium pH . Accordingly, during the course of the release experiments, the pH of actual release media as well as unbuffered media containing identical amounts of placebo microspheres were monitored as an indicative parameter of polymer hydrolysis.
  • pH-profiles of buffered release media and unbuffered media containing various microsphere formulations during the 30-day incubation period were generated. These pH profiles of in vi tro release media indicated that the buffered environment maintains a relatively constant physiological pH, and a pH-drop occurs only after 20 days and 25 days of incubation period for release media containing porcine insulin encapsulated 50:50 DL-PLGA and L-PLA microspheres respectively. Examination of the pH-profiles of unbuffered media containing placebo 50:50 DL-PLGA and L-PLA microspheres indicated an initial pH-drop due to the release of residual acid contained in the polymer, followed by a period of stable pH associated with polymer hydration and a final phase of continuous pH- drop due to polymer breakdown.
  • the relative percentages of unreleased insulin and insulin- related degradants formed within the microspheres were estimated based upon the total amount of insulin initially contained in the microsphere release samples by comparison of their peak area responses to a calibration curve of porcine insulin based on the assumption that deamidation does involve a chromophoric change. Size exclusion HPLC analyses of the unreleased insulin from various microsphere formulations indicated that a significant portion of the unreleased insulin had already undergone covalent dimerization within the microspheres prior to release. The percentage of covalent dimer formed was estimated by Area Normalization technique based on the assumption that the molar absorptivity of the dimer is equivalent to two monomeric units.
  • a method to correlate this visual perception of acid color for each indicator encapsulated microsphere with a pH value was therefore devised. This was done by constructing a pH-scale with an interval of 0.2 pH units using Standard USP buffer solutions of known pH values. The gradual color change of each indicator was visually inspected in a series of standard buffer solutions covering its pH transition interval, and the pH values at which the color of each indicator was visually perceptible to have completely transitioned to the acid color was recorded. These pH values were then correlated with the stability time points at which the corresponding indicators were visually perceived to have completely changed to the acid color within the microspheres. The intra-microsphere pH values estimated at various stability time points using this technique are tabulated in Table 3.
  • microspheres were then subjected to in vi tro release studies.
  • the in vi tro release kinetics of porcine insulin were significantly higher from microspheres containing sodium bicarbonate compared to microspheres prepared using identical fabrication technique excluding sodium bicarbonate. Specifically, cumulative percent insulin released in 30 days for 50:50 DL-PLGA microspheres containing sodium bicarbonate was 47.3% compared to 10.4 % for microspheres containing no sodium bicarbonate. After a 30 -day incubation period, the release study was terminated and the unreleased insulin was extracted and analyzed by reverse-phase HPLC and size exclusion HPLC.
  • Size exclusion HPLC analyses of the unreleased insulin from microspheres containing sodium bicarbonate indicated a significant reduction in covalent dimer formation compared to microspheres prepared excluding sodium bicarbonate.
  • a basic excipient such as sodium bicarbonate as an additive in 50:50 DL-PLGA microspheres almost prevented the formation of covalent insulin dimer to only trace levels that could not be reliably quantitated.
  • the total degradation into deamidated products was also reduced to only 7.1 % in the microsphere formulation containing sodium bicarbonate.
  • the present invention relates to modified biodegradable microspheres for encapsulation of a drug which comprise a biodegradable polymer and a basic excipient.
  • the modified biodegradable microspheres are useful in stabilizing the encapsulated drug and in improving the release kinetics of the drug.
  • the present invention also relates to a method of improving the release profile of a drug encapsulated within a biodegradable microsphere which comprises incorporating a basic excipient into the biodegradable polymer matrix which encapsulates the drug and forms the microsphere.
  • These modified biodegradable microspheres are particularly useful for protein or peptide drugs wherein controlled release formulations are especially desirable.
  • the biodegradable polymer used in the present invention comprises poly (L-lactic acid) or one of its copolymers with D-lactic acid or glycolic acid.
  • Pharmaceutically acceptable basic exipients for parenteral administration which can be incorporated into the polymer matrix for use in the present invention are well known in the art. Examples include, but are not limited, bicarbonates such as sodium bicarbonate and phosphate buffered saline. The amount of basic excipient to be incorporated into the polymer can be determined routinely by one of skill in the art based upon the ability of the excipient to neutralize acids released during polymer hydrolysis without causing an increase in the intra-microsphere pH.
  • a method of delivering a drug, preferably a protein or peptide drug to a patient is first encapsulated in a biodegradable polymer microsphere comprising a biodegradable polymer and a basic excipient.
  • a biodegradable polymer microsphere comprising a biodegradable polymer and a basic excipient.
  • Methods for encapsulating drugs, and in particular proteins, are well known in the art. Examples of well known encapsulation techniques include, but are not limited to, the Double- Emulsion-Solvent-Evaporation and Emulsion-Solvent- Evaporation techniques described herein, low-temperature phase separation, emulsion phase separation, prilling and spray drying.
  • the encapsulated drug is then administered to the patient preferably via a parenteral route such as intravenously, intramuscularly or subcutaneously .
  • a parenteral route such as intravenously, intramuscularly or subcutaneously.
  • Poly (D, L-lactic acid-co-glycolic acid) 50:50 inherent viscosity approximately 0.5 (RESOMER RG504) and Poly(L- lactic acid) molecular weight 2000 (RESOMER L104) were obtained from Boehringer Ingelheim Chemicals Inc. (Montvale, NJ) .
  • Polyvinyl alcohol, average molecular weight 30,000-70,000 was obtained from Sigma Chemical Company (St. Louis, MO) .
  • Crystalline porcine insulin was obtained from Eli Lilly and Company (Indianapolis, IN) . All other buffering agents and chemicals used were reagent grade. All solvents used for analysis were high-performance liquid chromatography (HPLC) grade and distilled water was purified to the 18 megaohm resistivity level by filtering through a Millipore Milli-Q water filtration system.
  • Example 2 Microsphere Preparation
  • Porcine insulin encapsulated 50:50 DL-PLGA and L-PLA microspheres were prepared using two different techniques, namely Double-Emulsion-Solvent Evaporation as described by Soriano et al . International Journal of Pharmaceutics 1996 142:135-142 and Emulsion-Solvent-Evaporation as described by Kwong et al . J. Control Release 1986 4:47-62.
  • porcine insulin (20 ⁇ 2 mg) was accurately weighed and dissolved in 100 ⁇ l of 30 % aqueous glacial acetic acid solution. About 600 ⁇ 20 mg of the polymer 50:50 DL-PLGA or L-PLA was accurately weighed and dissolved in either 3 ml or 1 ml of methylene chloride respectively depending on the polymer being used. The insulin solution was then slowly poured into the polymer solution dropwise and the resulting mixture was vortexed for 2 minutes using a touch mixer to form the first inner emulsion (w/o) .
  • the first emulsion was then poured, to 200 ml of a rapidly stirred aqueous solution of 1 % Polyvinyl alcohol to form the second emulsion (w x /o/w 2 ) .
  • the emulsion was continuously stirred using a plate stirrer for 2 hours to allow the methylene chloride to evaporate.
  • the microspheres were collected by decanting the supernatant and dried in an evacuated dessicator in the presence of phosphorus pentoxide .
  • the dried microspheres were then sieved through a 590 P opening sieve and weighed to determine the yield.
  • the decanted supernatant was assayed to determine the amount of unentrapped insulin.
  • Insulin release was measured by placing 20 ⁇ 0.5 mg of microspheres in microcentrifuge tubes containing 1 ml of release medium (isotonic phosphate buffered saline, pH 7.4 containing 0.02 % sodium azide as a bacteriostatic agent and 0.001 % TWEEN-85 as a surfactant to prevent the microspheres from forming clumps) .
  • release medium isotonic phosphate buffered saline, pH 7.4 containing 0.02 % sodium azide as a bacteriostatic agent and 0.001 % TWEEN-85 as a surfactant to prevent the microspheres from forming clumps.
  • the tubes were placed in a shaking water bath at 37°C at a speed of 45 rp .
  • the tubes were centrifuged at periodic time intervals and 200 ⁇ l aliquots were withdrawn and replaced with fresh medium.
  • the insulin released was analyzed by reverse phase HPLC. The pH of the release medium was periodically monitored
  • the pH of unbuffered medium containing an identical amount of placebo microspheres was also monitored at periodic intervals and used as an indicative parameter of polymer hydrolysis.
  • the unreleased insulin within the microspheres was extracted by dissolving the polymer in 400 ⁇ l of acetonitrile and subsequently extracting the encapsulated insulin in the buffer component of the highperformance liquid chromatography mobile phase (0.25 N phosphoric acid adjusted to pH 2.4 with triethylamine) used for reverse- phase analyses. The samples were then analyzed by reverse- phase as well as size exclusion chromatography.
  • Example 4 HPLC Analyses
  • Insulin and related substances were analyzed using a reverse phase gradient HPLC method employing a C-18 Symmetry column, 5 ⁇ m, 100 A, 150 X 3.9 mm (Waters
  • the mobile phase consisted of Acetonitrile : 0.25 N Phosphoric acid, pH adjusted to 2.4 with Triethyl amine . A gradient from 22% to 30% Acetonitrile in 25 minutes at a flow rate of 1 ml/minute was used.
  • the detector was set at a wavelength of 210 nm and an injection volume of 20 ⁇ l was employed. The related substances peak areas were compared against a calibration curve of insulin standards.
  • a size exclusion HPLC method consisting of an Insulin HMWP column, 7.8 X 300 mm (Waters Corporation, Milford, MA) was used to determine the percentage of covalent insulin dimer and high molecular weight transformation products.
  • the mobile phase consisted of 0.1% L-Arginine in water :Glacial acetic acid:Acetonitrile (65:15:20) at a flow rate of 0.5 ml/minute.
  • the detector was set at a wavelength of 275 nm and an injection volume of 100 ⁇ l was employed.
  • Example 5 Intra-Microsphere pH Estimation Study
  • the gradual pH-drop inside degrading 50:50 DL-PLGA microspheres was estimated by encapsulating acid-base indicators covering a wide range of pH-transition intervals to serve as pH-indicating probes.
  • Porcine insulin microspheres with a theoretical insulin loading of approximately 3.2% containing sodium bicarbonate (theoretical loading level of 7.7%) were prepared using the Emulsion-Solvent-Evaporation method. In this method about 600 ⁇ 20 mg of the 50:50 DL-PLGA was accurately weighed and dissolved in 6 ml of methylene chloride. About 20 ⁇ 2 mg of crystalline porcine insulin and 52 ⁇ 5 mg of sodium bicarbonate were accurately weighed, powdered and mixed to form a homogenous mixture. The mixture was suspended in the polymer solution and vortexed for 2 minutes using a touch mixer to form a homogenous suspension. Microspheres were then fabricated in an identical manner as described in Example 2. The loading level of sodium bicarbonate was based upon the maximum solid that could be physically suspended in the polymer solution to still render it adequately pourable.

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Abstract

Cette invention se rapporte à des microsphères biodégradables modifiées servant à l'encapsulation d'un médicament constitué par un polymère biodégradable et par un excipient basique. Cette invention se rapporte également à des procédés permettant d'améliorer le profil de libération d'un médicament et d'administrer un médicament à un patient grâce à l'encapsulation de ce médicament à l'intérieur de ces microsphères biodégradables modifiées.
PCT/US2000/014875 1999-06-03 2000-05-30 Microspheres de polyester biodegradables modifiees pour la stabilisation et l'amelioration du profil de liberation de medicaments encapsules dans ces microspheres Ceased WO2000074709A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU53055/00A AU5305500A (en) 1999-06-03 2000-05-30 Modified biodegradable polyester microspheres for stabilizing and improving the release profile of drugs encapsulated within the microspheres

Applications Claiming Priority (2)

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US13728999P 1999-06-03 1999-06-03
US60/137,289 1999-06-03

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WO2000074709A2 true WO2000074709A2 (fr) 2000-12-14
WO2000074709A3 WO2000074709A3 (fr) 2008-03-20

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005110369A3 (fr) * 2004-04-30 2006-11-30 American Pharmaceutical Partne Microsphères à libération continue et leurs méthodes de fabrication et d’utilisation
CN102357080A (zh) * 2011-11-04 2012-02-22 无锡中科光远生物材料有限公司 一种酸性环境中可实现药物快速释放的智能型多功能空心微球及其制备方法
CN113916865A (zh) * 2021-10-09 2022-01-11 中国工程物理研究院激光聚变研究中心 一种空心微球保气性能在线拉曼测量方法
WO2024193475A1 (fr) * 2023-03-17 2024-09-26 浙江大学 Préparation à libération contrôlée et son procédé de préparation

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5912015A (en) * 1992-03-12 1999-06-15 Alkermes Controlled Therapeutics, Inc. Modulated release from biocompatible polymers
AU4198793A (en) * 1992-07-24 1994-01-27 Takeda Chemical Industries Ltd. Microparticle preparation and production thereof

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005110369A3 (fr) * 2004-04-30 2006-11-30 American Pharmaceutical Partne Microsphères à libération continue et leurs méthodes de fabrication et d’utilisation
US8808746B2 (en) 2004-04-30 2014-08-19 Fresenius Kabi Usa, Llc Sustained-release microspheres and methods of making and using same
CN102357080A (zh) * 2011-11-04 2012-02-22 无锡中科光远生物材料有限公司 一种酸性环境中可实现药物快速释放的智能型多功能空心微球及其制备方法
CN102357080B (zh) * 2011-11-04 2014-07-16 无锡中科光远生物材料有限公司 一种酸性环境中可实现药物快速释放的智能型多功能空心微球及其制备方法
CN113916865A (zh) * 2021-10-09 2022-01-11 中国工程物理研究院激光聚变研究中心 一种空心微球保气性能在线拉曼测量方法
CN113916865B (zh) * 2021-10-09 2024-03-29 中国工程物理研究院激光聚变研究中心 一种空心微球保气性能在线拉曼测量方法
WO2024193475A1 (fr) * 2023-03-17 2024-09-26 浙江大学 Préparation à libération contrôlée et son procédé de préparation

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AU5305500A (en) 2000-12-28

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