CN101269215B - Glucoprotein incretion composition - Google Patents

Glucoprotein incretion composition Download PDF

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Publication number
CN101269215B
CN101269215B CN2008100374254A CN200810037425A CN101269215B CN 101269215 B CN101269215 B CN 101269215B CN 2008100374254 A CN2008100374254 A CN 2008100374254A CN 200810037425 A CN200810037425 A CN 200810037425A CN 101269215 B CN101269215 B CN 101269215B
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fsh
variant
glycoprotein hormones
lactose
compositions
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CN101269215A (en
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季晓铭
高霄梁
季斌
严惠敏
洪云海
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Shanghai Techwell Biopharmaceutical Co Ltd
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Shanghai Techwell Biopharmaceutical Co Ltd
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Priority to JP2009117421A priority patent/JP5143784B2/en
Priority to KR1020090042756A priority patent/KR101095647B1/en
Priority to PCT/CN2009/071806 priority patent/WO2009138042A1/en
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    • 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
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • 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
    • A61K38/24—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pregnancy & Childbirth (AREA)
  • Molecular Biology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention discloses a solid compound containing disaccharide and glycoprotein hormones or the variant thereof, wherein, the content of the glycoprotein hormones or the variant is not lower than 10 microgrammes per milligramme of compound or not lower than 100 international units per milligramme of compound. The compound provided by the invention has fine stability.

Description

A kind of glucoprotein incretion composition
Technical field
The present invention relates to protein purification and biomedicine field.Particularly, the present invention relates to the compositions of glycoprotein hormones and stabilizing agent thereof, it has good stable.
Background technology
Follicule-stimulating hormone (FSH) (Follicle-stimulating hormone is called for short FSH) is the glycoprotein hormones that is produced by hypophysis, and it is made up of α chain and two subunits of β chain.The α subunit of FSH and luteotropic hormone (leuteinizing hormone, be called for short LH) and chorionic gona dotropin (chorionicgonadotropin, abbreviation CG) α subunit is identical, have 92 aminoacid, molecular weight is about 14500D, and the 52nd and 78 locational agedoites are that the glycosylated aminoacid of N-takes place.The β subunit of FSH is made up of 111 aminoacid, and molecular weight is about 18000D, and wherein the 7th and 24 locational agedoites are that the glycosylated aminoacid of N-takes place.And the β subunit of LH is made up of 121 aminoacid, and molecular weight is about 14800D; The β subunit of CG then has 145 aminoacid, molecular weight 22000-39000D.
FSH is mainly used in treatment infertility and external supplementary reproduction clinically.FSH can extract from the urine of hypophysis or menopausal women, also can prepare by the DNA recombinant technique.
The first generation product that contains FSH is menotrophin (HMG), and as the Pergonal of Serono company, it is that FSH and LH ratio are about 1 mixture.But, need not add patient with exogenous LH for the LH that more amount is arranged in the body, the too high normal development that can influence follicle of LH level, inopportune inhibition meiosis inhibitory factor can cause the aging of ovum, is fertilized and the chance of implantation thereby reduce.Therefore for this part patient, be more suitable in using pure FSH preparation.On the other hand, too much LH causes polycystic ovary syndrome easily (Polycystic Ovarian Syndrome POOS), studies show that LH too much has disadvantageous effect to reproductive function, as causes hypomenorrhea, anovulation, infertile and miscarriage.Therefore more safer than HMG to POOS patient with pure FSH treatment, can reduce ovarian hyperstimulation syndrome (OvarianHyperstimulation Syndrome, OHSS) danger.
The Metrodin that Serono company releases is a kind of FSH preparation that contains minute quantity LH, and Metrodin-HP thereafter then is highly purified FSH preparation.
In addition, also develop a kind of highly purified menotrophin (pHMG) in recent years on the market, Menopur as Ferring company, it is with the high-purity FSH behind the purification and high-purity LH or high-purity hCG (human chorionic gonadotropin, human chorionic gonadotropin) allocates the product that forms in 1: 1 ratio, be mainly used in and substitute common HMG product, and overcome the anaphylaxis that causes because of a large amount of foreign proteins in the common HMG product human body.
This shows,, still,, be convenient to preserve and check, and then make preparation by the form that the high-purity glycoprotein of various means of purification acquisitions at first will be accomplished a crude drug in the market all in the development and application of being devoted to the high-purity glycoprotein hormones.The form of this crude drug is very important, generally should adopt solid form as far as possible and not adopt liquid form, because liquid is not easy storage and transport, and the acquisition of solid form mainly is by cryodesiccated means for glycoprotein hormones, but we know, highly purified glycoprotein hormones is easy to take place the degeneration inactivation in cryodesiccated process, therefore have to adopt the mode of liquid to preserve the crude drug of high-purity glycoprotein hormones in the prior art, but liquid form must be kept at below-20 ℃, otherwise easy inactivation; Liquid form owing to can run into freezes-course of dissolution, or even repeatedly freeze-course of dissolution the easier glycoprotein inactivation that causes; Liquid form also can run into packing container and put crackly danger etc. near fragility at low temperatures.
Therefore this area presses for a kind of crude drug form with glycoprotein hormones of good stability of developing.
Summary of the invention
The present invention aims to provide a kind of solid composite that contains highly purified glycoprotein hormones that can be used as crude drug.
In a first aspect of the present invention, a kind of compositions is provided, described compositions is a solid composite, wherein contains disaccharide and glycoprotein hormones or its variant.
In another preference, the content of described glycoprotein hormones or its variant is for being not less than 10 μ g/mg compositionss or being not less than 100 ius/mg compositions.
In another preference, the content of described glycoprotein hormones or its variant is for being not less than 20 μ g/mg compositionss or being not less than 200 ius/mg compositions.
In another preference, described glycoprotein hormones or its variant are selected from follicule-stimulating hormone (FSH) (FSH) or its variant, lutropin (LH) or its variant or its mixing.
In another preference, described disaccharide is selected from two or more mixing of lactose, sucrose, maltose, trehalose or its; More preferably lactose.
In another preference, described follicule-stimulating hormone (FSH) or its variant are HFSH or its variant.
In another preference, described HFSH or its variant are selected from the HFSH of reorganization or follicule-stimulating hormone (FSH) or its variant in its variant or Urina Hominis source.
In another preference, described lutropin or its variant are human luteinizing hormone or its variant.
In another preference, described human luteinizing hormone or its variant are selected from the human luteinizing hormone of reorganization or lutropin or its variant in its variant or Urina Hominis source.
In another preference, described solid composite is a lyophilized powder.
In another preference, described compositions is a solid, is made up of disaccharide and glycoprotein hormones or its variant, and wherein the content of glycoprotein hormones or its variant is for being not less than 10 μ g/mg compositionss or being not less than 100 ius/mg compositions.
In a second aspect of the present invention, a kind of pharmaceutical composition is provided, described pharmaceutical composition contains aforesaid solid composite.
In a third aspect of the present invention, provide the purposes of a kind of aforesaid solid composite in the medicine of the sterile syndrome of preparation treatment.
In view of the above, the invention provides a kind of crude drug form with glycoprotein hormones of good stability.
The specific embodiment
The inventor is through extensive and deep research, be surprised to find highly purified glycoprotein hormones and suitable stabilizers make up carry out lyophilization after, can obtain stable compositions.Stabilizing agent wherein is good with disaccharide, especially lactose.
The inventor finds; this moment, disaccharide not only played diluent and excipient; the more important thing is protectant effect; it can protect the glycoprotein molecule degeneration inactivation that contingent conformation change caused in freezing dry process; on the one hand, it also improves a lot to the stability of product in addition.On this basis, the inventor has finished the present invention.
Particularly, described in background technology part, available technology adopting liquid form preserve the high-purity glycoprotein hormones in the middle of product or crude drug form, be not easy to storage and transport, careless slightly, just can be to the very big influence of product generation.And adopt solid form to run into the result that freezing dry process causes the glycoprotein inactivation easily.
In exploring the process of improving art methods; the inventor notices high-purity glycoprotein and lactose is carried out suitable proportioning; particularly the concentration of high-purity glycoprotein and lactose is in an OK range; this moment, lactose can play protectant effect so, prevented the glycoprotein molecule degeneration inactivation that contingent conformation change caused in freezing dry process.
In the present invention, described disaccharide (disaccharide) is formed by glycosidic bond by dimolecular monosaccharide, as maltose, lactose, sucrose, trehalose etc.; Preferably from following one or more, as maltose, lactose and sucrose; It more preferably is lactose.
In the present invention, the variant of described glycoprotein hormones is meant that aminoacid disappearance takes place or by recombinant technique it carried out the glycoprotein hormones of modified, but its basic drug effect still exists or is enhanced.
In the compositions provided by the invention, the weight sum of disaccharide and glycoprotein hormones or its variant is the 60-100% of composition total weight, is preferably 80-99%, more preferably is 90-95%.
In compositions of the present invention, the biological value of described glycoprotein hormones or its variant is 500-30000 iu/mg protein, preferably is 3500-12000 iu/mg protein.If glycoprotein hormones wherein only is FSH or its variant, the biological value of FSH or its variant is 500-15000 iu/mg protein, preferably is 7000-12000 iu/mg protein; If glycoprotein hormones wherein only is LH or its variant, the biological value of LH or its variant is 500-8000 iu/mg protein, preferably is 2000-6000 iu/mg protein.
In compositions of the present invention, the purity of described glycoprotein hormones or its variant is more than 50%, preferably is more than 90%.
In every milligram of compositions provided by the invention, the content of glycoprotein hormones or its variant is not less than 100 ius, preferably is not less than 200 ius.
In every milligram of compositions provided by the invention, the content of glycoprotein hormones or its variant is not less than 10 μ g.If glycoprotein hormones wherein only is FSH or its variant, FSH or its variant content preferably are not less than 20 μ g/mg compositionss for being not less than 10 μ g/mg compositionss; If glycoprotein hormones wherein only is LH or its variant, the content of LH or its variant preferably is not less than 35 μ g/mg compositionss for being not less than 10 μ g/mg compositionss.
In the compositions provided by the invention, the weight ratio of disaccharide and glycoprotein hormones or its variant is 8-99: 1, and preferably be 12-60: 1.
In the compositions provided by the invention, the weight ratio of lactose and glycoprotein hormones or its variant is 8-99: 1, and preferably be 12-60: 1.If glycoprotein hormones wherein only is FSH or its variant, the weight ratio of lactose and FSH or its variant is 20-99: 1, and preferably be 30-50: 1; If glycoprotein hormones wherein only is LH or its variant, the weight ratio of lactose and LH or its variant is 8-99: 1, and preferably be 12-20: 1.
The degeneration inactivation can not take place in compositions provided by the invention glycoprotein hormones in freezing dry process, and this compositions has good stable.
The invention provides a kind of pharmaceutical composition, it comprises: (a) glycoprotein hormones or its variant; (b) disaccharide; (c) pharmaceutically acceptable carrier.
As used herein, term " pharmaceutically acceptable carrier " refers to be used for the treatment of the carrier of agent administration, comprises various excipient and diluent.This term refers to some medicament carriers like this: they itself are not necessary active component, and do not have undue toxicity after using.Suitable carriers is well known to those of ordinary skill in the art.(Mack Pub.Co. can find discussing fully about pharmaceutically acceptable excipient in N.J.1991) at Remington ' s Pharmaceutical Sciences.Acceptable carrier can comprise liquid on combination of Chinese medicine is learned, as water, saline, glycerol and ethanol.In addition, also may there be complementary material in these carriers, as disintegrating agent, wetting agent, emulsifying agent, pH buffer substance etc.
Described pharmaceutical composition can be prepared into various dosage forms according to different way of administration.These dosage forms are used in one of following mode: oral, spray suction, rectal application, nasal cavity applied medicine, buccal medication, local application, non-enterally administer, as in subcutaneous, vein, muscle, intraperitoneal, the sheath, in the ventricle, in the breastbone and intracranial injection or input, or by the medication of a kind of outer planting reservoir.Preferred subcutaneous administration mode when wherein treating.
It may be noted that in addition, the using dosage of effective ingredient and using method depend on all multifactorly in the pharmaceutical composition of the present invention, comprise patient's age, body weight, sex, natural health situation, nutriture, effective ingredient activity intensity, take, metabolic rate, the order of severity of disease and diagnosis and treatment doctor's subjective judgment.Advise safe and effective amount usually at least about 10 micrograms/kg body weight, and in most of the cases be no more than about 10 mg/kg body weight that preferably this dosage is about 10 micrograms/kg body weight-Yue 1 mg/kg body weight.Certainly, concrete dosage also should be considered factors such as route of administration, patient health situation, and these all are within the skilled practitioners skill.
The above-mentioned feature that the present invention mentions, or the feature that embodiment mentions can combination in any.All features that this case description is disclosed can with any composition forms and usefulness, each feature that is disclosed in the description can anyly provide the alternative characteristics of identical, impartial or similar purpose to replace.Therefore removing has special instruction, and the feature that is disclosed only is the general example of equalization or similar features.
Major advantage of the present invention is:
1, a kind of compositions of glycoprotein hormones of solid form is provided, has been convenient to storage and transport;
2, the compositions of the glycoprotein hormones of the inventive method acquisition has good stable, is applicable to the preparation corresponding preparation as crude drug.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example is usually according to the normal condition or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise percentage ratio and umber calculate by weight.
Unless otherwise defined, the same meaning that employed all specialties and scientific words and one skilled in the art are familiar with in the literary composition.In addition, any method similar or impartial to described content and material all can be applicable among the present invention.The usefulness that preferable implementation method described in the literary composition and material only present a demonstration.
Embodiment 1
The compositions that contains FSH
In the present embodiment, with the raw material of high-purity FSH (available from Shanghai Tianwei Biological Pharmaceutical Corp.) as the FSH pharmaceutical composition, wherein the biological value of FSH is 9521 ius/mg.
Preparation 50mL 0.01M sodium dihydrogen phosphate (transferring pH about 6.5 with NaOH) adds the 2g lactose, after the stirring and dissolving, filters with 0.22 μ m filter.Get the 10mL filtered solution, add the above-mentioned high-purity FSH of 10.0mg (available from Shanghai Tianwei Biological Pharmaceutical Corp.), after the dissolving, freeze dryer is put in sabot, carries out lyophilization by following program fully:
1. laminate was to-40 ℃ of pre-freezes 3 hours;
2. cold-trap is to-45 ℃;
3. startup vacuum pump;
4. laminate was kept 15 hours to-10 ℃;
5. laminate was kept 5 hours to+20 ℃;
6. outlet gets the 392mg freeze-dried powder.
The biological value result of this products measure FSH is as follows:
Reference examples
In this reference examples, high-purity FSH and lactose be mixed with contain the proportioning that FSH is lower than 50 ius/mg total composition, again its freezing dry process and stability are investigated.
In this reference examples, with the raw material of high-purity FSH (available from Shanghai Tianwei Biological Pharmaceutical Corp.) as the FSH pharmaceutical composition, wherein the biological value of FSH is 9521 ius/mg.
Preparation 500mL 0.01M sodium dihydrogen phosphate (transferring pH about 6.5 with NaOH) adds the 20g lactose, after the stirring and dissolving, filters with 0.22 μ m filter.Get the 100mL filtered solution, add the above-mentioned high-purity FSH of 5.0mg (available from Shanghai Tianwei Biological Pharmaceutical Corp.), after the dissolving, freeze dryer is put in sabot, carries out lyophilization by the program of embodiment 1 fully, gets the 3.89g freeze-dried powder.
Figure S2008100374254D00072
From the result of above-mentioned two examples as seen, adopt the FSH compositions that the present invention obtained, in freezing dry process, almost do not have the degeneration inactivation, and reference examples there is significantly deactivation phenomenom.
The stability contrast
The sample of embodiment 1 and reference examples is investigated its stability down at 30 ℃, and the result is as follows
Figure S2008100374254D00073
As seen, the employing FSH compositions that the present invention obtained is compared with reference examples and is had good stable.
Embodiment 2
The compositions that contains LH
In the present embodiment, with the raw material of high-purity LH (available from Shanghai Tianwei Biological Pharmaceutical Corp.) as the LH pharmaceutical composition, wherein the biological value of LH is 4307 ius/mg.
Preparation 50mL 0.01M sodium dihydrogen phosphate (transferring pH about 6.5 with NaOH) adds the 2g lactose, after the stirring and dissolving, filters with 0.22 μ m filter.Get the 10mL filtered solution, add the above-mentioned high-purity LH of 25mg (available from Shanghai Tianwei Biological Pharmaceutical Corp.), after the dissolving, freeze dryer is put in sabot, carries out lyophilization by the program of embodiment 1 fully, obtains the 402mg freeze-dried powder.
The biological value of this products measure LH and investigate down its stability at 30 ℃, the result is as follows
Figure S2008100374254D00081
As seen, adopt the LH compositions that the present invention obtained, almost do not have the degeneration inactivation, and have good stable.
Embodiment 3
The compositions that contains FSH, LH mixture
The sodium chloride solution of preparation 100mL 0.9% (transferring pH about 7.0 with NaOH or HCl) adds 4g maltose, after the stirring and dissolving, filters with 0.22 μ m filter.Get the 10mL filtered solution, add 10.0mg high-purity FSH (available from Shanghai Tianwei Biological Pharmaceutical Corp., biological value is 9521 ius/mg), add 25.0mg high-purity LH again (available from Shanghai Tianwei Biological Pharmaceutical Corp., biological value is that 4307 ius/mg), after the dissolving, freeze dryer is put in sabot fully, program by embodiment 1 is carried out lyophilization, obtains the 405mg freeze-dried powder.Recording the FSH biological value is 223IU/mg, and the LH biological value is 242IU/mg.
The stability result of this product under 30 ℃ is as follows:
FSH unit tire (IU/mg) Percentage ratio LH unit tire (IU/mg) Percentage ratio
Contrast in 0 day 223 100％ 242 100％
30 ℃ after 3 months 236 106％ 225 93％
30 ℃ after 6 months 208 93％ 230 95％
Embodiment 4
The preparation of FSH lyophilized injection
Be used to make 100 bottles of FSH lyophilized injections, and every bottle of example that contains 75IU FSH is as follows:
The FSH freeze-dried composition 35mg that embodiment 1 is prepared is dissolved in the 10mL injection apirogen water, carries out aseptic filtration with 0.22 μ m filter, and with injection apirogen water washing filter.
The 1g lactose is dissolved in the 30mL injection apirogen water, if necessary, regulates pH6.5 ± 0.2, carry out aseptic filtration with 0.22 μ m filter with HCl or NaOH.Join then in the above-mentioned FSH solution, be settled to 75mL with the injection apirogen water, mixing.
Above-mentioned solution branch is packed in the ampoule bottle, and every bottle of 0.75mL carries out lyophilization.
In the resulting ampoule bottle, every bottle contains about 75IU FSH and 10mg lactose.
The above only is preferred embodiment of the present invention, be not in order to limit essence technology contents scope of the present invention, essence technology contents of the present invention is broadly to be defined in the claim scope of application, any technology entity or method that other people finish, if it is defined identical with the claim scope of application, also or a kind of change of equivalence, all will be regarded as being covered by among this claim scope.

Claims (4)

1. a glycoprotein hormones solid composite contains lactose as stabilizing agent; Wherein glycoprotein hormones is selected from follicule-stimulating hormone (FSH) and lutropin, and the biological value of follicule-stimulating hormone (FSH) is 7000-12000 iu/mg protein, and the biological value of lutropin is 2000-6000 iu/mg protein; The weight ratio of lactose and follicule-stimulating hormone (FSH) is (30-50) in the compositions: 1; The weight ratio of lactose and lutropin is (12-20): 1.
2. solid composite as claimed in claim 1 is characterized in that described solid composite is a lyophilized powder.
3. the pharmaceutical composition that contains each described solid composite among the claim 1-2.
4. the purposes of each described solid composite in the medicine of the sterile syndrome of preparation treatment among the claim 1-2.
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JP2009117421A JP5143784B2 (en) 2008-05-15 2009-05-14 Glycoprotein hormone composition
KR1020090042756A KR101095647B1 (en) 2008-05-15 2009-05-15 Glycoprotein hormone composition
PCT/CN2009/071806 WO2009138042A1 (en) 2008-05-15 2009-05-15 A composition of glycoprotein hormone

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CN102038649B (en) * 2009-10-20 2015-10-14 丽珠医药集团股份有限公司 Urine-promoted follicle stimulating hormone freeze and preparation method thereof
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IT1206302B (en) * 1987-06-26 1989-04-14 Serono Cesare Ist Ricerca URINARY FOLLICLE-STIMULATING HORMONE
IE64738B1 (en) * 1990-03-20 1995-09-06 Akzo Nv Stabilized gonadotropin containing preparations
IT1250075B (en) * 1991-12-18 1995-03-30 Serono Cesare Ist Ricerca PHARMACEUTICAL COMPOSITIONS CONTAINING GONADOTROPINE.
WO1994025005A1 (en) * 1993-04-28 1994-11-10 Akzo Nobel N.V. Lyospheres comprising gonadotropin
ATE358139T1 (en) * 1999-04-16 2007-04-15 Inst Massone S A METHOD FOR PREPARING GONADOTROPIN COMPOSITIONS
NZ535008A (en) * 2002-02-08 2005-09-30 Alkermes Inc Polymer-based compositions for sustained release
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WO2009138042A1 (en) 2009-11-19
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