CA1326438C - Sustained and controlled release of water insoluble polypeptides - Google Patents

Sustained and controlled release of water insoluble polypeptides

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Publication number
CA1326438C
CA1326438C CA000577205A CA577205A CA1326438C CA 1326438 C CA1326438 C CA 1326438C CA 000577205 A CA000577205 A CA 000577205A CA 577205 A CA577205 A CA 577205A CA 1326438 C CA1326438 C CA 1326438C
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CA
Canada
Prior art keywords
peptide
polymer
water
pharmaceutical composition
salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CA000577205A
Other languages
French (fr)
Inventor
Piero Orsolini
Rolland-Yves Mauvernay
Romano Deghenghi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Debio Recherche Pharmaceutique SA
Original Assignee
Debiopharm SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Debiopharm SA filed Critical Debiopharm SA
Application granted granted Critical
Publication of CA1326438C publication Critical patent/CA1326438C/en
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Classifications

    • 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
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • 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)

Abstract

ABSTRACT OF THE DISCLOSURE

There is disclosed a pharmaceutical composition for sus-tained and controlled release of drug over an extended period of time comprising a polylactide, a copolymer of lactic and glycolic acid, a mixture of such polymers and a water-insoluble peptide which, when placed in an aqueous physiological-type environment releases the peptide in continuous manner for a period of at least one week, and with an initial release for the first twenty-four hours of not more than 30 % of the total amount released. There is thus provided the control of the release pattern and in general a decrease of the initial burst effect.

Description

-`- 1326~ 38 - l -DESCRI PT I ON

This invention relates to pharmaceutical compositions of therapeutically active but water-in~oluble polypeptide~, which provide a continuous, controlled and sustained relea e of such peptides when placed in a physiological-type environ-ment by means of implant or injections under the skin or into the muscle of animals and humans.

This invention is further characterized by the use of bio-degradable and bio-compatible polymers and copolymers as matrix in which the water-insoluble polypeptides are disper-sed or encapsulated.

The need of producing sustained release of peptides for par-enteral administration has been recognized for a long time (cf. T.M.S. Chang "Biodegradable Semipermeable Microcapsule~
containing enzymes, hormones, vaccines and other biologicals"
in J. Bioengineering 1, 25 (1976); R. Langer "Controlled Release of Macromolecules" in Chemtech, February 1982, pp 98-105: F.G. Hutchinaon and B.J. A. Furr "Biodegradable car-riers for the sustained release of polypeptides" in TIBTECH, April 1987 (vol. 5) pp 102-106.

~r , A number of such formulations, but applied to water soluble polypeptides, have been described in EPS 0052510 "Microencap-sula~ion of water soluble polypeptide3", published 27.08.86 and in EPS 0058481 "Continuous release pharmaceutical compos-itions", published 01.10.86.

The novel, surprising and totally unexpected feature of the present invention resides in the fact that therapeutically useful sustained and controlled release compositions can advantageously be obtained by using essentially water-insoluble peptides, possessing immea~urably low solubility in aqueous solution at room or body temperature and yet provid-ing an effective and controlled release of such peptides when their compositions are administered parenterally in a physio-logic, essentially aqueous environment.

It is a novel and ~urprising consequence of the present in-vention that polypeptides which are normally water soluble in nature or when prepared by synthesis, can be advantageously rendered water insoluble by forming insoluble addition salts, such as with pamoic acid, tannic acid, stearic acid and other non-toxic water-insoluble acids, prior to their microencap-sulation or disper~ion in a biodegradable polymeric matrix.

1326~38 -- 3 ~

The use of sparingly ~oluble or water insoluble derivatives is of course well known, even in the peptide field (cf Schally et al. US Patent 4,010,125 March 1, 1977, column 7, line 25), when slow-release depot dosage forms are needed.

However, when biodegradable polymers such as polylactic acid, polyglycolic acid, polyhydroxybutyric acid, polyortho-esters, polyacetals and the like are used as drug delivery systems, the release of the peptides in a continuous manner has con-sistently required an appreciable water solubility. Reported experiments have shown that the biodegradation of polymers (such as polylactide and polylactide-co-glycolide for exam-ple) leads to water-uptake and generation of aqueous channels or pores from which peptides leak out becau~e they are water soluble .

Our discovery that peptides can be released from matrixes and microcapsules with a highly desirable release pattern when their water solubility is diminished down to practically zero levels is totally surprising and contradicts the teachings of the prior art. In particular we found that the release of certain peptides, such as D-Trp6-LHRH, from polymeric mat-rixe~, is better in terms of uniformity and duration, the more water-insoluble the addition salt of the peptide is.

/ -'~ y 132~438 "Water-insolubililty" i8 hereby defined as the amount o peptide which can be ~easured in solution when the salt i8 dispersed or stirred for 4 hours in distilled water at tem-peratures of 40C or below, such amount being 25 mg/l or less (0 to 25 ppm).

It is highly desirable to administer biologically active polypeptides continuously and for a sustained period of time, from one week to several months. It i8 also highly desirable that the pattern of release be controlled, 80 as to avoid uneven releases of the peptide at the beginning, in the mid-dle or at the end of the therapeutic cycle. It has been often found that peptides are released from biodegradable matrixes in bursts (also called burst effects), either at the begin-ning of the cycle or at the end, when the polymeric matrix is eroded through hydrolysis.

An important feature of the present invention is a control of the release pattern, and in general a decrease of the initial burst effect. The water insoluble peptide ~8 released to a lesser extent that its water soluble derivatives, thus affor-ding a more prolonged release time and the avoidance of over-dosing the patient. ~y transforming a normally water soluble peptide into an insoluble one, we are able to limit the ini-tial bur~t effect (i.e. the amount of peptide released in the first 24 hours) to less than 30% of the total dose.

./. .
B

1326~38 Example~I

Fifty grams of a copolymer of D,L-lactide and glycolide with a 50/50 molar ratio of D,L-lactide to glycolide and an ave-rage molecular weight of 50,000 is dissolved in 9S0 grams of methylene chloride.

The solution is pa~sed through a millipore filter to remove any particulate ~atter and pyrogens. To this solution, one gram of D-Trp6 LHRH pamoate is added and dispersed with a high shear mixer.

The resulting mixture i8 placed in a rotating evaporator and the majority of the methylene chloride i~ removed under va-cuum. The resulting thick dispersion is poured onto a glass plate and spread with an adjustable blade set at 0.7 mm.

After air drying the resulting film is vacuum desiccated for 48 hour~ and then extruded through a 0.8 mm orifice at 70C
under pressure. The re~ulting rods are ground cryogenically at -40C.

The resulting granular ~aterial i9 sieved through a 180 mi-crometer screen and the undersize fraction is collected and sterilized by exposure to gamma radiation between 2.5 and 2.8 Mrad.

/- -1326~3~
Example II

The same procedure as in example I i8 followed by substitut-ing D-Trp6-LHRH pamoate with D-Trp6-LHRH stearate salt.

.
E~pIe III

The same procedure as in example I is followed with the pamo-ate salt of D-Phe-Cys-Tyr-D~Trp-Lys-Val-Cys-Trp-NH2 as the water insoluble peptide.

Ex mple IV

The procedure of example I i~ applied to one of following water-insoluble pamoate salts:

D-~al(2)6 LHRH pamoate D-Ser(0-tBu)6-des Gly10-AzglylO-LHRH pamoate D-Ser(But)6 LHRH(l-9) ethylamide pamoate D-Leu6-des Gly10-LHRH ethylamide pamoate Example V

The procedure of examples I to IV is followed with D,L
lactide-co-glycolide polymers in which the molar ratio wa~
67% D,L lactide 33% glycolide, 75% D,L lactide 25% glycolide or 100% D,L lactide.

./. .

Example VI

The procedure of examples I to V is followed with the water-insoluble pamoate, tannate or stearate salts of one of the following peptides: oxytocin, vasopressin, ACTH, calcitonin, epidermal growth factor, prolactin, inhibin, interferon, LHRH, ~omatostatin, insulin, glucagon, atrial natriuretic factor, endorphin, a renin inhibitor, GHRH, peptide-T, or synthetic analogues and modifications thereof.

Release~pae~e~n~in animàIs~rat~) A typical release pattern of an implanted formulation of D-Trp6-LHRH pamoate in rats is the following: ng/ml of radio-assayed D-Trp~-LHRH in plasma (mean of 8iX rats): (to) 0.04, (1 hr) 7.74, (6 hrq) 0.80, (day 2) 0.85, (day 4) 0.77, (day 7) 0.25, (day 11) 0.12, (day 14) 0.11, (day 18) 0.11, (day 21) 0.14, (day 25) 0.18.

The preceding exa~ples are not limitative to the described water-insoluble peptides or to the biodegradable polymers used, as it is apparent to a person skilled-in-the-art.

Claims (27)

1. A pharmaceutical composition designed for sustained and controlled release of a peptide comprising a polylactide polymer, a polymer of lactic and glycolic acid, or a mixture of said polymers and a water-insoluble peptide which, when placed in an aqueous physiological-type environment releases the peptide in a continuous manner for a period of at least one week, and with an initial release for the first twenty-four hours of not more than 30% of the total amount released.
2. A pharmaceutical composition as claimed in claim 1 in which the water-insoluble peptide is a pharmaceutically acceptable salt of LHRH or a synthetically prepared analogue thereof.
3. A pharmaceutical composition as claimed in claim 1 in which the pharmaceutically acceptable salt is selected form the group of pamate, tannate and stearate salts.
4. A pharmaceutical composition as claimed in claim 1 in which the water-insoluble peptide is a pahmaceutically acceptable salt of oxytocin, vasopressin, ACTH, calcitonin, epidermal growth factor, prolactin, inhibin, interfereon, somatoatatin, insulin, glucagon, strial natriuretic factor, endorphin, a renin inhibitor, growth hormone releasing hormone, peptide T and synthetic analogues and modifications thereof.
5. A pharmaceutical composition as claimed in claim 1 in which the water-insoluble salt is the pamoate salt of D-Trp6-LHRH.
6. A pharmaceutical composition as claimed in claim 1 in which the water-insoluble peptide is the pamoate salt of .
7. A pharmaceutical composition as claimed in claim 1 comprising particles ranging in size from 1 to 500 µm.
8. A pharmaceutical composition as claimed in claim 1 in a solid shape sterilized by gamma radiation.
9. A pharmaceutical composition as claimed in claim 7 sterilized with gamma radiation and suspended in a pharmaceutically acceptable carrier.
10. A pharmaceutical composition for providing an effective and controlled release of a peptide which comprises a water-insoluble peptide salt which is substantially uniformly dispersed throughout, a polylactide polymer, a polyglycolide polymer, a polymer of lactic and glycolic acids or a mixture of said polymers, said pharmaceutical composition comprising solid particles for administration by parenteral injection or as a subcutaneous implant into a physiological environment, wherein the peptide is released in a continuous manner for at least one week in said physiological environment.
11. A pharmaceutical composition as claimed in claim 10 wherein said water insoluble peptide is selected from the group consisting of pamoate, tannate and stearate salts of D-TRP6-LHRH, and the polymer is a D,L-lactide and glycolide polymer.
12. A pharmaceutical composition for providing an effective and controlled release of a peptide which comprises a water-insoluble peptide salt which is dispersed within microcapsules of a polylactide polymer, a polyglycolide polymer, a polymer of lactic and glycolic acids or a mixture of said polymers for administration by parenteral injection or as a subcutaneous implant into a physiological environment, wherein the peptide is released in a continuous manner for at least one week in said physiological environment.
13. A pharmaceutical composition as claimed in claim 12 wherein said water insoluble peptide is selected from the group consisting of pamoate, tannate and stearate salts of D-TRP6-LHRH, and the polymer is a D,L-lactide and glycolide polymer.
14. A process for preparing a pharmaceutical composition designed for sustained and controlled release of a peptide, said process comprising selecting a water-insoluble peptide salt;
dispersing the water-insoluble peptide salt into a solution of a polylactide polymer, a polyglycolide polymer, a copolymer of lactic and glycolic acids, or a mixture of said polymers and a solvent; removing the solvent of the solution to form a residue;
and shaping the residue into solid particles of said pharmaceutical composition suitable for administration by parenteral injection or as a subcutaneous implant.
15. A process for preparing a pharmaceutical composition designed for sustained and controlled release of a peptide said process comprising selecting a water insoluble peptide salt;
dispersing a water-insoluble peptide salt into a solution of a polylactide polymer, a polyglycolide polymer, a copolymer of lactic and glycolic acids or a mixture of said polymers; adding a coacervation agent to the solution to form microcapsules of the peptide salt and polymer(s); pouring the resulting microcapsules into a pharmaceutically acceptable hardening liquid; and collecting the microcapsules for use as a pharmaceutical composition suitable for administration by parenteral injection or as a subcutaneous implant.
16. A process as claimed in claim 14 or 15 which further comprises selecting said water-insoluble peptide from pharmaceutically acceptable salts of LHRH and synthetically prepared analogues thereof.
17. A process as claimed in claim 16wherein the pharmaceutically acceptable salt is selected from the group consisting of pamoate, tannate and stearate salts.
18. A process as claimed in claim 14 or 15 which further comprises selecting said water-insoluble peptide from pharmaceutically acceptable salts of oxytocin, vasopressin, ACTH, calcitonin, epidermal growth factor, prolactin, inhibin, interferon, somatstatin, insulin, glucagon, atrial natriuretic factor, endorphin, a peptide renin inhibitor, growth hormone releasing factor, peptide T and synthetic analogues thereof.
19. A process as claimed in claim 14 or 15 wherein said water-insoluble peptide salt is dispersed within said solution by shear mixing.
20. A process as claimed in claim 14 or 15 which further comprises sterilizing said composition by exposure to gamma radiation at between 2.5 and 2.8 Mrad.
21. The process of claim 14 wherein said peptide, polymer or copolymer is selected so as to provide a continuous release of said peptide when placed in a physiological environment.
22. The process of claim 14 further comprising selecting a water-insoluble peptide and polylactide polyglycolide polymer or copolymer molar ratio, and dosing said polymer or copolymer with said peptide salt so that said subcutaneous implant provides a continuous release of peptide when placed in a physiological environment.
23. The process of claim 15 further comprising selecting a water-insoluble peptide and polylactide polyglycolide polymer or copolymer molar ratio, and dosing said polymer or copolymer with said peptide salt so that said microspheres provide a continuous release of peptide when placed in a physiological environment.
24. A process for preparing a pharmaceutical composition for sustained and controlled release of a peptide said process comprising:
forming a water-insoluble salt of LHRH or a synthetic analog thereof;
dispersing the water-insoluble peptide salt with mixing into a solution of a polylactide polymer, a polyglycolide polymer, a copolymer of lactic and glycolic acids or a mixture of said polymers and a solvent;

forming microparticles of the peptide salt and polymer(s) by evaporating the solvent;
drying the microparticles;
extruding the microparticles into rods;
grinding the rods into granular material;
sieving the granular materials; and collecting a fraction and sterilizing the fraction for use as the pharmaceutical composition.
25. A process for preparing a pharmaceutical composition designed for sustained and controlled release of a peptide, said process comprising forming a water insoluble peptide salt from a water-soluble peptide; dispersing said water-insoluble peptide salt into a solution of a polylactide polymer, a polyglycolide polymer, a copolymer of lactic and glycolic acids or a mixture of said polymers; adding a coacervation agent to the solution to form microcapsules of the peptide salt and polymer(s); pouring the resulting microcapsules into a pharmaceutically acceptable hardening liquid; and collecting the microcapsules for use as a pharmaceutical composition suitable for administration by parenteral injection or as a subcutaneous implant.
26. The process of any one of claims 22-25,further comprising selecting said peptide from the group consisting of pamoate, tannate and stearate salts of D-Trp6-LHRH........ and selecting a mixture of D,L-lactide and glycolide as said polymer.
27. The process of claim 26 wherein the rods are ground cryogenically into the granular material.
CA000577205A 1987-09-21 1988-09-13 Sustained and controlled release of water insoluble polypeptides Expired - Lifetime CA1326438C (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB8722134A GB2209937B (en) 1987-09-21 1987-09-21 Water insoluble polypeptides
GB8722134 1987-09-21

Publications (1)

Publication Number Publication Date
CA1326438C true CA1326438C (en) 1994-01-25

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US (2) US5192741A (en)
JP (1) JPH0713023B2 (en)
AT (1) AT397035B (en)
AU (1) AU611944B2 (en)
BE (1) BE1001685A5 (en)
CA (1) CA1326438C (en)
CH (1) CH675968A5 (en)
DE (2) DE122004000023I2 (en)
DK (1) DK175311B1 (en)
ES (1) ES2009346A6 (en)
FI (1) FI96919C (en)
FR (1) FR2620621B1 (en)
GB (1) GB2209937B (en)
GR (1) GR1002244B (en)
IE (1) IE60608B1 (en)
IL (1) IL87790A (en)
IT (1) IT1225148B (en)
LU (1) LU87340A1 (en)
NL (1) NL193818C (en)
NO (2) NO178604C (en)
PT (1) PT88557B (en)
SE (1) SE503406C2 (en)
ZA (1) ZA886827B (en)

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