CA1247271A

CA1247271A - Biodegradable amphipathic copolymers

Info

Publication number: CA1247271A
Application number: CA000485079A
Authority: CA
Inventors: Jeffrey R. Churchill; Francis G. Hutchinson
Original assignee: Imperial Chemical Industries Ltd
Current assignee: Imperial Chemical Industries Ltd
Priority date: 1984-06-26
Filing date: 1985-06-25
Publication date: 1988-12-20
Also published as: JPH07106987B2; HU193994B; DK287885A; IE851396L; AU587977B2; GR851474B; FI81591C; NO167752B; IL75407A; HUT38261A; DE3582088D1; NO167752C; US4877606A; FI81591B; JPH0751517B2; YU106385A; JPS6115846A; NO852547L; IL75407A0; DK287885D0

Abstract

PH. 33162 ABSTRACT

TITLE: BIODEGRADABLE AMPHIPATHIC COPOLYMERS

A pharmaceutically or veterinarily acceptable amphipathic, non cross linked linear, branched or graft block copolymer, which has a minimum weight average molecular-weight of 1000, in which the hydrophobic component is biodegradable or hydrolytically unstable under normal physiological conditions, and the hydrophilic component may or may not be biodegradable or hydrolytically unstable under such conditions, and which copolymer is self-dispersible in water; together with mixtures of such a copolymer and a drug, which may be water-soluble or water-insoluble, which mixtures are self-dispersible in water; and processes for the manufacture of such copolymers and such mixtures.

Description

Z~l TITL~: BIODE~R~DABLE A~PEIIPA~IC COPO~ME~S.

This invention relates to biodegxadable amphipathic copolymers, and in particular it relates to such copolymers which are rapidly self-dispersible in watex to form stable dispersions.

Such copolymers are useful in the manufacture of continuous release formulations of drugs, and are particularly u~eful for the manufactuxe of such formulations in which the drug is sensitive to denatuxation or degradation by exposure to organic solvents, non-neutral pH or elevated temperature, for example many polypeptides drugs~ The copolymers of the present invention permit the manufacture of continuous release formulations of these drugs unde~ conditions which avoid non-neutral pH and elevated tempe~ature, and under conditions such that exposure to organic solvents is avoided, or reduced to minimal levels in solvent mixtures containing only a small proportion of organic solvent.

It is to be understood that in this specification the term "self-dispersible" as applied to a copolymer means a copolymer which, when:added to water disperses to form a stable dispersion, without the addition of any surfactant or other additive. In this context, a "stable" dispersion is one which does not significantly agglomerate or precipitate within the time normally rPquired to process the copolymer into a continuous release drug formulation, say 24 hours.

i~'7Z71 ~ oswell and Scribnar, ln United States Patent Number 3,773,919, and Yolles, in United States Patent Number 3,887,699, have described the use of biodegradable polymers, in particular polylactide and poly(lactide co-glycolide), in the manufacture o~
sustained release pharmaceutical formulations, and although their disclosures include some polypeptide drugs, we have found that the conditions of manuEacture, involving a tempexature o~ at least 130C., are sufficient to almost completely decompose many polypeptide drugs, so that satisfactory continuous release formulations are not obtainable using the technology of these United States patents.

Furthermore, Hutchinson in European Patent Specification Number 58481 disclosed that, even if processed differently, so as to avoid decomposition of the polypeptide drug, the copolymers described by Boswell and Scribner, and by Yo:Lles, could not be used to obtain satisfactory continuous release formulations of polypeptides. Rather, the release profile was biphasic and discontinuous, an initial release period resulting fxom surface leaching of the polypeptide being followed by a prolonged "dead phase", in which none or very little, was released, followed in turn by the major release of the polypeptide consequent upon the copolymer matrix absorbing wate~ and being biodegraded.

Hutchinson did, however, disclose that satisfactory continuous release formulations of some polypeptides could be made by using polylactide or poly (lactide co-glycolide~ of generally lower molecular weights than those disclosed by Boswell and Scribner, and Yolles, and at lower temperature, but the processiny still requi~ed the use of organic solvents, to which many polypeptides axe labile.

L2~7~Z7~

Chuxchill and Hutchineon in Eu~opea~ Patent SpeciEication Number 92918 ~ave disclosed t~e u~e of biodegxadable amphipathic copolymers, of the general types used in the present invention, in the manufacture of continuous ~elease oxmulations. Howevex, the copolymexs there desc~ibed are not self-dispe~sible in water to fo~m stable dispersion~, but require the usa o~
oxganic solvents, which, as indicated above, can be denaturing to polypeptides, in the subsequent p~ocessing into a continuous release fo~mulations.

It is an object of the p~esent invention to p~ovide a biodegradable amphipathic copolymex which is self-dispersible in wate~, and which can the~efore be used to manufacture continuous release formulations of dxugs without recourse to the use of high temperatures or non-neutral pH, and, for water-soluble drugs such as polypeptides, without exposure of the d~ug to the use of oxganic solvents du~ing manufacture. Such copolymers may be self-dispersible as initially synthesised, or copolymers which axe not inhe~ently self-dispersible may be rende~ed so by the pxocesses described he~ein.

The biodeg~adable amphipathic copolyme~s of this invention axe also useful for the manufacture of sustained continuous release injectable formulations oE
drugs which, in contrast with polypeptides, axe o~ low molecular weight and low water solubility. For such drugs, the copolymers of this invention act as very efficient dispersing agents, and can give colloidal suspensions which can be administexed by injection to give sustained continuous delivery of lipophilic drugs.

727~

In addition, the biocleg~adable amphipathic copolymers of this invention can be used to manu~actuxe drug formulations which are targetabLe to paxticulax organs in the human or animal body. It is known tha~
paxticles or microsphexes of diferent ~izes accumulate in diffexent organs of the body aftex int~avenou~
injection, depending upon the size of the particles injected. ( For a ~eview, see Tomlinson, "Mic~osphere Delivery Systems For Drug Targeting And Controlled Release" in Int. J~ Phaxm. Tech. and Prod. Mfr., 4,(3), p49-57, 1983). Fo~ example, particles of less than 50 nm can pass through t~e fenestrations of the liver endothelium and become localised, perhaps after lymphatic transport, in the spleen, bone marrow and possibly tumoux tissue. Intravenous, intra-artexial or intrapexi~oneal injection of paxticles of approximately 0.1 to 2.~ ~m. leads to a rapid clearance of particles from the blood stream by macrophages o the reticuloendothelial system, with eventual localisation of these in the lyosomes of the Kuppfer cells of the liver. Intravenous delivery of particles above 7-12 ~m.
lead~ to mechanical filt~ation by the lungs, while particles between 2 and 12 ~m. will become entxapped within the capillary netwoxks of not only the lung but also the liver and spleen. Intxa-arterial delivery of paxticles greater than 12 ,um. leads to their blockage of the first capillaxy bed encountered. The copolymers of this invention can be used to manufacture dispersions of controlled particle size, w~ich can be oxgan-taxgeted in the manner described above.

Scheme 1 illustrates diagxammatically the processes involved in this invention.

-5- ~ Z7~

8cheme 1 Monomer A Monomer B
___ I
Copol~mer (not sel~-dispersible) Freeze driable ¦
organic solvent ~ ~' Copolymer soLution Exces5 water ~

Copolymer dispersion k~_FFee~,~

Copolymer (self-dispersible) ~ ~Drug Excess water ~(water insoluble) Copolymer dispersion ~O~ganic solvent Drug Druy (wate~ soluble) \Copolymer/d~ug solution . ~ Water ~ ~
\ \¦ Excess water Water optionally with organic solvent Copolymer/d~ug dispersion Freeze dry Copolymer/drug powder (self-dispersible) Heat/pressure 1 Dosage Form 7 ~ 7 ~

T~us, according to the invention, the~e i~
prov.ided a phaxmaceutically or ve~exinarily acceptable amphipathic, non-cross~linked linear, branched or graft block copolymer, which has a minimum weight average molecular weight of lO00, in which the hydrophobic component is biodegradable or hydrolytically unstable under normal physiological conditions, and the hydrophilic component may ox may not be biodegradable or hydrolytically unstable under such conditions, characterised in that it is self-dispersible in watex to form a stable dispersion.

According to a further feature of the invention, thexe is provided a process for the manufacture of a self-dispersible copolymer as defined above, which comprises freeze-drying a frozen stable aqueous dispersion of a p~armaceutically o~ veterinarily acceptable amphipathic, non-cross-linked linear, branched or graft block copolymer, which has a minimum weight average molecular weight of 1000, in which the hydrophobic component i5 biodegxadable o~ hydxolytically unstable under such conditions, and the hydrophilic component may or may not be biodegradable or hydxolytically unstable under suc~ condition~.

When an "aqueous dispersion" is referred to herein, it is to be understood as compxising a dispersion in water alone, or in water containing a small proportion, for example up to 10%, of a watex-miscible o~ganic solvent.

The copolymers which may be used as the staxting materials in the above process are those described in Euxopean Patent Specification No. 92918, refexred to above.

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The frozen, stable aqueous dispe~sion used a~
the starting material Eor the above process may be obtained by dissolving the copolymer described immediately above, in it non-self-dispersible form, as initially synthesised, in a minimum amount of a water-miscible solvent, which either ha~ a low boiling point, ~ay below 100C., ~or example methanol o~
ethanol, or is freeze- driable, for example dioxan or acetic acid, vigorously agitating said solution while an exce~ of water i9 added slowly, to form an extremely fine, stable aqueous dispersion, and then freezing said dispersion.
According to a further fea uxe of the invention, there is provided a solid, copolymer/drug powder material compxising up to 99% by weight of a drug, the remainder being a pharmaceutically o~
veterinarily acceptable amphipathic, non-cross-linked linea~, branched or graft block copolymer as de~ined above, charactexised in that sai.d solid, powde~ material i~ self-dispersible in water to form a stable dispersion.
.

Accoxding to a fuxther ~eatu~e of the invention, there is provided a process fox the manufacture of a solid, copolymex/dru~ powder material, as defined immediately above, which comprises fxeeze-drying a frozen, stable aqueous dispersion of the copolymex and the drug.

The frozen, stable a~ueous dispersion used as the starting material for the above process may be obtained, w~en the drug is water-soluble, for example a polypeptide, by dispersing a self-dispersible copolymer, as defined above, in water, buffering the dispersion to ~'7~

physiological or neutral pH, mixing the bu~fe~ed dispersion with an aqueous ~olution of the water-soluble drug, and freezing the resulting copolymer/
drug dispersion.

Particular water-soluble polypeptides which may be uqed in this invention are, or example, oxytocin, vasop~esqin, adrenocorticotxophic hormone (ACTH), epidermal growth factor (EGF), transfoxming gxowth factor antagonists, prolactin, luliberin or luteinizing hormone releasing hoxmone (LH-RH), L~-RH
agonists or antagoniqts, growth hormone, growth hormone releasing factor, insulin, somatostatin, bombesin antagonists, glucagon, interfexon, gastrin, tetragastrin, pentagast~in, urogastrone, secxetin, calcitonin, enkephalins, endo~phins, angiotensins, renin, bradykinin, bacitracins, polymyzins, colistins, tyrocidin, gramicidines, and synthetic analogues and modifications and p~armaceutically-active fragments thereof, monoclonal antibodies and soluble vaccines.

When the drug is watex-insoluble, the frozen, stable aqueous dispersion used in the above pxocess may be obtained by dissolving the drug and the self-dispersible copolymer in a minimum amount of a wa er-miscible organic solvent, for example dioxan, acetic acid, acetonitrile, methanol or ethanol, slowly adding an excess of water to the vigorously agitated solution to produce a fine, stable dispersion, a~d then f~eezing the dispersion.

Any drug of low watex-solubility is appropriate for use in this aspect of the invention.

Alternatively, one o~ the ~reeze-dxying processes may be avoided by taking the copolymer in its non-self-dispe~sible form, di~solving it in a watex-miscible organic solvent, precipitating it as a fine dispersion by slow addition o an axcess of wate~ with vigorous agitation, adding a solution of a drug, either in water, if the drug i9 water-soluble, or in a water miscible o~ganic solvent or in a mixture the~eo~ with wate~ if the drug is water-insoluble, to the copolymer dispersion, and then freezing and fxeeze-drying the total mixture.

Cextain pharmaceutically or veterinarily acceptable amphipathic, non-cross-linked linea~,~
branched or gxaft block copolymers, which have a minimum weight avexage molecular weight of 1000, in which the hydrophobic component is biodegradable or hydrolytically unstable under normal physiological conditions, and in which the hydxophilic component may or may not be biodegradable or hydrolytically unstable under such conditions, are self-dispexsible in watex as synthesised. These are copolymers which contain a large proportion, that is, more than 50%j of hydrophile relative to hydrophobe, or copolymers in which the hydrophobe is of low molecular weight, for example ~ o~
less than S000.

Additionally, the stxucture of the copolymer, and the nature of the individual hydrophilic and hydrophobic polymers therein, control the degree of self-dispersibility in water of the copolymer obtained therefrom. Thus, for example, polylactide-graft-polyvinylpyrrolidone (PVP~ is self-dispersing when it contains 50~ or more of PVP, even though the polylactide may be of ~elatively high molecular weight, fox example 7'~

Mw o greatex than 30,000, and polylactide/polyeth~lene glycol 1900 (equal weights) is self-dispe~sible.
However, polylactide/polyethylene glycol 5000 (equal weights~ is sel~dispe~sible with difficulty, and above this molecular weight the copolymers are not immediately self-dispersible in water, but ~equire initially ~he addition of a small propo~tion o~ an organic solvent, which can subsequentLy be removed by evapo~ation or free2e-dxying.

A-~ indicated above, the materials of this invention are useful in the manufacture of sustained continuous release formulations of drugs. As has been described above, a mixture o a copolymer of the invention with a d~ug can be manufactured under such conditions that the drug is not exposed to high temperatuxe, to non-neutral pH, to high concentrations of oxganic solvent, or to organic solvent at elevated tempexatuxe, and such copolymer-dxug mixtures can be proce~sed into suitable pharmaceutical or veterinary formulations by conventional procedur'es, for example by compression moulding at low temperatures (many can be conveniently compression moulded at about 60C., well below the decomposition tempexatuxe o~ most dxu~ , including polypeptide drugs which are among those which are most susceptible to decomposition at elevated temperatures), to form implantable depot formulations as described, for example, by Hutchinson (European Patent Specification ~umber 58481) and by Chuxchill and Hutchinson (European Patent Specification Number 92918), which give a sustained continuous release of the drug. Alternatively, or water-insoluble drugs, the copolymer-drug mixture can be simply dispersed into sterile water to give a fine aqueous dispersion which can be used as an injectable, sustained 7~h7~1 continuous ~elease formula~ion, or, iE the pa~ticle ~ize is suitably controlled, a oxmulation which i5 ta~geted to a particular oxgan, as described above.

The paxticle size of such an aqueous dispe~sion can be cont~olled within faixly close limits by controlling the particle size of the copolymex used.
Thi~ is achieved during the manuacture of the self-dispexsible form of the copolymer used, and i9 achieved by suitable adjustment of the ~ate of addition of water to the solution of copolymer in the f~eeze-driable, water-miscible solvent, and contxol of the ~ate of agitation during this process. The particle size of the dispersion so obtained may be measu~ed in conventional manner, for example by optical microscopy, Coultex counter ox nanosizer.

Useful co-excipients in the manufacture of sustained, continuous ~elease formulations of polypeptides using the above-descxibed copolyme~/drug mixtuxe~, are low or high molecular weight, water soluble polymers which are compatible, or paxtially compatible therewith, such as gelatin, polyvinyl-pyrrolidone, dextran, polyethylene glycols, sodium alginate and water oluble, synthetic, non-therapeutic polypeptides. Such co-excipients provide addi~ional hydrophilic ~egions, or pores, in the polymer matxix, and also stabilise the tertiary stxucture of the polypeptide by chain entanglement, which is achievable by virtue of their being compatible ox paxtially compatible with the polypeptide.

~'72'7~

Exam ~
_._ Two grammes of an AB type biodegradable copolymer comprising 25% by weight of a methoxypoly-ethylene glycol oE molecular weight 5900 (component A) and 75% by weight of poly(D,L-lactide) (component B) wexe dissolved in glacial acetic acid (2 ml.), a,nd ~he solution was stirred vigorously w~ile distilled water (21 ml.) was added slowly, to pxoduce an extremely fine dispersion. The dispersion was frozen, and frqeze dried at 0.01 mm. of mercury (13.3 Pa) or 24 houxs, to give a d~y powder copolymer.

On addition of the dry powdex to watex, with stix~ing, it redispersed to form a very ~ine dispersion.

~xample 2 The dry powdex copolymex of Example 1 (0.5 g.) was dispe~sed with vigorous stirring into distilled water (5 ml.) containing sodium azide (0.01%), and the dispersion was buffered to pH8 with O.lN sodium hyd~oxide. Bovine se~um albumin (BSA) (0.125 ~.) was dissolved in distilled water (1.0 ml.) and 14C-methylated BSA (10 ul. of a 5 uCi per ml. solution in O.OlM sodium phosphate buffer~ was added, the BSA
solution was added to the copolymer dispersion, and the 25 mixture was frozen, then f~eeze dried at 0.01 mm. of mercury (13.3 Pa) for 24 hours.

The f~eeze dried product was moulded at 60-70 to give slabs 1 cm. square and of thickness 0.2 cm., 0.09 cm. and 0.04 c~n. The diffe~ent slabs were each separately immersed in 2 ml. of phosphate buffered '7'27~

saline (pH 7.4) containing 0.02% sodium azide, at 37C.
At intervals, the medium was xemoved and replaced with fresh buffer, and the radioactivi-ty xeleased into the removed medium was assayed.

I Time I Cumulative % BSA relea~ed .

1 10-2 cm. slab.l 0.09 cm. slab¦ 0.04 cm. slab ¦

1 1 houx ¦ 10.8 ¦ 23.8 ¦ 46.6 1 4 hours ¦ 23.4 1 48.5 ¦ 77.3 ¦ 24 hours ¦ 64.4 ¦ 86.5 1 86.7 ¦ 3 days 1 86.4 ¦ 92.2 1 88.8 1 12 days 1 90.1 1 92.3 1 90.9 I I _ I I .

E~ample 3

2.5 Grammes of a poly (D,L-lactide-co-glycolide)-graft(polyvinylpyrrolidone) copolymer, containing 50~ by weight of poly (D,L-lactide-co-glycolide) compri~ing equimolar proportions of lactide and glycolide, and 50% by weight of polyvinyl-py~rolidone, were dissolved in glacial acetic acid (5 ml.) and stir~ed vigorously while distilled watex (20 ml.) was added slowly, to produce a very fine dispersion, which was then frozen and freezs dried at 0.1 mm. of mercury (1~.3 Pa) for 24 ~ours, to give a dry powder copolymer.

, -14~ 71 On addition o~ the d~y powde~ copolyme~ to water, with stixring, it radisper~ed almos~ immediately to ~orm a very fine dispe~sion.

~am~le 4 2.0 Grammes of an ABA type biodegradable block copolymer comprising 80% by weight of poly(D,L-lactide) (component A) and 20~ by weight of polyethylene gylcol of molecular weight 2000 (component B) was added to absolute ethanol (3 ml.) and stirred vigorously while water (1.5 ml.) was added slowly to pxoduce an extremely fine dispersion. A further 15 ml. of water was added, with vigorous agitation, to ~ive a dilute dispersion of the copolymer, which was then buffered to pH8 by addition of O.lN sodium hydroxide.

Bovine serum albumin (BSA~ (0.5 g.) was dissolved in water (5 ml.) and 14C-methylated BSA
(70 ul. of a SuCi/ml. solution in O.OlM sodium p~osphate) was added. The BSA solution was then mixed with the copolyme~ disper~ion, f~ozen, and freeze dxied at 0.01 mm. of mexcury (13.3 Pa) fo~ 30 hours.

The free~-e-dried powdex was moulded at 60C.
to give slabs 1 cm. square and of thickness 0.36 cm., 0.16 cm. and 0.06 cm. The diffexent slabs were each separately immersed in 2 ml. of phosphate buf~exed saline, pH 7.4, at 37C. At intervals, the medium was removed and replaced with fresh buffer, and the radioactivity ~eleased into the removed medium was assayed.

-15~ 27~

Time Cumulative ~ BSA released . 0.36 cm. ~labØ16 cm. slab 0 _ 1 h~u~ _ _ ~ 23. a 4 houxs 17.0 28.0 58.4 24 hours 40.3 58.2 87.2 4 days 65.8 82.0 96.0 1I d-y- 82.1 96.0 100 ~sample 5 Purified methoxypolyethylene glycol of molecular weight 1900, rigorously dried at 160C. for 1 hour at 0.1 mm. of mercuxy (13.3 Pa) (10 g.) and reshly pxepaxed, ~igorously dried D,L-lactide (10 g.) were stirred under nitrogen at 160C., stannous octoate (stannous 2-ethylhexanoate) (50 ul.) was added, and the mixture was kept at 160C. fox 3 hours, to give a straw-coloured, slightly vi~cous liquid which solidified on cooling. The solid product (0.5 g.) was added to distilled wate~ (5 ml.) and stirred at 37C. for 18 houxs, after which time it has formed an extxemely fine dispersion or colloidal suspension, which appeared entirely clear, except for a very faint blue haze when held to the light.

In contrast, a simple mixture of the ~ame methoxypolyethyleneglycol (0.25 g.) and poly(D,L-lactic acid) (0.25 g.) in distilled watex (S ml.) did not give a dispersion afte~ stirring at 37C for a similar pexiod, but the polyester remained as a semi-solid, non-dispersed p~ase.

Example 6 An AB block copolymer of poly(d,l-lactide) and methoxy-polyethylene glycol containing 50% (wt) polyester and 50~ 9 (wt) of polyethe~ was prepared by the ring opening polymerisation of d,l-lactide in the presence of methoxypolyethylene glycol 5000 at 160C.
using an organotin catalyst.

lOOmg. of the block copolymer and lOmg. of an antioestrogen, ICI 189150, which has very low aqueous solubility, wexe dis~olved in 0.4ml. of glacial acetic acid, and 2ml. of watex were added slowly with vigorous agitation to give a colloidal suspension of dxug/polymer in the acetic acid/watex mixture. The mixtuxe was fxozen and fxeeze dried at O.Olmm.Hg. (13.3 Pa) for 24h~., to give a solid freeze dried product.

On addition of 0.9% sodium chloride solution in water the freeze dxied product redispersed to give a stable dispersion suitable for injection.

Claims

What we claim is:-

1. A pharmaceutically ox veterinaily acceptable amphipathic, non-cross-linked linear, branched or graft block copolymer, which has a minimum weight average molecular weight of 1000, in which the hydrophobic component is biodegradable or hydrolytically unstable under normal physiological conditions, and the hydrophilic component may or may not be biodegradable or hydrolytically unstable under such conditions, characterised in that it is self-dispersible in water to form a stable dispersion.

2. A copolymer as claimed in claim 1 which either has a large proportion of hydrophile to hydrophobe or has a hydrophobe weight average molecular weight of less than 5000.

3. A process for the manufacture of a self dispersible copolymer as defined in claim 1, which comprises freeze-drying a frozen stable aqueous dispersion of a pharmaceutically or veterinarily acceptable amphipathic, non-cross-linked linear, branched or graft block copolymer, which has a minimum weight average molecular weight of 1000, in which the hydrophobic component is biodegradable or hydrolytically unstable under such conditions, and the hydrophilic component may or may not be biodegradable or hydrolytically unstable under such conditions.

4. A process for the manufacture of a frozen aqueous dispersion of a pharmaceutically or veterinarily acceptable amphipathic, non-cross-linked linear, branched or graft block copolymer, which has a minimum weight average moleculare weight of 1000, in which the hydrophobic component is biodegradable of hydrolytically unstable and the hydrophobic component may of may not be biodegradable or hydrolytically unstable, which comprises dissolving such a copolymer in the non-self-dispersible form in a water-miscible solvent which either has a low boiling point or is freeze-driable, vigorously agitating said solution while an excess of water is added, and freezing the resulting dispersion.

5. A solid, copolymer/drug powder material comprising up to 99% by weight of a drug, the remainder being a pharmaceutically or veterinarily acceptable amphipathic, non-cross-linked linear, branched or graft block copolymer as claimed in claim 1 characterised in that said solid, powder material is self-dispersible in water to form a stable dispersion.

6. A copolymer/drug powder material as claimed in claim 5 wherein the drug is water-soluble and is selected from oxytocin, vasopressin, adrenocortico-trophic hormone (ACTH), epidermal growth factor (EGF), transforming growth factor antagonists, prolactin, luliberin or luteinizing hormone releasing hormone (LH-RH), LH-RH agonists or antagonists, growth hormone, growth hormone releasing factor, insulin, somatostatin, bombesin antagonists, glucagon, interferon, gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin, enkephalins, endorphins, angiotensins, renin, bradykinin, bacitracins, polymyxins, colistins, tyrocidin, gramicidines and synthetic analogues and modifications and pharmaceutically-active fragments thereof, monoclonal antibodies and soluble vaccines.

7. A process for the manufacture of a solid, copolymer/drug powder material as claimed in claim 5, characterised by freeze-drying a frozen, stable aqueous dispersion of the copolymer and the drug.

8. A process for the manufacture of a frozen, stable aqueous dispersion of a copolymer and a water-soluble drug, as defined in claim 7, characterised by dispersing a self-dispersible copolymer, as claimed in claim 1, in water, buffering the dispersion to physiological or neutral pH, mixing the buffered dispersion with an aqueous solution of the water-soluble drug, and freezing the resulting copolymer/drug dispersion.

9. A process for the manufacture of a frozen, stable aqueous dispersion of a copolymer and a water-insoluble drug, as defined in claim 7, characterised by dissolving the drug and the self-dispersible copolymer in a minimum amount of a water-miscible organic solvent, slowly adding an excess of water to the vigorously agitated solution of produce a fine, stable dispersion, and then freezing the dispersion.

10. A process for the manufacture of a frozen, stable aqueous dispersion of a copolymer and a drug, as defined in claim 7, characterised by dissolving the copolymer, in its non-self-dispersible form, in a water-miscible, organic solvent, slowly adding an excess of water to the vigorously agitated solution, adding a solution of the drug, either in water if the drug is water-soluble, or in a water-miscible solvent or in a mixture thereof with water if the drug is water-insoluble, to the copolymer dispersion, and then freezing the copolymer/drug dispersion so obtained.