MXPA97009674A - Molecular ionic conjugates of n-acilated derivatives of poly (2-amino-2-desoxi-d-glucose) and polipepti - Google Patents
Molecular ionic conjugates of n-acilated derivatives of poly (2-amino-2-desoxi-d-glucose) and polipeptiInfo
- Publication number
- MXPA97009674A MXPA97009674A MXPA/A/1997/009674A MX9709674A MXPA97009674A MX PA97009674 A MXPA97009674 A MX PA97009674A MX 9709674 A MX9709674 A MX 9709674A MX PA97009674 A MXPA97009674 A MX PA97009674A
- Authority
- MX
- Mexico
- Prior art keywords
- acyl group
- group
- percent
- polypeptide
- copolymer
- Prior art date
Links
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- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 45
- 150000001412 amines Chemical class 0.000 claims abstract description 37
- 229920001184 polypeptide Polymers 0.000 claims abstract description 34
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 34
- 239000000203 mixture Substances 0.000 claims abstract description 33
- 229920001577 copolymer Polymers 0.000 claims abstract description 27
- 125000002252 acyl group Chemical group 0.000 claims description 63
- 239000003795 chemical substances by application Substances 0.000 claims description 37
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- 239000005017 polysaccharide Substances 0.000 claims description 22
- 238000005917 acylation reaction Methods 0.000 claims description 20
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- 238000000034 method Methods 0.000 claims description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- FZHXIRIBWMQPQF-UHFFFAOYSA-N Glc-NH2 Natural products O=CC(N)C(O)C(O)C(O)CO FZHXIRIBWMQPQF-UHFFFAOYSA-N 0.000 claims description 10
- FZHXIRIBWMQPQF-SLPGGIOYSA-N aldehydo-D-glucosamine Chemical compound O=C[C@H](N)[C@@H](O)[C@H](O)[C@H](O)CO FZHXIRIBWMQPQF-SLPGGIOYSA-N 0.000 claims description 10
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- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical group ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
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Abstract
The present invention relates to a copolymer comprising an N-acylated derivative and a composition comprising said copolymer and a polypeptide, the polypeptide comprising at least one effective ionogenic amine, wherein at least 50 weight percent of the polypeptide present in the composition is attached to the polyme
Description
IONIC MOLECULAR CONJUGATES OF N-ACILATED DERIVATIVES OF POLK2-AMINO-2-DE80XI-D-GLUCOSE > AND POLYPEPTIDOB
BACKGROUND OF THE INVENTION [0002] Polymeric drug delivery systems have been developed for the controlled release of pharmaceutical polypeptides. For example, synthetic polyesters such as poly (DL-lactic acid), poly (glycolic acid), poly (lactic-glycolic acid) and poly (e-caprolactone) have been used in the form of microcapsules, films or canes to release biologically active polypeptides. See, for example, U.S. Patent Nos. 4,767,628 and 4,675,189 and PCT Application No. WO 94/00148. In addition to the synthetic polymer chains, the natural polymers and their derivatives have been used as components in similar prolonged release compositions that dissociate by enzymatic degradation. An example of these natural polymers are those based on chitin, a poly (N-acetylglucosamine). However, because chitin is insoluble in water, others have examined solubilizable derivatives that are based primarily on a partially deacetylated chitin, for example, chitosan. See for example. Sanford, P.A. et al., Eds., Advances in Chitin & Chitosan (1992). Although
Chitosan can be found in certain fungi, the production of biodegradable chitosan is usually done in synthetic form. See Mima, et. al., J. Appl. Polym. Sci. 28: 1909-1917 (1983). The synthetic derivatives of chitosan have also been prepared to alter the in vivo biological characteristics of the polymer. See Muzzarelli, et al., Carbohydrate Res. 207: 199-214 (1980). The use of chitin, as well as derivatives of chitin, has been proposed in several drug delivery systems. See, for example. European Patent Applications Nos. 486,959; 482,649; 525,813 Al and 544,000 Al; and, the Patent of the United States of America No. 5,271,945.
SUMMARY OF THE INVENTION In one aspect, the present invention features a copolymer that includes an N-acylated derivative of poly (2-amino-2-deoxy-D-glucose), wherein, between 1 and 50 percent of the amines free of poly (2-amino-2-deoxy-D-glucose) are acylated with a first acyl group, the first acyl group is COE ^ wherein E ^ is selected from the group consisting of C3-33 carboxyalkyl, carboxyalkenyl C3 -33, C7_3g carboxyarylalkyl and carboxyarylalkenylCg_3g and, between 50 and 99 percent of the poly (2-) amines
amino-2-deoxy-D-glucose) are acylated with a second acyl group, the second acyl group is COE2 wherein E2 is selected from the group consisting of C C_30 alkyl, C2-3 alkenyl. C6_37 arylalkyl and C8_37 arylalkenyl, assuming that at least one of the pounds amines of the derivative is acylated with the first acyl group and up to 30 percent of the free hydroxy groups of the poly (2-amino-2-deoxy-D) -glucose) are acylated with the first acyl group or with the second acyl group. The copolymer preferably has a molecular weight of about 3,000 to 90,000 daltons as determined by gel permeation chromatography or any analogous method. In other preferred embodiments, more than 90 percent of the free amines of the poly (2-amino-2-deoxy-D-glucose) are acylated with either the first acyl group or the second acyl group. Preferably, between 10 and 30 percent of the free amine of the poly (2-amino-2-deoxy-D-glucose) are acylated with the first acyl group. Some of the free hydroxy groups (eg, between 1 and 30 percent) of the derivative can be acylated with either the first acyl group or the second acyl group. In a preferred embodiment, the copolymer has the formula:
wherein: R? _, for each repeating unit or individual repeating unit, is selected from the group consisting of the first acyl group, second acyl group and H; R2, for each individual repeating unit, is selected from the group consisting of the first acyl group, second acyl group and H; R3, for each individual repeating unit, is selected from the group consisting of the first acyl group, second acyl group and H; R is selected from the group consisting of the first acyl group, second acyl group and H; R5 is selected from the group consisting of the first acyl group, second acyl group and H; Rg is selected from the group consisting of the first acyl group, second acyl group and H; R7 is selected from the group consisting of COH and CH2OR8;
R8 is selected from the group consisting of the first acyl group, second acyl group and H; n is between 2 and 200; and for between 1 and 50 percent of the repeating units, Rx is the first acyl group and, for between 50 and 99 percent of the repeating units, R ^ is the second acyl group, as long as it stops at least one of the repeating units, R ^ is the first acyl group. The terms COE ^ and COE2, mean -C = 0-E? Y
C = 0-E2, respectively. The carboxyalkyl, carboxyalkenyl, carboxarylalkyl and carboxarylalkenyl substituents may contain from 1 to 4 carboxylic acid functions. Examples of the first acyl group include, but are not limited to, succinyl, 2- (C 1-30 alkyl) succinyl, 2- (C2_3 alkenyl) succinyl, maleyl, phthalyl, glutaryl, and itaconyl. Examples of the second acyl group include but are not limited to, acetyl, benzoyl, propionyl and phenylacetyl. The present invention also features a composition that includes the above copolymer and a polypeptide, the polypeptide comprising at least one effective ionogenic amine, wherein at least 50 weight percent of the polypeptide present in the composition is ionically bound to the polymer. Preferably, the
The composition comprises between 5 and 50 weight percent of the polypeptide. Examples of suitable polypeptides include 1-growth-hormone-releasing peptide (GHRP), luteinizing hormone-releasing hormone (LHRH), somatostatin, bombesin, gastrin-releasing peptide (GRP), calcitonin, bradykinin, galanin, hormone-stimulating hormone. melanocytes (MSH), growth hormone releasing factor (GRF), growth hormone (GH), amylin, tachykinins, secretin, parathyroid hormone (PTH), encaphelin, endothelin, calcitonin gene-releasing peptide (CGRP), neuromedins, parathyroid hormone-related protein (PTHrP), glucagon, neurotensin, adrenocorticotrophic hormone (ACTH), peptide YY (PYY), glucagon-releasing peptide (GLP), vasoactive intestinal peptide (VIP), adenylate cyclase activator peptide the pituitary (PACAP), motilin, substance P, neuropeptide Y (NPY), TSH and biologically active analogs thereof. The term "biologically active analogues" is used herein to cover natural, recombinant and synthetic peptides, polypeptides and proteins having physiological or therapeutic activity. In general, the term covers all fragments and derivatives of a peptide, a protein or a polypeptide that exhibit an agonist effect
or antagonist qualitatively similar to that of the unmodified or natural peptide, protein or polypeptide, for example, those in which one or more of the amino acid residues that occur in the natural compounds are substituted or deleted or, in which terminal residues N- or C- have been structurally modified. The term "effective ionogenic amine" refers to a free amine present in the polypeptide, which is capable of forming an ionic bond with the free carboxylic groups of the copolymer. Release of the polypeptide from the composition can be modified by changing the chemical structure of the composition. Increasing the molecular weight of the polymer will decrease the rate of the peptide released from the conjugate. Increasing the number of carboxylic acid groups in the polymer will increase the amount of polypeptide ionically bound to the composition and, consequently, increase the amount of peptide release from the conjugate. The release of the polypeptide can be further modulated by means of the steps of: (a) treating the composition with soluble salts of divalent ions or polyvalent metal ions of weak acids (eg, calcium, iron, magnesium or zinc); (b) coating the particles with a thin absorbable layer made of a
glycolide copolymer or a silicone oil in a spherical, cylindrical or flat configuration; or (c) microencapsulating the composition in an absorbable glycolide copolymer. In one embodiment, the composition comprises between 0.01 and 20 weight percent of a polyvalent metal. Depending on the choice of polypeptide, the compositions can be used to treat various types of disorders. For example, somatostatin, bombesin, GRP, LHRH and analogs thereof have been shown to treat various forms of cancer. It has been shown that growth factors such as GH, GRF and GHRP and their analogues stimulate growth in both adolescents and the elderly. Calcitonin, amylin, PTH and PTHrP and their analogues have been shown to treat osteoporosis and other bone disorders. The compositions are designed for parenteral administration, for example, intramuscular, subcutaneous, intradural or intraperitoneal injection. Preferably, the compositions are administered intramuscularly. The compositions of the invention may be in powder form or as a microparticulate which will be administered as a suspension with a vehicle
pharmaceutically acceptable (eg, water with or without a carrier substance, such as for example mannitol or polysorbate). The compositions may also be composed in the form of a stick for parenteral implantation using a trocar, for example, intramuscular implantation. The dose of the composition of the present invention for the treatment of the aforementioned diseases or disorders varies depending on the form of administration, the age and body weight of the person and the condition of the person to be treated. and, finally, it will be decided by the attending physician or veterinarian. This amount of the composition as determined by the treating physician or veterinarian will be referred to herein as a "therapeutically effective amount". In another aspect, the present invention presents a process for synthesizing a copolymer, the process comprising the steps of: reacting the chitosan with a weak acid to produce a polysaccharide of lower molecular weight; reacting between 1 and 50 percent of the free amines of the lower molecular weight polysaccharide with a first acylating agent, the first acylating agent is selected from the group consisting of polycarboxyalkane C4-C34, polycarboxyalkene
c4 ~ c34 'polycarboxylarylkane Cg-C or, polycarboxyarylalkylene C? -C40 ° an acylated derivative thereof; and, reacting between 50 and 100 percent of the free amine of the lower molecular weight polysaccharide with a second acylating agent, the second acylating agent is selected from the group consisting of monocarboxyalkane c _3i, monocarboxyalkene 3-3. C7-33 monocarboxyrylalancane, C9-35 monocarboxyrylalkylene or an acylation derivative thereof. The reaction of the lower molecular weight polysaccharide with both the first acylating agent and the second acylating agent can be measured with an amine detection agent (e.g., fluorescamine) to ensure that between 1 and 50 percent of the the free amines of the lower molecular weight polysaccharide are acylated with the first acylating agent and between 50 and 99 percent of the free amines of the lower molecular weight polysaccharide are acylated with the second acylating agent. See, e.g., Bailey, P.D., An Introduction to Peptide Chemistry (Wiley, NY) (1990); Oppenheimer, H, et al. Archives Biochem. Biophys. 120: 108-118 (1967); Stein, S, Arch. Biochem. Biophys. 155: 203-212 (1973). Reacting the chitosan with the weak acid (eg, nitrous acid) cleaves the polymer, thereby reducing its molecular weight (e.g.,
2,500 - 80,000 daltons). In the preferred embodiments, the first acylation group and the second acylation group are reacted successively with the lower molecular weight polysaccharide, for example, either the first acylating agent is reacted before the second acylating agent is reacted. react or the second acylating agent is reacted before the first acylating agent or, simultaneously. As a result of the acylation of the free amines, some of the free hydroxy groups of the lower molecular weight polysaccharide can be acylated. The degree or extent of the acylation of the free hydroxy groups can be altered by changing the pH or the solvents or agents used during the acylation reactions or, the acylation agents used. Examples of acylation derivatives include, without limitation, N-acylated anhydrides and heterocycles (e.g., imidazoles and pyrazoles). See, for example. Bodans et al., The Practice of Peptide Synthesis, 87-150 (Springer-Verlag, 1984). The polycarboxyalkane, polycarboxyalkene, polycarboxyrylalkane and polycarboxyrylkene agents or the acylation derivatives thereof contain or originate from reagents containing from 2 to 5 carboxylic acid functions. Substituents monocarboxyalkane, monocarboxyalkene,
monocarboxyrylalancane and monocarboxyrylalkene contain or originate from reagents containing only a single carboxylic acid group. Examples of the first acylating agent include, without limitation, succinic anhydride, 2- (C1_30 alkyl) succinic anhydride, 2- (C2_3 Q) alkenyl succinic anhydride, maleic anhydride, glutaric anhydride, itaconic anhydride and phthalic anhydride. Examples of second acylating agents include, but are not limited to, acetic anhydride, benzoic anhydride, N, N'-diacetyl-3,5-dimethylpyrazole, N, N'-diacetyl imidazole, phenylacetic anhydride, propionic anhydride and butyric anhydride. In another aspect, the invention features a process for synthesizing a composition, the process comprising the steps of: reacting the chitosan with a weak acid to produce a lower molecular weight polysaccharide; reacting between 1 and 50 percent of the free amines of the lower molecular weight polysaccharide with a first acylating agent, the first acylating agent is selected from the group consisting of polycarboxyalkane C4-C34, polycarboxyalkene C4-C34, polycarboxiarylalkano C3- C 0, polycarboxyarylalkene C ^ o-C40 or, an acylation derivative thereof; reacting between 50 and 100 percent of the free amine of the lower molecular weight polysaccharide with a
second acylating agent, the second acylating agent is selected from the group consisting of monocarboxyalkane c2-31-itionocarboxyalkene C3-31, monocarboxyrylalancane C7_38, monocarboxyrylalkylene C9- 35 or an acylation derivative thereof; neutralizing the lower molecular weight polysaccharide acylated with a base; and, mixing the acylated and neutralized lower molecular weight polysaccharide with a polypeptide salt, wherein the polypeptide salt comprises at least one ionogenic amine to form a polypeptide-copolymer ion conjugate. The step of neutralization preferably produces lower molecular weight emulsifiable or water soluble polysaccharide. In preferred embodiments, the base is an inorganic base (e.g., sodium hydroxide). The polypeptide salt is preferably a weak acid salt (eg, acetate, lactate or citrate). The ionic conjugate can be isolated by filtration or by centrifuging the resulting mixture. The conjugates of the invention can easily be converted into injectable microparticles or microparticles and onto implantable films or sticks, without the need for processing involving multi-phase emulsions. Preferably, the microparticles are manufactured by (a) dissolving the composition in an aprotic organic solvent miscible with water; (b) mixing
organic solvent in water; and, (c) isolating the microparticles from the water. In preferred embodiments, the organic solvent is selected from the group of acetone, acetonitrile, tetrahydrofuran, dimethylformamide and dimethylethylene glycol. Other features and advantages of the present invention will be apparent from the detailed description and claims.
DETAILED DESCRIPTION OF THE INVENTION The synthesis and use of the copolymer and the copolymer-polypeptide ion conjugates of this invention are well within the skill of one of ordinary skill in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Also, all publications, patent applications, patents and other references mentioned herein, are incorporated by reference. It is believed that one skilled in the art can, based on the present disclosure, utilize the present invention to its fullest extent. The following specific modalities will therefore be
interpreted as merely illustrative and not limitative of the rest of the exhibition in any way.
Example 1; Depolymerization of Ouitoaana Chitosan (Protan, Inc., Portsmouth, NH) was dissolved in aqueous acetic acid by shaking with a mechanical stirrer for one day. Nitrogen gas was bubbled through the solution, while an aqueous solution of sodium nitrite was added. After half an hour, the solution was filtered through a sintered glass funnel, under reduced pressure, to remove the insoluble particles that are present in the initial chitosan solution. To the filtered solution was added an aqueous solution of NaOH, and the solution was stirred vigorously in methanol to precipitate the polymer. The resulting precipitate was then filtered and, alternatively washed five times with water and methanol. The precipitate was then dried in a vacuum oven at 60 ° C for two days. The depolymerized chitosan comprises an aldehyde group at one end of the chain. The terminal or aldehyde end group can be reduced to a primary hydroxyl group by reaction with NaBH 4. The despolyzed product can be analyzed by gel permeation chromatography (GPC) to determine both its molecular weight and its weight distribution
molecular (MWD), compared to the norms or reference standards of Pullulan. NRM (nuclear magnetic resonance) and IR (infrared) studies can be used to determine the amount of N-acylation of the depolymerized product.
Example 2: Partial Succinylation of De-polymerized Ouitosan. The depolymerized chitosan of Example 1 was dissolved in aqueous 0.1M acetic acid. To this solution was added methanol, followed by the addition of a solution of succinic anhydride in acetone. The resulting solution was stirred at room temperature for 24 hours. With the completion of succinylation, the solution was then precipitated in aqueous acetone. The resulting precipitate was collected by centrifugation and washed five times with methanol. The precipitate was then dissolved in 0.5M of
KOH and dialyzed against water at a pH of 7. The dialyzed solution was then concentrated under reduced pressure, precipitated in aqueous acetone and dried in a vacuum oven at 60 ° C. To obtain varying levels of succinylation, the degree of the reaction can be monitored as the acylation proceeds or proceeds, by analyzing the number of the non-acylated amine. The number of non-acylated amine groups can
determined by quenching a sample drawn from the reaction mixture with an amine detector agent (e.g., fluorescamine). The amount of amine present can be measured electrophoretically using a standard curve for the polymer. Additionally, the succinic anhydride can be added in succession until the desired percentage of acylation is obtained. The exact degree of acylation of the purified product can be determined using ^ -H NMR spectroscopy and conductometric titration.
Example 3; Acetylation of N-succinylated Chitosan The partially succinylated sample of Example 2 was dissolved in aqueous 0.1M acetic acid. To this solution was then added methanol and acetic anhydride, and the reaction mixture was stirred at room temperature for one day. This solution was then precipitated in aqueous acetone. The resulting precipitate was collected by centrifugation and washed five times with methanol. The precipitate was then dissolved in 0.1 N KOH and dialysed against water at a pH of 7. The final solution was lyophilized to obtain the final product. The acylation process can be measured spectrophoretically as mentioned in Example 2 and, the exact degree of acylation of the purified product can be determined using
^ H NMR spectroscopy and conductometric titration.
Example 4; Preparation of the ionic conjugate of poly (N-acyl-D-slucosamine) -peptide. The potassium salt of the N-succinylated chitosan of Example 3 was dissolved in water. An aqueous solution of the acetate salt of the somatostatin polypeptide analog SOMATULINE ™ (D-Nal-c [Cys-Tyr-D-Trp-Lys-Val-Cys] -Thr-NH2; Kinerton, Dublin, Ireland) was added to the stirred polymer solution. A precipitate formed and was filtered and dried in a vacuum oven at 40 ° C. The polypeptide content of the resulting ionic conjugate can be determined by the difference between the amount of the initial peptide added and the amount of the free residual peptide contained in the filtrate and in the rinse solution. The peptide content of the resulting ionic conjugate can be determined by comparing the carbon / nitrogen ratio of the initial N-succinylated chitosan with that of the resulting ionic conjugate. GPC analysis can be used to determine molecular weight and MWD, differential scanning calorimetry (DSC) to determine thermal properties, and NMR and IR for chemical identity.
OTHER MODALITIES It will be understood that insofar as the invention has been described together with the detailed description thereof, the foregoing description is intended to illustrate and not to limit the scope of the invention, which is defined by the scope of the appended claims . Other aspects, advantages and modifications are within the claims.
Claims (20)
- CLAIMS; A copolymer comprising an N-acylated poly (2-amino-2-deoxy-D-glucose), wherein between 1 and 50 percent of the free amines of the poly (s-amino-x-deoxy) D-glucose) are acylated with a first acyl group, the first acyl group is COE ^ wherein E ^ is selected from the group consisting of carboxykyl c3 ~ 33, carboxyalkenyl C3-33, carboxiarylalkyl C7_3g and carboxyarylalkenylCg_39, between 50 and 99 percent of the amines of the poly (2-amino-2-deoxy-D-glucose) are acylated with a second acyl group, the second acyl group is COE2 wherein E2 is selected from the group consisting of alkyl .. 30, C_30 alkenyl, C6_37 arylalkyl and Cg_37 arylalkenyl, assuming that at least one of the free amines of said poly (2-amino-2-deoxy-D-glucose) is acylated with the first acyl group and, up to 30 percent of the free hydroxy groups of the poly (2-amino-2-deoxy-D-glucose) are acylated with the first acyl group or with the second acyl group.
- 2. A copolymer according to claim 1, wherein the copolymer has a molecular weight of about 3,000 to 90,000 daltons as determined by gel permeation chromatography.
- 3. A copolymer according to claim 1, wherein more than 90 percent of the free amines of the poly (2-amino-2-deoxy-D-glucose) are acylated with either the first acyl group or the second acyl group.
- 4. A copolymer according to claim 1, wherein between 10 and 30 percent of the free amines of the poly (2-amino-2-deoxy-D-glucose) are acylated with the first acyl group.
- 5. A copolymer according to claim 1, wherein the copolymer has the formula: wherein: R1, for each repeating unit or individual repeating unit, is selected from the group consisting of the first acyl group, second acyl group and H; R, for each individual repeating unit, is selected from the group consisting of the first acyl group, second acyl group and H; R3, for each individual repeating unit, is selected from the group consisting of the first acyl group, second acyl group and H; R 4 is selected from the group consisting of the first acyl group, second acyl group and H; R5 is selected from the group consisting of the first acyl group, second acyl group and H; Rg is selected from the group consisting of the first acyl group, second acyl group and H; R7 is selected from the group consisting of COH and CH2OR8; Rg is selected from the group consisting of the first acyl group, second acyl group and H; n is between 2 and 200; and for between 1 and 50 percent of the units, R; L is the first acyl group and, for between 50 and 99 percent of the repeating units, R ^ is the second acyl group, assuming that for at least one of the repeating units, R ^ is the first acyl group.
- 6. A copolymer according to claim 1, wherein the first acyl group is COE] ^, wherein Ei is C3-C33 carboxyalkyl.
- 7. A copolymer according to claim 6, wherein the first acyl group is succinyl.
- 8. A copolymer according to claim 7, wherein the second acyl group is acetyl and R7 is COH or CH2OH.
- 9. A composition comprising the copolymer of claim 1 and a polypeptide, the polypeptide it comprises at least one effective ionogenic amine, wherein at least 50 weight percent of the polypeptide present in the composition is ionically bound to the polymer.
- 10. A composition according to claim 9, wherein the composition comprises between 5 and 50 weight percent of the polypeptide.
- 11. A composition comprising the copolymer of claim 5 and a polypeptide, the polypeptide comprising at least one effective ionogenic amine, wherein at least 50 weight percent of the polypeptide present in the composition is ionically linked to the copolymer.
- 12. A composition according to claim 11, wherein the composition comprises between 5 and 50 weight percent of the polypeptide.
- 13. A composition according to claim 12, wherein the polypeptide is somatostatin or a somatostatin analogue.
- 14. A composition according to claim 10, wherein the first acyl group is succinyl and the second acyl group is acetyl.
- 15. A process for synthesizing a copolymer, the process comprises the steps of: reacting the chitosan with an acid weak to produce a polysaccharide of lower molecular weight; reacting between 1 and 50 percent of the free amines of the lower molecular weight polysaccharide with a first acylating agent, the first acylating agent is selected from the group consisting of polycarboxyalkane C4-C34, polycarboxyalkene C4-C34, polycarboxyrylalkane Cg- C4Q, polycarboxyarylkene C10-C40 or an acylation derivative thereof; and reacting between 50 and 100 percent of the free amine of the lower molecular weight polysaccharide with a second acylating agent, the second acylating agent is selected from the group consisting of onocarboxyalkane 2_3i, monocarboxyalkene c3-3 it monocarboxiarylalkan 07.33 , monocarboxyrylalkylene Cg_35 or an acylation derivative thereof.
- 16. A process according to claim 15, wherein the percentage of free amines that are acylated is determined by the use of a free amine detector agent.
- 17. A process according to claim 15, wherein the first acylating agent is succinic anhydride, the second acylating agent is acetic anhydride and the weak acid is nitrous acid.
- 18. A process to synthesize a composition, the process comprises the steps of: reacting the chitosan with a weak acid to produce a polysaccharide of lower molecular weight; reacting between 1 and 50 percent of the free amines of the lower molecular weight polysaccharide with a first acylating agent, the first acylating agent is selected from the group consisting of polycarboxyalkane C4-C34, polycarboxyalkene C4-C34, polycarboxiarylalkano C3- C40 polycarboxyarylalkene C 10 -C 40 or an acylation derivative thereof; and reacting between 50 and 100 percent of the free amine of the lower molecular weight polysaccharide with a second acylating agent, the second acylating agent is selected from the group consisting of COOH, C2_3 monocarboxyalkane, C3-31 monocarboxyalkene , monocarboxyrylalancane 07.33, monocarboxyrylalkylene Cg_35 or an acylation derivative thereof; neutralizing the lower molecular weight polysaccharide acylated with a base; and mixing the acylated and neutralized lower molecular weight polysaccharide with a polypeptide salt, wherein the polypeptide salt comprises at least one ionogenic amine to form a polypeptide-copolymer ion conjugate.
- 19. A process according to claim 18, wherein the percentage of free amines that are acylated is determined by the use of a free amine detector agent.
- 20. A process according to claim 18, wherein the first acylating agent is succinic anhydride, the second acylating agent is acetic anhydride and the weak acid is nitrous acid.
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