NO318810B1 - Process for the preparation of octreotide pamoate. - Google Patents

Description

The invention relates to a method for producing octreotide pamoate.

The application is separated from Norwegian application no. 19960076.

Peptide medicines often show a low bioavailability in blood after oral or parenteral administration, which e.g. is due to their short biological half-lives caused by their metabolic instability. If they are administered orally or nasally, they also often show poor resorption through the mucous membrane. A therapeutically relevant level in blood over an extended period of time is difficult to achieve.

The parenteral administration of peptide drugs as a depot preparation

in a biodegradable polymer, e.g. as microparticles or implants, have been proposed and enable extended release after a residence time in the polymer that protects the peptide against enzymatic or hydrolytic action by the biological medium.

Although some parenteral depot preparations of peptide drugs in a polymer in the form of microparticles or an implant are known, in reality satisfactory peptide release profiles are only achieved in very few cases. Special measures must be taken for continuous peptide release to achieve a therapeutically active drug serum level and, if desired, to avoid excessively high serum concentrations of the drug, which produce unwanted pharmacological side effects.

Release of the peptide drug is dependent on a number of factors, e.g. of the type of peptide, and for example whether it is present in its free form or in another form, e.g. in the form of a salt, which can affect its solubility in water. Another important factor is the choice of polymer, based on the many possibilities described in the literature.

Each type of polymer has its characteristic rate of biological degradation. Free carboxyl groups can be formed which contribute to the pH value in the polymer and thus further affect the peptide's water solubility and thus its release.

Other factors that can influence the release of the depot preparation are the drug content in its polymeric carrier, how this is distributed in the polymer, the particle size and, in the case of an implant, in addition, its shape. Furthermore, this applies to the place in the body where the preparation is supposed to work.

To date, no extended-release somatostatin preparation for parenteral administration is available on the market, perhaps because it has not been possible to obtain a preparation with a satisfactory serum level profile.

Polymer preparations with drugs designed to provide a prolonged and delayed release of the drug are known in the art.

US-PS 3,773,919 deals with preparations with controlled release of the drug in which the medicant, for example a water-soluble peptide drug, is dispersed in a biodegradable and biologically compatible linear polylactide or a polylactide-co-glycolide polymer. Meanwhile, no pattern for drug release has been described and there is no reference to a somatostatin. US-PS 4,293,539 describes antibacterial preparations in the form of microparticles.

US-PS 4,675,189 describes sustained release preparations of the LHRH analogue decapeptide nafarelin and related LHRH analogues in polylactide-co-glycolide polymers. No pattern of release described.

T. Chang, J. Bioeng., vol. 1, pages 25-32, 1976, describes sustained release of biological compounds, enzymes and vaccines from microparticles.

Polymers/copolymers of lactic acid and 1actide/glycolide copolymers and related compositions for operational use and for sustained release and biodegradability are described in US-PS 3,991,776, 4,076,798 and 4,118,470.

EPO patent application 0 203 031 describes a number of somatostatin octapeptide analogues, e.g. compound RC-160 with the formula:

D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys"Trp"NH2

with a bridge between the -Cys parts, (cf. column 15-16).

The possibility of microencapsulation of somatostatins with polylactide-co-glycolide polymer is mentioned in claim 18, but no guidance is given as to how to achieve a continuous therapeutically active serum level.

US-PS 4,011,312. describes that one can achieve a continuous release of an antimicrobial drug, e.g. the water-soluble polymyxin B from a polylactide-co-glycolide matrix with a low molecular weight (below 2000) and a relatively high glycolide content in the form of an implant, when the implant is introduced into the teat canal of a cow. The medication is released within a short period of time due to the high glycolide content and the polymer's low molecular weight, both of which stimulate a rapid biological breakdown of the polymer and thus a correspondingly rapid release of the medication. A relatively high drug content further contributes to a rapid drug release. Somatostatins are not mentioned and the pattern of release is not described either.

EPO patent 58,481. relates to the continuous release of a water-soluble peptide" from a polylactide polymer implant which is stimulated by reducing the molecular weight of at least some of the polymer molecules, by introducing glycolide units into the polymer molecule, by increasing the block polymer character of the polymer when the polylactide-co-glycolide molecules are used, by increasing the content of drug in the polymer matrix and by increasing the surface area of the implant.

Although somatostatins are mentioned as water-soluble peptides, no somatostatin release profiles are described, nor are indications given as to how all these parameters can be combined to achieve, for example, a continuous somatostatin serum level for at least one week,

e.g. one month.

EPO patent 92,918 describes that a continuous release of peptides, preferably hydrophilic peptides, over an extended period of time can be achieved, when the peptide is incorporated into a conventional hydrophobic polymer matrix, for example a polylactide, which is made more accessible to water by introducing a hydrophilic unit in its molecule, for example polyethylene glycol, polyvinyl alcohol, dextran, polymethacrylamide. The hydrophilic contribution to the amphipathic polymer is given by all the ethylene oxide groups in the case of a polyethylene glycol unit, by the free hydroxyl groups in the case of a polyvinyl alcohol unit or a dextran unit and by the amide groups in the case of a polymethacrylamide unit. Due to the presence of the hydrophilic unit in the polymer molecules, the implant will acquire hydrogel properties after absorption of water. Somatostatin is mentioned as a hydrophilic peptide, but no release profile is described, and it is not indicated which type of polymer is preferred for this peptide and which molecular weight and how many hydrophilic groups it must have.

US patent GB 2,145,422 B describes that a sustained release of drugs of a variety of types, for example vitamins, enzymes, antibiotics, antigens, can be achieved over an extended period of time when the drug is incorporated into an implant, for example of microparticle size such as consists of a polymer of a polyol, for example glucose or mannitol, with one or more, preferably at least three, polylactide ester groups. The polylactide ester groups preferably contain, for example, glycolide units.

No peptides, e.g. somatostatins, are mentioned as drugs and it is also not described

serum drug levels.

The present invention relates to a method for producing an octreotide pamoate, characterized in that octreotide is reacted with embonic acid or a reactive derivative thereof.

It has been found that the octreotide pamoate salt is very stable in preparations containing it.

The naturally occurring somatostatin is a

tetradecapeptide with the structure:

This hormone is produced by the hypothalamus gland as well as by other organs, such as the gastrointestinal tract, and intermediates, same with GRF, Q.v. the neuroregulation of pituitary growth hormone release. In addition to inhibiting GH release from the pituitary gland, somatostatin is a potent inhibitor of a number of systems, including the central and peripheral nervous system and gastrointestinal and vascular smooth muscle. It also inhibits the release of insulin and glucagon.

The term "somatostatin" includes its analogs or derivatives. Derivatives and analogues mean straight-chain, bridge-forming or cyclic polypeptides in which one or more amino acid units have been omitted and/or in which one or more functional groups and/or one or more groups have been replaced with one or more other isosteric groups. In general, the term covers all modified derivatives of a biologically active peptide that exhibit a qualitatively similar effect to the unmodified somatostatin peptide.

Agonist analogues of somatostatin can thus be used to replace natural somatostatin in its impact on the regulation of physiological functions.

The present invention relates to somtostatin derivatives called octreotide.

The term derivative also includes the corresponding derivatives that carry a sugar residue.

When somatostatins carry a sugar residue, this is preferably linked to an N-terminal amino group and/or to at least one amino group present in a peptide side chain, more preferably to an N-terminal amino group. Such compounds and their preparation are indicated in e.g. WO 88/02756. Octreotide derivatives include compounds with the moiety

- D- Phe - Cys - Phe - DTrp - Ly s "Thr "Cys

which has a bridge between the Cys residues.

Particularly preferred derivatives are l^-fa-glucosyl{1,4-deoxyfructosyl-DPhe-Cys-Phe-DTrp"Lys"Thr"Cys"Thr"ol and Na-((3-deoxyfructosyl-DPhe-Cys-Phe- DTrp-Lys-Thr<* >Cys"Thr"ol, each of which has a bridge between the -Cys moieties.

The somatostatins can e.g. exist in free form, in salt form or in the form of complexes thereof. Acid addition salts can be formed with e.g. organic acids, polymeric acids and inorganic acids. Acid addition salts include e.g. the hydrochloride and the acetates. Complexes are formed e.g. from somatostatins by adding inorganic substances, e.g. inorganic salts or hydroxides such as Ca and Zn salts and/or by the addition of polymeric organic substances.

The present invention provides the pamoate salt, which is particularly useful for implants and the method for its manufacture.

The pamoate can be obtained in the usual way, e.g. in that embonic acid (pamoic acid) is reacted with octreotide, e.g. in free base form. The reaction can be carried out in a polar solvent, e.g. at room temperature.

The somatostatins are indicated for use in the treatment of disorders in which administration of the drug is expected over a long period of time, e.g. disorders with an etiology extensive or associated with excessive GH secretion, e.g. in the treatment of acromegaly, for use in the treatment of gastrointestinal disorders, e.g. in the treatment or prophylaxis of peptic ulcer, enterocutaneous and pancreaticocutaneous fistula, irritable bowel, gastric emptying, watery diarrhea, acute pancreatitis and gastroenterophagic endocrine tumors (eg vipomas, GRFomas, glucagonomas, insulinomas, gastrinomas and carcinoid tumors) as well as gastrointestinal bleeding, breast cancer and complications related to diabetes.

They can be administered in the usual way, for example by subcutaneous or intramuscular injection for, for example, indications that are known for the drug contained therein.

Sustained-release preparations containing octreotide pamoate can be administered for all known indications of octreotide or its derivatives, for example those listed in GB 1.199.82 9 A, pages 89-96, as well as for acromegaly and for breast cancer.

EXAMPLE 1:

Octreotide pamoate.

10.19 g of octreotide free base (10 mM) and 3.88 g of embonic acid (10 mM) are dissolved in 1 liter of water/dioxane (1:1). The reaction mixture is filtered and freeze-dried to give a yellow powder [a]20 D = + 7.5-(C = 0.35, in DMF) of octreotide pamoate hydrate. Factor = 1.4 where the factor is equal to weight of freeze-dried powder/weight of octreotide contained therein.

The pamoate can replace the octreotide acetate in the microparticles described in the Norwegian parent application 19903001.

In the case of gamma irradiation, the stabilizing effect of using pamoate salt instead of acetate salt is even more pronounced (see Table 2 below). Gamma irradiation was performed with 25 kGy, which is the dose necessary to guarantee adequate sterilization. Microspheres with acetate showed a total degradation of 3.7% and 3.8% after gamma irradiation, where the degradation consists of 11 - 13 different degradation products. Microspheres with the pamoate salt of octreotide showed a total degradation of 1.4% and 2.9% after gamma irradiation and degradation consists of 5 to 6 different degradation products.

Immediately after production, 2.9% degradation of microspheres containing the acetate salt was detected. After storage for 6 months at room temperature, the amount of degradation had increased by approx. 3%, to 6%. In the microspheres containing octreotide pamoate, the amount of degradation products is increased by only 1% under the same storage conditions (see Table 3).

In addition, octreotide pamoate has the advantage that a finished sterile product can be offered to patients. Sterilization of the final product is not possible when octreotide acetate salt is used in the production of microspheres.

Claims (1)

1. Method for producing an octreotide pamoate, characterized in that octreotide is reacted with embonic acid or a reactive derivative thereof.