HK1096870A - Sustained release of peptides from pharmaceutical compositions - Google Patents

Description

Sustained release of peptides from pharmaceutical compositions

The present invention is a divisional application entitled "sustained release of peptides from pharmaceutical compositions" having an application date of 8/31/1995 and having applicant's number 95195473.3.

Technical Field

The present invention relates to parenteral administration of sustained release peptide compositions.

Background

Peptides are usually administered parenterally, such as by subcutaneous injection, as they are often degraded in the gastrointestinal tract.

Many peptide drugs (such as insulin, LHRH and somatostatin) require continuous or repeated administration to a patient over a period of time. But such continuous injections cause inconvenience and discomfort to the patient.

Sustained release formulations can release the peptide over a longer period of time without repeated injections. Solid polymeric microcapsules and matrices, such as polylactic acids, which act as biodegradable polymers, have been developed. See, e.g., Hutchinson, U.S. Pat. No. 4,767,628 and Keat, et al, U.S. Pat. No. 4,675,189. Hydrogels have also been used as sustained release formulations of peptides. These hydrogels include various polymers such as poly-N-isopropylamide (NIPA), cellulose ethers, hyaluronic acid, lecithin and agarose to control release. See, e.g., PCT application WO 94/08623.

Some peptides have been reported to form soluble polymers or insoluble microparticles when added to a solution. See, pharm. res.8 of Eckhardt et al: 1360(1991). Recently, the possibility of using these peptide polymers as sustained release preparations has been investigated. See european application 0510913a2 (1992); and Wan et al Pharmaceutical Research vol.1110 supply Ps291 and Ps243 (1993). however, these polymeric sustained release compositions require the peptide to be dissolved in saline or a biologically compatible buffer and then incubated until a liquid crystalline gel is formed.

Summary of The Invention

The present invention provides pharmaceutical compositions that automatically form sustained release gels in patients after administration without the need for temporary dissolution or incubation. The present invention is based on the ability to formulate some soluble peptide salts into parenteral sustained release gel formulations without the need to incorporate any biologically degradable polymers or other carrier matrices to control the release profile of the peptide. The novel peptide compositions automatically gel after interaction with the body fluid of a patient and then are released continuously over an extended period of time. Thus, the novel peptide compositions reduce the volume, expense and production time of known sustained release polymer peptides.

In general, the invention features parenteral administration of solid, non-particulate, sustained release compositions. The composition mainly comprises: 1) a soluble, gelable peptide salt, and 2) 30% by weight of a soluble carrier in the form of a pharmaceutically acceptable monomer, compounded into a solid cylindrical form, wherein the solid composition is automatically gelable upon interaction with a patient's bodily fluids and provides sustained release of the peptide in the patient's body for a period of at least three days.

The invention also features semi-solid, sustained release drug suspensions for parenteral administration to a patient. This suspension essentially comprises: 1) a soluble, gelable peptide salt and 30% by weight of a pharmaceutically acceptable, soluble carrier, and 2) less than 50%, preferably 20% or 10% of a solvent required to solubilize the peptide salt, to provide a semi-solid state of the suspension, wherein the semi-solid suspension spontaneously forms a gel upon interaction with the liquid phase of the patient's body, and provides sustained release of the peptide in the patient's body for a period of at least up to three days.

The invention also features the use of a soluble and gelable peptide salt of a selected peptide for the manufacture of a solid formulation that provides for continuous release of the peptide in a patient over a period of at least up to three days. The medicament comprises a soluble, gel-forming peptide salt and up to 30% by weight of a pharmaceutically acceptable, soluble monomer carrier.

In addition, the invention features the use of a soluble and gelable peptide salt of a selected peptide for the manufacture of a formulation in the form of a semi-solid suspension which provides for continuous release of the peptide in a patient over a period of at least up to three days. The medicament comprises 1) a soluble, gel-forming peptide salt and up to 30% by weight of a pharmaceutically acceptable, soluble carrier, and 2) less than 50% of a solvent in an amount necessary to solubilize the peptide salt to provide a semi-solid state of the suspension, wherein the semi-solid suspension spontaneously forms a gel upon contact with the body fluid of a patient and provides sustained release of the peptide in the patient for a period of at least three days.

In another aspect, the invention features peptide drugs for administration to a patient and methods for providing sustained release of the peptide for up to at least three days. Such extended continuous release of the drug is accomplished by single parenteral, e.g., intramuscular, subcutaneous, intradermal, or intraperitoneal, injection of a solid pharmaceutical composition comprising a soluble, gel-forming peptide salt and up to 30% by weight of a pharmaceutically acceptable, soluble, monomeric carrier, e.g., mannitol, sorbitol, or lactose, wherein the solid composition automatically forms a gel upon contact with the body fluid of a patient and releases the peptide continuously in the patient for a period of at least three days.

As used herein, "gelable peptide salts" refers to peptide salts that form gels upon contact with body fluids. Whether a peptide salt is "gellable" and has the desired biological activity can be determined by in vitro and in vivo assays as described below. The term "peptide" refers to a molecule, natural or synthetic, comprising two or more amino acids linked to each other by the carboxyl group of one amino acid and the amino group of another amino acid. Thus, the term includes polypeptides and proteins. "soluble" peptide salts are those which have a solubility in water of 0.1 mg/ml, preferably 1.0 mg/ml, at pH7.0, 25 ℃.

The terms "biologically active analog" and "analog" are used interchangeably herein and include naturally occurring, recombinant, and synthetic peptides and derivatives or peptide fragments thereof, such as peptides modified in their N-or C-terminal structure, which have substantially the same agonistic or antagonistic effect as the naturally occurring or unmodified peptide.

Peptides suitable for use in the present invention include Growth Hormone (GH), Growth Hormone Releasing Peptide (GHRP), growth hormone releasing factor, epidermal growth factor, interferon, insulin, growth hormone release inhibitor, bombesin, calcitonin gene related peptide (CCRP), dextrin, parathyroid hormone (PTH), parathyroid hormone related peptide (PTHrp), gastric hormone releasing peptide (GRP), Melanocyte Stimulating Hormone (MSH), adrenocorticotropic hormone (ACTH), Luteinizing Hormone (LH), Luteinizing Hormone Releasing Hormone (LHRH), cytokinase, sorbose (sorbine), cholecystokinin, glucagon-like protein (GLP), gastric hormone, brain peptide, neuregulin, endothelin, substance P, neuropeptide Y (NPY), peptide YY (PYY), vasoactive peptide of intestinal blood Vessels (VIP), pituitary adenylate cyclase activating oligopeptide (PACAP). Bradykinin, Thyrotropin Releasing Hormone (TRH), beta-cell bromoatropine (fragments of ACTH) or biologically active analogs of the aforementioned peptides.

Preferred soluble, gelable peptide salts of the invention include salts of somatostatin and its analogs, such as SOMATULINE (BIM 23014C) (Kinerton, Ltd. Dublin, Ireland, see, e.g., Johnson et al, Eur. J. Endocrinol. 130: 229-34, 1994), salts of calcitonin and its analogs, salts of LHRH analogs such as the antagonist "GANIREX" (GRX; see, e.g., Nestor et al, J. Pharmacology, 35 (21): 3942-3948, 1992), and salts of GH, GRF, PTH, PTHrp and their biologically active analogs.

Examples of preferred salts are those formed with pharmaceutically acceptable organic acids (e.g., acetic acid, lactic acid, maleic acid, citric acid, malic acid, ascorbic acid, succinic acid, benzoic acid, methanesulfonic acid, toluenesulfonic acid) and with inorganic acids such as hydrohalic acid (hydrochloric acid), sulfuric acid or phosphoric acid.

The gelable peptidyl salts of the present invention are complexed with a pharmaceutically acceptable, monomeric, soluble carrier to facilitate manufacture and/or administration. Examples of the carrier include polyhydric alcohols such as mannitol and sorbitol, sugars such as glucose and lactose, surfactants, organic solvents and polysaccharides.

The solid compositions of the invention may be produced in cylindrical form having a diameter of less than 3 mm, preferably less than 2 mm, to facilitate administration with a standard cannula. The gel preferably releases the peptide continuously for more than 14 days, more preferably for at least 30 days.

The present invention also includes semi-solid suspensions. The terms "semi-solid suspension" and "semi-solid composition" are used generically herein to refer to a suspension of a viscous, paste-like peptide salt in a liquid solvent, such as sterile water. The semi-solid suspensions of the invention comprise 1) a solid, a soluble gel-forming peptide salt and up to 30% by weight of a pharmaceutically acceptable soluble carrier; and 2) a solvent, such as a water-soluble solvent, e.g. sterile water, in an amount of less than 50%, preferably 20% or 10% of the amount of solvent required to solubilize the peptide salt to provide a semi-solid state. The suspension is also administered by parenteral one-time injection, and automatically gelatinizes after reacting with body fluid of a patient. The amount of solvent, e.g. (water), in the suspension must be less than the amount required for complete dissolution of the peptide salt, i.e. the peptide to solvent ratio must be greater than the solubility of the peptide, e.g. the somatomedin analogue, SOMATULINE, at 26.0 mg/ml in water at PH7.0 and 25 ℃.

The invention further features forming a sustained release gel in a patient. A peptide pharmaceutical composition comprises a soluble, gel-forming peptide salt and up to 30% by weight of a pharmaceutically acceptable, soluble carrier and one or more body fluids of a patient. Wherein the peptide salt automatically forms a gel after interaction with the body fluid of the patient and provides sustained release of the peptide in the patient for a period of at least three days. The pharmaceutical composition, which may form a gel, may be solid or may include a solvent, such as sterile water, in an amount of less than 50% of the amount of solvent required to solubilize the peptide salt, to provide a semi-solid state of the pharmaceutical composition.

In another aspect, the invention features a method of making a solid pharmaceutical composition by a) combining a soluble and gelable peptide salt and up to 30% by weight of a pharmaceutically acceptable soluble carrier to form a mixture; b) combining the mixture with a liquid excipient to form a semisolid formulation; c) extruding the semi-solid formulation into an elongated filament; d) cutting the filaments into semi-solid cylindrical rods and e) drying the semi-solid cylindrical rods to form solid cylindrical rods, preferably having a diameter of less than 2 or 3 mm.

In addition, the invention features an injection system for administering a semi-solid, sustained release drug suspension. The system comprises a) a first syringe having a hollow needle with a nozzle at one end and a slidable plunger extending from the opening at the other end, wherein a soluble and gellable peptide salt is disposed between the nozzle and the plunger in the hollow needle; b) another syringe also has a hollow needle, one end is an outlet nozzle, another end is a plunger slidable in the needle barrel, extend out of the needle barrel through an opening, contain the medicinal liquid carrier between outlet nozzle and plunger; c) a connector comprising a fluid conduit, the connector being adapted to connect the nozzle of a first syringe to the outlet nozzle of a second syringe so that fluid is delivered from the outlet nozzle to the nozzle; and d) a temporary sealing membrane located in the second syringe for separating the liquid carrier from the gelable peptide salt in the first syringe, wherein sufficient force is applied to the plunger of the second syringe to rupture the membrane and the liquid carrier in the second syringe flows into the first syringe through the connector to mix with the gelable peptide salt to form a semi-solid, sustained release drug suspension.

Unless defined otherwise, 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 belongs. Although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the following methods and materials are preferred. Other features and advantages of the invention will be set forth in the detailed description and in the claims.

Brief description of the drawings

FIG. 1 is a comparison of in vitro release rates and transport curves for solid and semi-solid pharmaceutical compositions.

FIG. 2 is a graph of the effect of in vitro surfactant TWEEN80 and carrier hyaluronic acid on the release rate and transport profile of peptides from solid pharmaceutical compositions.

FIG. 3 is a graph relating to the effect of monosaccharides on the release rate and transport profile of solid pharmaceutical compositions in vitro.

Figure 4 is a graph of the effect of different diameters of solid pharmaceutical compositions on their release rate and transport profile.

FIG. 5 is a graph comparing plasma concentrations of different doses of a peptide standard solution in rats over time.

Fig. 6 is a comparison of the delivery curves for plasma levels of different doses of solid peptide compositions in mice.

Figure 7 is a comparison of the blood transport curves of two solid pharmaceutical compositions at different doses in mice.

Figure 8 is a comparison of the blood transport curves of three different doses of solid pharmaceutical compositions in rats.

FIG. 9 is a comparison of the concentration of peptides in blood of standard peptide solutions and solid compositions in dogs over time.

FIG. 10 is a comparison of the concentration of peptides in blood of standard peptide solutions and solid compositions in dogs over time.

FIG. 11 is a comparison of the concentration of peptides in blood of standard peptide solutions and solid compositions in dogs over time.

Fig. 12 is a graph of the transit of peptides in the blood following administration of a very high dose of a solid composition (500 μ g/kg of SOMATULINE) to dogs.

Fig. 13 is a graph of peptide transport in blood after administration of a solid pharmaceutical composition containing a carrier to dogs.

FIG. 14 is a comparison of plasma levels of peptide in dogs after administration of a particular dose of peptide as a standard solution, solid composition or semi-solid suspension, respectively.

Figure 15 is a case of a peptide transfer curve in blood within 5 days post-dog application from a semi-solid suspension.

Figure 16 is a graph of the plasma level transport profile of peptide in the form of a high dose (6 mg/kg) transport profile semisolid suspension for dogs within 56 days post-dose.

FIG. 17 is a comparison of plasma level transport curves for 15 days after administration of the semi-solid suspension and the polyatic-ethylene glycol microspheres, respectively, to dogs.

Fig. 18 is a side cross-sectional view of a syringe-like device for injecting semi-solid drug suspensions.

Detailed Description

The present invention relates to pharmaceutical compositions (e.g., solid columns or semi-solid suspensions) that automatically form sustained release gels upon entry into a patient, and novel syringe-like devices for injecting the compositions into the patient. Syringe-like devices are used for administration of semi-solid suspensions and standard cannulae are used for administration of solid compositions.

The novel composition comprises in each unit at least the amount of the peptide component as a product of the daily dose and the number of days of its activity. Upon contact of the components with body fluids, the peptide is automatically gelled, and is released from the gel of the sustained release composition according to a plasma level profile comparable to that of a known sustained release composition (e.g., a polymer peptide formulation) or a peptide administered by daily continuous injection using an infusion pump operating in a stable delivery mode.

Peptides suitable for pharmaceutical compositions

When the peptide salts useful in the compositions of the invention are administered to a patient, they must be capable of forming a gel in body fluids such as lymph or serum, and after the gel has formed, must be capable of controlling the release of the peptide at a rate suitable for therapeutic use as a drug. For example, as described in the examples below, a gel of the somatostatin analog, SOMATULINE, is capable of maintaining a blood peptide concentration of at least 1.0 ng/ml for one month at sufficient doses to be at the levels required for the treatment of, for example, acromegaly.

Preferred peptides for use in the novel compositions include growth hormone release inhibitor, calcitonin, parathyroid hormone (PTH), parathyroid hormone-related peptide (PTHrp), soluble agonists or antagonists of LHRH, GRF and other soluble analogs that have agonistic or antagonistic effects on these proteins. Peptides comprising at least one hydrophobic residue, such as the non-naturally occurring residues naphthylalanine (Nal), norleucine (Nle) and halogenated phenylalanine, and naturally occurring residues such as Trp, Ile, Phe, Val, Leu, Met, Ala, GLy, or Cys, are preferred, which make the peptide more gelogenic. The hydrophobicity of amino acids can be measured by the methods described in the following documents: eisenberg ann.rev.biochem.53: 595-623(1984).

The configuration of the peptide is preferably modified, e.g.by reducing enzymatic degradation by D-amino acids, by forming cyclic peptides by disulfide bonds or by lactam bonds between the side chains of two amino acid residues. These characteristics of suitable peptides are believed to allow or promote the automatic gelling of the peptide salt after it has entered the patient.

The following publications disclose the sequences of PTH peptides and analogs thereof: john P.Bilezikian (ed.) parathyroid gland foundation and clinical concept at page 239-58 (Raven Press, NH 1994); nissenson et al, "Structure and function of Parathyroid hormone and Parathyroid hormone releasing hormone receptors", receptors, 3: 193- "202 (1993); bachem California 1992-1993 catalog (Torrance, CA); and Sigma peptides and amino acids 1994 catalogue (st.

The following publications disclose the sequences of PTHrp peptides and analogs thereof: yasuda et al, J. Biochem, 264: 7720 7725 (1989); and Burtis, w.j., clinical chemistry, 38 (11): 2171-2183(1992). Further examples can be seen in the following documents:

PCT Application94/01460(1994)；PCT Application 94/02510(1994)；PCTApplication 93/20203(1993)；PCT Application 92/11286(1992)；PCT Application 93/06846(1993)；PCT Application92/10515(1992)；PCT Application 92/00753(1992)；EPApplication 477885 A2(1992)；EP Application 561412 A1(1993)；EP Application 451867 A1(1991)；GermanApplication 4203040 A1(1993)；U.S.Patent No.4,771,124(1988)；U.S.Patent No.4,656,250(1987)；U.S.Patent No.5,229,489(1993)；and Bachem California 1993-94 Catalog，30-34(1993)。

the following publications disclose the sequences of somatostatin analogs:

PCT Application WO 91/09056(1991)；EP Application 0 505 680 A1(1992)；EPApplication 0 363 589 A2(1990)；EP Application 0 203 031A2(1986)；U.S.Patent No.4,904,642(1990)；U.S.PatentNo.4,871,717(1989)；U.S.Patent No.4,853,371(1989)；U.S.Patent No.4,725,577(1988)；U.S.Patent No.4,684,620(1987)；U.S.Patent No.4,650,787(1987)；U.S.Patent No.4,603,120(1986)；U.S.Patent No.4,585,755(1986)；U.S.Patent No.4,522,813(1985)；U.S.Patent No.4,486,415(1984)；U.S.Patent No.4,485,101(1984)；U.S.Patent No.4,435,385(1984)；U.S.Patent No.4,395,403(1983)；U.S.Patent No.4,369,179(1983)；U.S.Patent No.4,360,516(1982)；U.S.Patent No.4,358,439(1982)；U.S.Patent No.4,328,214(1982)；U.S.Patent No.4,316,890(1982)；U.S.Patent No.4,310,518(1982)；U.S.Patent No.4,291,022(1981)；U.S.Patent No.4,238,481(1980)；U.S.Patent No.4,235,886(1980)；U.S.Patent No.4,224,190(1980)；U.S.Patent.No.4,211,693(1980)；U.S.Patent No.4,190,648(1980)；U.S.Patent No.4,146,612(1979)；U.S.Patent No.4,133,782(1979)；Van Binst et al.， Peptide Res.，5：8(1992)；Prevost et al.， Cancer Res.，52：893(1992)；and Bachem California 1993-1994 Catalog 94-95(1993)。

the following publications disclose the sequences of GRF analogs:

PCT Application WO 91/18998(1991)；PCTApplication WO 92/18537(1992)；PCT Application WO92/00095(1992)；PCT Application WO 91/03053(1991)；EPApplication 314866 A2(1989)；EP Application 136475 B1(1991)；EP Application 320785 A2(1989)；U.S.Patent No.4,732,972(1988)；J.S.Patent No.4,627,312(1986)；EPPatent Application 511003 A1(1992)；and BachemCalifornia 1993-1994 Catalog 64-65(1993)。

the following publications disclose the sequences of LHRH analogs:

U.S.Patent No.4,307,083；U.S.PatentNo.4,292,313；U.S.Patent No.4,124,577；U.S.Patent No.4,111,923；U.S.Patent No.4,101,538；U.S.Patent No.4,101,537；U.S.Patent No.4,093,611；U.S.Patent No.4,087,419；U.S.Patent No.4,087,418；U.S.Patent No.4,087,417；U.S.Patent No.4,083,967；U.S.Patent No.4,062,835；U.S.Patent No.4,031,072；U.S.Patent No.4,031,070；U.S.Patent No.4,031,069；U.S.Patent No.3,824,227；U.S.Patent No.3,824,065；Rivier et al.， J. Med.Chem.，29：1846(1986)；Ljungquist et al.， Proc. Natl.Acad.Sci.， USA， 85：8256(1988)；Coy et al.， Amer， Clin.Res.，10：139(1978)；Sundaram et al.， Life Sci.，28：83(1981)；Rivier et al.， Life Sci.， 23：869(1978)；Humphrey et al.， J.Med.Chem.，21：120(1978)；and BachemCalifornia 1993-1994 Catalog 67-68(1993)。

the following publications disclose the sequences of calcitonin analogs:

EP Application 464549 A1(1992)and Bachem California 1993-1994 Catalog 28(1993)。

in vitro assay for applicable peptide salts

The feasibility of a given peptide salt for use in the present invention can be tested by simple in vitro tests. The peptide salt in powder or suspension form is mixed with a body fluid such as lymph, plasma, or serum in a container. The vessel was heated to 30 ℃ on a water bath or oil bath and visually inspected for gel formation.

The in vitro light diffraction test can also be used to determine whether a body fluid is suitable for use in the present invention. Such as powdered peptide salt, is mixed with 20-50% water by weight on a microscope slide, mixed well, such as after 5 minutes, and then subjected to a reverse microscope such as ZEISS^The slide was analyzed on AXIOVERT100 with polarized light and if the polarized light was diffracted, it was shown by the presence of a very bright light indicating that the peptide salt formed a gel and was suitable for use in the present invention.

Another in vitro test was used to study the release profile of the solid and semi-solid compositions of the invention. It utilizes MICROETTE^TMSubdermal diffusion cells (Hanson Research, Palo Alto, CA) as an automated collection system comprised six thermostatted cells, a mechanical agitation and a sample collector. In the study of solid cylindrical SOMATULINE^TMIn the test conditions of the transfer curve of (1), the automatic sampling system is as follows: release medium 0.9% NaCl, initial volume 7 ml, bar weight 1.6 to 1.8 mg, temperature 37 ℃, stirring rate 60 rpm, final stirring rate 400 rpm (for 15 minutes) and replacement volume 481 μ l. Samples were taken at 4, 10, 20, 40, 65, 90, 180 and 270 minutes, respectively.

Samples collected in the autosampler were analyzed on High Pressure Liquid Chromatography (HPLC) and quantified on Hewlett Packard series 1090 liquid chromatography with an autoinjector (Teknokroma, Barcelona, Spain). An ultraviolet-visible diode analyzer was used for the analysis.

NUCLEOSIL with a diameter of 25cm × 4.0mm is used^TMC-18 column. The experimental conditions for HPLC were as follows: component A0.1% TFA in AcCN: H₂O (80: 20); component B0.1% TFA in water at a flow rate of 0.9 ml/min, injection volume of 20 μ l, temperature room temperature, detection UV-280 nm and acquisition time-20 min. SOMATULINE^TMThe retention time of (a) was calculated to be 14 minutes. The gradient system used for HPLC is listed in table 1.

TABLE I

Time (minutes)	% of component A	% of component B
			0	25	75

17	69.2	30.8
			19	25	75
25	25	75

In vivo assay for sustained release peptides

If a particular peptide salt is capable of forming a gel in any of the above in vitro assays, the in vivo assay can be used to test the feasibility of the peptide salt for animal and human therapy. The blood level transport curve of the peptide salt can be obtained by injecting the peptide salt into an animal such as Sprague Dawley rat or dog, taking blood samples at specific time intervals, such as 1-5 days at hourly intervals, or 5-45 days at 12 or 24 hour intervals, to determine the peptide concentration therein. This demonstrates the feasibility of a peptide gel or peptide/carrier gel for therapeutic administration of the peptide.

Animals were anesthetized with pentobarbital (60 mg/kg i.p. for rats) and jugular vein cannulated for blood sampling. Peptides tested are e.g. SOMATULINE^TMThe semi-solid suspension or solid composition (or standard solution for comparison) of (a) is administered in a specific dose, e.g. 1.0, 3.0 or 6.0 mg of SOMATULINE^TMPer kilogram subcutaneous injection. After the peptide composition or solution is administered into the body, heparinized blood samples are taken at set time intervals through a cannula and centrifuged to obtain plasma. The amount of peptide in plasma was obtained by standard radioimmunoassay. The technology can directly measure the amount of the peptide without extracting the peptide from the rat plasma. The data obtained were plotted (concentration in blood nanograms/milliliter versus time) to establish a blood level release profile.

In addition, the presence of a peptide in an animal can also be determined indirectly by any biological response of the animal to the peptide. For example, the effect and presence of an analog of somatostatin as measured by inhibition of GRF-induced growth hormone release in a standard assay. This indirect method can also be used to detect peptides in a patient.

If monitored for 1-3 days, the in vivo assay can be used to determine whether a particular peptide forms the desired sustained release gel in vivo. Peptides may be suitable for use in the present invention if they provide sustained release of the peptide at therapeutic levels, e.g., for at least 3 days. The assay can also be used to test the effectiveness of a peptide salt or complex of a peptide and a carrier for a particular treatment in a particular animal and to obtain the necessary dosage to be administered by comparing the known dosage requirements of a peptide and a particular disease with the plasma concentration release profile. For example, it is known that treatment of acromegaly entails maintaining a blood concentration of 1.0 ng/ml of an analog of somatostatin. Similarly, the assay can be used to estimate the desired effect and dosage of a peptide salt for the treatment of a particular human disease.

Carriers suitable for pharmaceutical compositions

Although there are some peptide salts that can form gels, e.g. SOMATULINE^TMThe salt can be directly prepared into a solid composition without any carrier, but the composition of the present invention can also be prepared by using a carrier homogeneously complexed with the peptide. The carrier should be water soluble, monomeric, and eliminated directly by the human body. Preferably a carrier having a molecular weight of less than 1000 daltons. The carrier is selected so that the composition has its physical properties, but does not significantly affect the sustained release characteristics of the composition. Indeed, as described below, some carriers may be used to reduce or increase the release rate and transit time of the composition.

Suitable carriers include surfactants such as TWEEN80, polyols such as mannitol and sorbitol, monosaccharides such as lactose and glucose, organic solvents and polysaccharides.

Process for preparing solid pharmaceutical composition

The preparation method of the present invention avoids the problem of dissolution of many peptides, as it is not necessary to dissolve the peptide prior to injection. Another advantage of the solid composition of the invention is its stability. The anhydrous solid composition avoids the problems of degradation, crystallization, agglomeration and the like associated with hydrated sustained release formulations such as hydrogels.

The following is a method of mixing the peptide and the carrier and loading the resulting solid pharmaceutical composition into a syringe through a trocar.

A carrier, such as sorbitol, is dissolved in a liquid vehicle, such as water or an organic solvent, as prepared, and the resulting solution is mixed with the desired peptide to form a homogeneous semi-solid mixture. If the final solid composition does not contain a carrier, the peptide is mixed with water or other liquid excipients alone to form a semi-solid mixture. The semi-solid mixture is then transferred to an extrusion chamber, such as a stainless steel syringe or a feed extrusion zone, with a plunger or screw and an extrusion nozzle having an inner diameter of 0.5-3 mm. The mixture is extruded, cut into small rods of a certain length, then collected and dried thoroughly under vacuum, preferably in the form of sticks of 2 or 3 mm diameter at the end. Elongated rodlets having the desired cross-section after drying can be made by passing a non-solid material through a sieve plate using various known techniques.

The carrier used for the preparation can be removed by evaporation, freeze-drying or vacuum-drying and the exact mass percentage of peptide in the rods, i.e. the equivalent dose per unit length of the cylinder, is determined. Five small rods are taken from each batch, weighed, and then programmed to remove all peptides, e.g., in a suitable solvent such as 0.1% aqueous acetic acid, and the amount of peptide suggested is determined by standard HPLC methods as used in the in vitro assay described above. Before use, the uniformity of the small rods was also checked by calculating their weight/length ratio. The length and weight of the five cylinders were measured and the ratio was calculated. As long as the relative error (RSD) is less than 5% can be passed. RSD ═ SD_{Length/weight ratio}Average_{Length/weight ratio}]X 100, and thus, is also a measure of length to weight ratio uniformity.

Once the stick is received, the dosage can be determined by length and weight measurements. Based on the calculated peptide concentration, the rods are cut to the length corresponding to the desired dose, weighed on a scale prior to administration, and then loaded into a hollow needle, such as a cannula.

After the needle is capped, the trocar is inserted from the rear, preferably in the shape of a funnel, to facilitate insertion of the small solid rod. The metal plunger then pushes the wand, pushing it from the needle into the patient.

In a preferred embodiment, the rear of the trocar is attached to a sterile stainless steel, plastic or glass cylinder where the semi-solid composition is extruded, sheared, and dried. The cylinder is positioned so that the small rod, after drying, falls by gravity into the barrel. The pre-assembled trocar is then attached to a standard cannula with its metal piston system and activation system.

Process for preparing semi-solid suspensions and freeze-dried compositions

Semi-solid suspensions can be prepared using the same peptides and carriers used to prepare the solid compositions, whereas semi-solid peptide suspensions use 10% to 90% by weight of an aqueous solvent (e.g., sterile water) as compared to solid compositions to form highly viscous or pasty compositions. The water is preferably added immediately prior to administration of the composition to a patient.

Semisolid suspensions can be prepared by the same process as described above for the preparation of solid compositions, i.e. extrusion, but without the final step of removing the excipients. The semi-solid extruded rod may be injected directly into a patient using a syringe-like device as described below or the dried solid rod may be hydrated prior to injection to form a semi-solid suspension.

Semisolid compositions can also be prepared by freeze-drying, which simplifies the unit dose control process and allows for simple sterilization of the composition prior to filling into a syringe. First, the peptide, with or without carrier, is dissolved in water and the resulting solution is sterilized under pressure through a 0.22 micron filter, e.g., using a syringe with a plunger. After filtration, the solution must be handled under sterile conditions. The volume is accurately controlled using, for example, a micropipette, the sterile solution is lyophilized in a sealed syringe and the lyophilized solid is compressed under vacuum with a piston.

The syringe containing the compacted sterile solid is then packaged under vacuum, under conditions such that the solid composition remains stable for an extended period of time without refrigeration or other special storage conditions. Prior to administration, the solid composition need only be hydrated with water, e.g., using the following two-part device containing the desired volume of sterile water in separate syringe-like cylinders. The freeze-dried solid is rehydrated to form a viscous semi-solid suspension which can be used for injection into a patient.

Solutions of the peptide composition are undesirable because once injected into the body, the solutions disperse and do not form the sustained release gel of the invention. Accordingly, the amount of water added should be carefully selected to be less than the amount required to dissolve an amount of the peptide composition, e.g., 26 mg of SOMATULINE to avoid formation of a solution, at 25 ℃, PH7.0^TMThe acetate salt of (A) requires only 1.0ml or less of water. Less than 50% of the water required to dissolve the peptide salt is used, preferably less than 20% or 10% water. It is ensured that a semi-solid or pasty suspension is formed instead of a solution.

In a preferred embodiment, the needle is connected to the cylinder of the syringe by a funnel connector, which may be the needle or part of the syringe. The needle may be attached to the syringe or attached prior to use, with needles of different lengths and outer diameters being selected according to the route of injection, e.g. intramuscular, intradermal or subcutaneous. The inner surface of the needle is preferably smooth to facilitate injection of the semi-solid composition.

The syringe preferably has a small plunger diameter (1-5 mm) so that a very small amount of the semi-solid composition (10-300 microliters) can be formed into a significant length within the syringe barrel, thereby allowing more accurate visual and dose measurements.

Composition examples

Example 1: 100% SOMATULINE^TMSolid composition

Adding 140 mg of water to somatotropin release inhibiting factor analog SOMATULINE^TM(Kinerton, ltd., Dublin, Ireland) in 60 mg of acetate. Unless otherwise specified, the following list is SOMATULINE^TMIn the examples of (1), SOMATULINE is used^TMOf (a). The mixture was kneaded in a2 ml plastic syringe with a spatula and then introduced into a stainless steel syringe having a chamber with an internal diameter of 5 mm and an extrusion head with an internal diameter of 2.5 mm. The mixture was extruded into strands by syringe under the action of a syringe pump, and the resulting strands were cut into 3 cm small rods and collected on a glass slide. The rods were vacuum dried for 24 hours, and the resulting rods, 1.4 mm in diameter, contained 10 mg of SOMATULINE^TMIn centimeters. The small rods were loaded into a trocar with an inner diameter of 1.5 mm and a length of 3 cm.

Example 2: 80% SOMATULINE^TM20% solid composition of mannitol

Referring to the procedure of example one, 1 gram of mannitol (Roquette, lesrien, France) was first mixed with 9 grams of water to form a solution. Adding 0.140 g of the solution to 0.060 g of SOMATULINE^TMAfter the extruded filaments were sheared and collected on a glass slide, they were dried under vacuum for 24 hours, and the resulting 2.9 cm rods contained 40 mg of SOMATULINE^TM(20% by weight mannitol and 80% by weight SOMATULINE)^TM)。

Example 3: 100% SOMATULINE^TMSemi-solid suspensions

To 300 mg of SOMATULINE^TM100 ml of water was added to prepare a semi-solid suspension. The resulting mixture was kneaded in a 5 ml plastic syringe with a spatula. Each syringe was filled with 200 mg of the semi-solid composition (60 mg peptide).

Example 4: 80% SOMATULINE^TM20% semi-solid suspension

0.1125 mg of mannitol and 14.8875 g of water were mixed to form a carrier solution. 400 mg of SOMATULINE^TMDissolved in 14.60 g of the carrier solution. Each plastic syringe was then filled with 2.0 ml of the resulting solution and freeze-dried. The resulting solid was pressed to volume 100 with a plungerMicroliter. Prior to administration, the solid composition was hydrated with 133.33 microliters of water to form a semi-solid suspension.

Example 5: 90% SOMATULINE^TM10% sorbitol solid composition

0.5 grams sorbitol (Roquette, Lestrein, France) was mixed with 9.5 grams water to form a solution according to the method of example 2. Adding 0.140 g of the solution to 0.060 g of SOMATULINE^TMThe mixture is weighed, kneaded and extruded. The pressed filaments were sheared and collected on slides and dried under vacuum for 24 hours, resulting in 2.5 cm rods containing 3.5 mg of SOMATULINE^TM(10% by weight sorbitol and 90% by weight Somatuline^TM)。

Example 6: 84% SOMATULINE^TM16% Tween80 solid composition

An 8% aqueous solution of tween80 carrier was prepared by mixing 0.8 g of tween80 (Sigma, st. louis Mo) and 9.2 g of water according to the method of example 2. Adding 0.140 g of the carrier solution to 0.060 g of SOMATULINE^TMThe mixture is weighed, kneaded and extruded. The pressed filaments were sheared and collected on slides and dried under vacuum for 24 hours, resulting in 2.5 cm rods containing 3.5 mg of SOMATULINE^TM。

In vitro comparative examples

The following examples demonstrate the utility and ineffectiveness of various modifications of the solid, semi-solid compositions of the present invention.

Example 7: comparison of solid and semi-solid compositions

100% SOMATULINE was tested in an in vitro assay as described above^TMSolid composition and 30% SOMATULINE^TMWhether the transport curve of a semi-solid suspension of 70% water is different. Each composition contains the same amount of SOMATULINE^TM. The results are shown in FIG. 1. There was no significant difference between the two compositions.

Example 8: effect of Carrier on peptide Release Rate

The in vitro test described above was also used to observe different vectors versus different SOMATULINES^TMThe effect of the transport profile and release rate of the solid composition. Comprises (1) 100% of SOMATULINE^TM，(2)86％SOMATULINE^TMAnd 14% tween80, (3) 85% SOMATULINE^TMAnd 15% hyaluronic acid, (4) 90% SOMATULINE^TMAnd 10% sorbitol and (5) 80% SOMATULINE^TMAnd 20% mannitol. The test results are shown in the attached FIGS. 2 and 3. FIG. 2 shows the comparison with 100% SOMATULINE^TMIn contrast, hyaluronic acid decreased the transport curve, but tween80 increased it. FIG. 3 shows the comparison with 100% SOMATULINE^TMIn contrast, the monomeric soluble carriers mannitol and sorbitol only slightly increased the release rate.

Example 9: effect of the diameter of the solid pharmaceutical composition on the Release Rate of the peptide

The in vitro assay described above was also used to measure the diameter of the rods versus SOMATULINE^TMInfluence of the solid composition transport profile and release rate. The solid composition is prepared from SOMATULINE^TMAnd mannitol (80: 20) mixture. The case of 0.26 and 0.43 mm in diameter was investigated, respectively. The results of this test are shown in FIG. 4. The smaller diameter of 0.26 mm gives a faster in vivo release rate than the larger diameter of 0.43 mm. In addition, the smaller diameter sticks are fully released in less than half the time it takes for the larger diameter sticks to fully release.

In vivo embodiment

The following animal experiments demonstrated the somatostatin analogue SOMATULINE^TMThe drug release and transport curves of various solid and semisolid compositions of acetate are compared with those of standard liquid medicines.

Example 10: in vivo comparison between gels formed from peptide solutions and solid peptide compositions

The in vivo assay described above was used to study the injection of SOMATULINE^TMOf the standard solution and the method according to the invention100% SOMATULINE was used^TMThe plasma concentration profile varies when the composition is a solid. The solutions were prepared by dissolving the peptide in physiological serum and then injected subcutaneously at doses of 1.0 mg/kg and 0.5 mg/kg, respectively. Rats were anesthetized with pentobarbital (60 mg/kg, i.p.) and the right jugular vein was cannulated for blood sampling. After surgery, rats were allowed to recover for two days before starting the experiment, and the animals were placed in free-moving cages. After administration of the drug solution, heparinized blood samples were obtained from the cannulae, serum was centrifuged and SOMATULINE in serum was measured by Radioimmunoassay (RIA)^TMThe amount of (c). RIA does not require extraction of peptides from rat plasma and can be measured directly.

Then 1.5 mg/kg and 3 mg of SOMATULINE^TMThe above experiment was repeated at a dose per kilogram. The results (mean data for 6 rats) are presented in Table II and FIG. 5, which shows that the in vivo residence time increases with increasing dose and maximum release rate. As expected, the standard solution first reaches a peak of peptide release, the so-called "peak effect", and then steadily decreases over time.

TABLE II

SOMATULINETMPlasma concentration (ng/ml)
				Time (hours)	0.5mg/kg	1.5mg/kg	3mg/kg
0.00	0.05	0.14	0.89
				0.25	26.38	44.03	53.84
0.50	30.02	55.52	70.20

1.00	38.21	78.71	95.65
				2.00	45.39	68.07	112.32
4.00	36.37	66.22	126.61
				8.00	10.07	41.72	91.70
12.00	3.38	20.52	74.10
				24.00	0.32	3.88	12.34

Maximum concentration C of peptide in 0.5 mg/kg solution_max45 ng/ml, 1.5 mg/kg of C in solution_max78 ng/ml, and 126 ng/ml in 3 mg/kg solution.

Next 100% SOMATULINE in solid form^TM(0.5 mg/kg, 1.5 mg/kg, and 3 mg/kg) were administered to rats. The results (average data for 5 mice) are shown in Table III and FIG. 6. Indicating a sustained release effect even at a minimum dose of 0.5 mg/kg. The solid composition avoids the initial "explosive effect" of the solution, e.g. 3.0 mg/kg of solid composition C_max39 ng/ml and 3.0 mg/kg of solution C_max126 ng/ml.

TABLE III

SOMATULINETMPlasma concentration (ng/ml)
				Time (hours)	0.5mg/kg	1.5mg/kg	3mg/kg
0.00	0.00	0.00	0.00
				0.08	1.89	2.60	3.38
0.25	3.49	4.23	7.24
				0.50	3.97	5.43	11.85
1.00	6.05	7.04	17.01
				2.00	9.09	17.51	22.49
3.00	11.85	18.75	33.08
				4.00	11.44	17.55	39.64

Example 11: intramuscular injection of solid compositions

Four rats were used100% SOMATULINE at 0.5 mg/kg and 3 mg/kg doses^TMThe solid composition was repeated for the above test, administered intramuscularly. The results are shown in FIG. 7. Sustained release was shown over 72 hours with the expected dose effect without the explosive effect of the solution.

Example 12: subcutaneous injection of solid compositions

100% SOMATULINE was administered to six rats at doses of 0.5, 1.5 and 3 mg/kg^TMThe solid composition was subjected to the above in vivo test, subcutaneous administration, and the results are shown in FIG. 8. As expected, the peptide concentration in plasma increased with the increase in the amount of the drug (0.5 mg/kg, C)_maxAt 8.15 ng/ml, 1.5 mg/kg, C_max11.170 ng/ml, 3 mg/kg, C_max33.59 ng/ml). In addition, the explosion effect of the standard solution in example 10 disappears.

Example 13: comparison in dogs

The above experiment was repeated to study the pharmacokinetics of peptide solutions and solid compositions in dogs, five dogs were injected subcutaneously with 84.8 microgram/kg of SOMATULINE^TMAfter the standard solution of (3), its transport profile and release rate were investigated. For comparison, 100% SOMATULINE was injected subcutaneously at a comparable dose of 100 μ g/kg in five identical dogs^TMSolid compositions, the same tests were carried out.

As shown in FIG. 9, the plasma concentration vs. time graph shows the typical transport curve of the peptide solution (. smallcircle.), i.e.short release time (10 hours), C_max46.28 ng/ml (at 20 min). On the other hand, the pharmacokinetics of the solid composition (●) showed a great difference. As shown in FIG. 9, C_maxBy dropping to 3.56 ng/ml (at 1 hour), the release of peptide, which is maintained at least 0.1 ng/ml, is extended by more than ten times, as much as 120 hours.

Similarly, the standard SOMATULINE^TMSolutions (. smallcircle.) intravenously at 100. mu.g/kgDosing, quickly, about 1 minute, to reach C_maxI.e., a plasma concentration of about 807 ng/ml. (FIG. 10). On the other hand, the solid composition containing 100% peptide (●) was administered intramuscularly at a dose of 100. mu.g/kg, with very different results. At 2 hours, the solid composition reached a very low C_max(1.69 ng/ml) and a sustained release profile was developed over 96 hours. (FIG. 10)

In another comparative study, six additional dogs were subcutaneously injected with SOMATULINE at a dose of 200 μ g/kg^TMStandard solution, results show C_max125.96 ng/ml (20 min), the duration was less than 24 h (fig. 11, o ═ solution). Solid composition (100% SOMATULINE) at the same dose (200. mu.g/kg) in the same group of dogs^TM) The same in vivo test as above was repeated by the same subcutaneous administration method. As in the previous comparative experiment, the solid compositions show a completely different release profile, C_maxAt 13.26 ng/ml (at 1 hour), the release of at least 0.1 ng/ml peptide concentration was maintained for over 120 hours. (FIG. 11, ● ═ solid compositions)

Example 14: effect of increasing dose in vivo

The same solid composition (100% SOMATULINE) was used for the same group of dogs^TM) The above in vivo test was repeated with subcutaneous administration, but at a dose 5 times higher than that of example 13 (500. mu.g/kg). As in example 13 above, the explosive effect was controlled and plasma C was used_maxWas 10.62 ng/ml (at 4 hours). In addition, the sustained release time was extended to 144 hours (FIG. 12).

Example 15: effect of in vivo surfactants

Using a composition containing SOMATULINE^TMAnd surfactant Tween80 (84% SOMATULINE)^TM16% tween 80) was repeated on the same group of dogs. Administered subcutaneously at a dose of 100 μ g/kg. As shown in FIG. 13 (compare FIG. 9), the surfactant more or less accelerated the SOLMATULINE^TMI.e. an increased release rate and an increased initial peak arrival, and a more or less reduced sustained release time.

Example 16: subcutaneous injection of semisolid suspensions

The same animals were injected subcutaneously with a semi-solid suspension of 30% SOMATULINE^TMAnd 70% water, and 15% SOMATULINE^TMAnd 85% water, at the same dose of 200 μ g/kg, the in vivo test described above was repeated. The results show no significant difference from the results obtained with the solid composition of example 13 at the equivalent dose. The semisolid composition is SOMATULINE at 24 hr^TMRespectively, was 1.76 ng/ml and 1.61 mg/ml, and the solid composition was 1.51 mg/ml (fig. 14). The semi-solid composition also has a higher release rate after 2 days than the solid composition. The former 0.9 and 0.87/ml, the latter 0.34 ng/ml. The time for releasing the peptide from both the solid and semi-solid compositions is maintained for at least 120 hours with a small standard error.

Example 17: injecting high doses

The in vivo test was repeated on six dogs in the third group. High dose (3 mg/kg) of SOMATULINE^TMMaking into hydrated semi-solid suspension (30% SOMATULINE)^TMAnd 70% water) were tested and administered intramuscularly. As shown in fig. 15, the results indicate that there is sustained release of the peptide even at such high doses. C_maxStill less than 10 mg/ml (925 ng/ml), drug concentrations in plasma above 2.4 ng/ml are much longer lasting, up to more than 15 days.

Very high dose (6 mg/kg) of the same semi-solid suspension (30% SOMATULINE) as described above^TMAnd 70% water) the above in vivo test was repeated on four dogs. The high dose test was performed to assess the limits of release rate control, as observed by a possible so-called "run-away phenomenon," i.e., loss of control of drug release at high doses. Conventional sustained release formulations have a maximum percentage of drug that can be contained in the formulation, e.g., for poly (lactic-co-glycolic acid)Alkyd (PLA) microspheres are typically 15%. Once this maximum limit is reached, the formulation loses the sustained release profile and releases the drug immediately. This test showed a dose of 6.0 mg/kg SOMATULINE in plasma^TMC of (A)_maxHigh, but still within the therapeutic limit of about 52 ng/ml. In addition, as shown in FIG. 16, the release of the peptide was still controlled without escape phenomena, i.e., sustained, at higher levels, 1-7 days, above 10 ng/ml; about 1-10/ml for 8-33 days; and greater than 0.1/ml for at least 56 days. Plasma levels above 7 ng/ml were maintained for only 1 day at the dose of 3 mg/kg (FIG. 15), compared to 12 days at the dose of 6 ng/kg.

Example 18: PLGA microspheres versus semi-solid pharmaceutical compositions.

The semi-solid SOMATULINE of the present invention was compared by performing the above in vivo test on 6 dogs^TMComposition and method for treating diabetes/composition and method for treating diabetes comprising 30 mg of SOMATULINE^TMThe transport curve and release rate of PLGA microspheres (lnbiotech. paris, france) the dosage of the microspheres was compared to the dosage of the first semi-solid composition of example 17, i.e. 3.0 mg/kg. Fig. 17 shows that the plasma concentration profiles of the semi-solid composition (●) and microspheres (. smallcircle.) both exceeded 15 days.

As shown, the semi-solid composition showed better time and dose control for the detonation effect compared to the loaded microspheres (156 ng/ml after 30 minutes for microspheres and 2.6 ng/ml after 4 hours for semi-solid composition). In addition, the semi-solid composition exhibited somewhat longer hold times with a release rate of 2.48 ng/ml at day 15 and microspheres with a release rate of 1.09 ng/ml at day 15.

Syringe device

Syringe devices for the administration of semi-solid suspensions are readily manufactured by the prior art. The device is the same as a standard syringe and comprises a combination of a cylindrical tube, a needle and a plunger. The needle is hollow with the largest pores and a smooth inner surface, preferably at least the 6 gauge inner surface. The outside diameter and length of the needle are selected for subcutaneous and intramuscular use. The plunger used to expel the semi-solid composition from the needle through the needle and into the patient may be rubber or plastic, as is the case with current disposable syringes. The small rod of the piston for pushing the stopper is an inexpensive and simple plastic component.

Fig. 18 shows an injection device 10 that can be used to record and inject a semi-solid composition. The injection device 10 comprises an empty needle 1 which is connected to a first syringe 3. The powdered solid composition 2, e.g. lyophilized, is loaded into the first syringe 3 and preferably stored under vacuum after the first piston 6 is inserted into the first syringe 3. The connector 4 includes a first end 11, a second end 12 and a longitudinal bore 13 between the first end 11 and the second end 12. The first end 11 is connected to the first syringe 3 and the second end 12 is connected to the second syringe 7. The needle 1 is housed in a longitudinal hole 13 and the connector 4 is preferably made of plastic or metal. Sterile water 15 is loaded into the second syringe 7 and a barrier 20 located therein prevents the flow of water from the second syringe 7 to the first syringe 3. The baffle 20 is preferably made of a perforated material such as a thin metal foil or plastic film. The stop 20 is broken by the force of the depression of the piston 9 and as soon as the stop 20 is broken, the plunger 9 can be depressed further, thereby forcing water 15 from the second syringe 7 through the needle 1 into the first syringe 3. It is critical to avoid separation of the barrier from the syringe wall so that it does not enter the first syringe. The interaction of the water 15 and the solid pharmaceutical composition results in the formation of a semi-solid composition in the first syringe 3 the needle 1 and first syringe 3 are then separated from the connector 4 for injection of the semi-solid composition to a patient in standard manner. The plug lock 14 prevents the first piston 6 from descending, thereby avoiding the dry solid composition 2 from entering the second syringe 7.

In another arrangement, a standard syringe is used which is connected to a plastic tube by a centrally apertured connector. The first syringe is initially free of the needle attached thereto, but after water and other carriers flow from the second syringe through the bore of the connector, the needle is attached to the first syringe, which contains the peptide. In this device, the barrier may be located within the bore or within the first syringe.

Other contents

The foregoing invention and its specific details have been described in some detail for purposes of illustration only and are not intended to be limiting. The scope of the invention is set forth in the appended claims. Other aspects, advantages, and modifications are within the claims.

Claims (15)

1. A solid non-particulate, sustained release pharmaceutical composition for parenteral administration to a patient, said composition consisting essentially of (1) a soluble, gelable peptide salt and (2) up to 30% by weight of a pharmaceutically acceptable, monomeric, soluble carrier, compounded into a solid cylindrical form, wherein said solid composition automatically gels upon interaction of the contained peptide salt with the body fluids of the patient, said peptide being selected from the group consisting of analogs of soluble hydrophobic luteinizing hormone releasing factor; growth hormone releasing factor; parathyroid hormone; parathyroid hormone-related protein; calcitonin or soluble growth hormone releasing factor, parathyroid hormone-related protein and biologically active analogs of calcitonin.

2. A composition in the form of a semi-solid sustained release pharmaceutical suspension for parenteral administration to a patient, said suspension consisting essentially of (1) a soluble, gelable peptide salt and a pharmaceutically acceptable, monomeric, soluble carrier in an amount up to 30% by weight based on the total weight of the peptide salt and the carrier, and (2) a solvent in an amount of less than 50% of the amount of solvent required to solubilize all of the peptide salt, wherein said semi-solid suspension automatically gels upon interaction of the contained peptide salt with body fluid of the patient, said peptide being selected from the group consisting of analogs of soluble hydrophobic luteinizing hormone-releasing factor; growth hormone releasing factor; parathyroid hormone; parathyroid hormone-related protein; calcitonin or soluble growth hormone releasing factor, parathyroid hormone-related protein and biologically active analogs of calcitonin.

3. The composition of claim 1 or 2, wherein the peptide is an analog of soluble luteinizing release hormone.

4. The composition of claim 1, wherein the carrier is selected from mannitol, sorbitol, or lactose.

5. The composition of claim 1, wherein the solid composition is in the form of a cylinder having a diameter of less than 3 mm.

6. The composition of claim 2, wherein the amount of solvent is less than 10% of the amount of solvent required to solubilize all of the peptide salt.

7. A process for producing the solid pharmaceutical composition of claim 1, the process comprising:

a) mixing a soluble, gelable peptide salt selected from the group consisting of analogs of soluble hydrophobic luteinizing hormone releasing factor with a pharmaceutically acceptable soluble carrier in an amount up to 30% by weight based on the total weight of the peptide salt and the carrier to form a mixture; growth hormone releasing factor; parathyroid hormone; parathyroid hormone-related protein; calcitonin or soluble growth hormone releasing factor, parathyroid hormone-related protein and biologically active analogs of calcitonin;

b) compounding the mixture with a liquid excipient to form a semi-solid formulation;

c) extruding the semi-solid formulation to form an elongated filament;

d) cutting the filaments into semi-solid cylindrical rods;

e) drying the semi-solid rods into solid cylindrical rods.

8. Use of a soluble, gelable peptide salt of a selected peptide selected for its sustained release in a patient for at least three days in the manufacture of a solid medicament comprising said soluble, gelable peptide salt of said peptide and up to 30% by weight of a carrier in the form of a pharmaceutically acceptable, soluble monomer, based on the total weight of the peptide salt and the carrier, wherein said medicament is capable of self-gelling following interaction of the peptide salt comprised therein with body fluid of the patient, said peptide being selected from analogues of soluble hydrophobic luteinizing hormone releasing factor; growth hormone releasing factor; parathyroid hormone; parathyroid hormone-related protein; calcitonin or soluble growth hormone releasing factor, parathyroid hormone-related protein and biologically active analogs of calcitonin.

9. Use of a soluble, gelable peptide salt of a selected peptide selected for its sustained release in a patient for a period of at least three days in the manufacture of a medicament in the form of a semi-solid suspension comprising said soluble, gelable peptide salt of said peptide and up to 30% by weight of a pharmaceutically acceptable, monomeric, soluble carrier, based on the total weight of the peptide salt and carrier, and less than 50% of the solvent amount required to solubilize all of the peptide salt, to maintain the semi-solid state of said suspension, wherein said suspension is self-gelling following the action of the peptide salt contained therein with the body fluids of the patient, said peptide being selected from the group consisting of analogs of soluble hydrophobic luteinizing hormone releasing factor; growth hormone releasing factor; parathyroid hormone; parathyroid hormone-related protein; calcitonin or soluble growth hormone releasing factor, parathyroid hormone-related protein and biologically active analogs of calcitonin.

10. Use according to claim 8 or 9, wherein the peptide is an analogue of soluble luteinizing releasing hormone.

11. The use of claim 8 or 9, wherein the peptide is growth hormone releasing factor; parathyroid hormone; parathyroid hormone-related protein; calcitonin or soluble bioactive growth hormone releasing factor, parathyroid hormone-related protein and calcitonin analogs.

12. The use of claim 8, wherein the formulation does not include a carrier.

13. Use according to claim 8 or 9, wherein the carrier is selected from mannitol, sorbitol or lactose.

14. The use of claim 8, wherein the formulation is in the form of a cylinder having a diameter of less than 3 mm.

15. The use of claim 9, wherein the amount of solvent is less than 10% of the amount of solvent required to dissolve the total peptide salt.