United States Patent:  6,008,189

Assignee:  Teikoku Seiyaku Kabushiki Kaisha (Kagawa-ken, JP)

Filed:  January 21, 1998

The present invention relates to an improved intravaginal preparation containing a physiologically active peptide, which comprises a physiologically active peptide, a sucrose fatty acid ester and an organic acid with a pharmaceutically acceptable carrier or diluent, by which the physiologically active peptide can be absorbed safely and efficiently.

DISCLOSURE OF THE INVENTION

Under taking into account the above-mentioned various factors, the present inventors have further intensively studied to find an improved preparation in order to solve the above-mentioned problems, and have now found during the development of a preparation suitable for administration of a physiologically active peptide by other means than injection that an intravaginal preparation containing an organic acid alone or an intravaginal preparation containing a sucrose fatty acid ester alone can show an improved absorption of the active ingredient, but when both of them are incorporated into the intravaginal preparation, it shows far excellent absorbability of the active ingredient, and have accomplished the present invention. Thus, the present invention provides an improved intravaginal preparation having high absorbability of the active ingredient which comprises a physiologically active peptide and at least a sucrose fatty acid ester and an organic acid or a pharmaceutically acceptable salt thereof.

BEST MODE FOR CARRYING OUT THE INVENTION

The physiologically active peptide used in the present invention includes peptides having a molecular weight of less than 15,000. Suitable examples of the peptide are insulin, angiotensin, vasopressin, desmopressin, LH-RH (luteinizing hormone-releasing hormone), somatostatin, calcitonin, glucagon, oxytocin, gastrins, somatomedins, secretin, h-ANP (human atrial natriuretic polypeptide), ACTH (adrenocorticotropic hormone), MSH (melanocyte stimulating hormone), .beta.-endorphin, muramyl-dipeptide, enkephalin, neurotensin, bombesin, VIP (vasoactive intestinal polypeptide), CCK-8 (cholecystokinin-8), PTH (parathyroid hormone), CGRP (calcitonin gene relating polypeptide), TRH (thyrotropin-releasing hormone), TSH (thyroid stimulating hormone), endothelin, TSH (thyroid stimulating hormone), and their derivatives.

The various peptides used in the present invention include not only naturally occurring peptides but also physiologically and pharmaceutically active synthetic and semi-synthetic derivatives or analogues thereof. For example, calcitonin used in the present invention includes not only natural calcitonins such as salmon calcitonin, human calcitonin, porcine calcitonin, eel calcitonin, chicken calcitonin, but also analogues such as (Asu^1.7)-eel calcitonin, i.e. elcatonin. The most preferable peptide used in the present invention is calcitonin and PTH.

The amount of the physiologically active peptide contained in the intravaginal preparation of the present invention varies according to the kind of the peptide to be used, but it should be an effective amount for exhibiting the desired pharmacological activity thereof. For example, when calcitonin is used, it should be contained in an effective amount for the therapy of morbid conditions of diseases such as Paget's disease, hypercalcemia and osteoporosis. When PHT, CGRP, somatomedin or an analogue thereof is used, it is used in an effective amount for the therapy of bone metabolic disorders. When insulin is used, it is used in an effective amount for regulating the glucose level in blood, and treating diabetes. The effective amount of the other physiologically active peptides used in the present invention is also determined likewise.

The sucrose fatty acid ester used in the present invention includes an ester of sucrose with one or more fatty acids, for example, esters including from monoesters consisting of a molecule of sucrose and a molecule of fatty acid to octaesters consisting of a molecule of sucrose and eight molecules of fatty acid, and it is usually used in the form of a mixture of these esters. The sucrose fatty acid ester is generally referred to as sugar ester and is widely used an extremely safe additive in food, cosmetics and medicines. The fatty acid of the sucrose fatty acid ester includes, stearic acid, palmitic acid, lauric acid, oleic acid, and the like. Suitable examples of the sucrose fatty acid ester are sucrose stearic acid ester, sucrose palmitic acid ester, sucrose oleic acid ester, sucrose lauric acid ester, sucrose behenic acid ester, and sucrose erucic acid ester, and among them, sucrose stearic acid ester, sucrose palmitic acid ester, sucrose oleic acid ester and sucrose lauric acid ester are more preferable. One or more these esters are used in the present invention. The sucrose fatty acid ester is contained in an amount of 0.1 to 30 w/w %, preferably in an amount of 0.5 to 15 w/w % to the total weight of the preparation.

The organic acid used in the present invention is selected from the group consisting of a saturated aliphatic carboxylic acid having 2 to 6 carbon atoms, an unsaturated aliphatic carboxylic acid, an aromatic carboxylic acid, ascorbic acids, and a pharmaceutically acceptable salt thereof. The saturated aliphatic carboxylic acid includes a monobasic acid, a hydroxycarboxylic acid and a polycarboxylic acid. Suitable examples of the monobasic acid are acetic acid, propionic acid, butyric acid, valeric acid, capric acid, etc. Suitable examples of the hydroxycarboxylic acid are malic acid, lactic acid, tartaric acid, citric acid, etc. Suitable examples of the polycarboxylic acid are malic acid, succinic acid, tartaric acid, citric acid, fumaric acid, malonic acid, glutaric acid, adipic acid, etc. Suitable examples of the unsaturated aliphatic carboxylic acid are fumaric acid, maleic acid, etc. Suitable examples of the aromatic carboxylic acid are benzoic acid, phthalic acid, etc. The ascorbic acids are ascorbic acid, isoascorbic acid, etc. Among these organic acids, citric acid, tartaric acid, malic acid, lactic acid, succinic acid and benzoic acid are more preferable. One or more these organic acids are used in the present invention. The organic acid is contained in an amount of 0.1 to 20 w/w %, preferably in an amount of 0.5 to 10 w/w % to the total weight of the preparation.

These organic acids were found from natural plants and animals, like citric acid, tartaric acid, malic acid, lactic acid, and are widely distributed into natural resources, and are adopted routinely as food and drinks. The safety of these organic acids has been established as actual proof from ancient times. Besides, these organic acids have been also used as an additive in the pharmaceutical compositions.

As mentioned above, since the safety of the sucrose fatty acid ester and the organic acid used in the present invention has undoubtedly been established, the intravaginal preparation of the present invention can be a pharmaceutical preparation with an extremely high safety.

The intravaginal preparation of the present invention may optionally contain an animal protein and/or vegetable protein, which is/are not an essential component of the present preparation, but in order to prevent the active peptide from enzymatic-decomposition which may occur during the absorption procedure of the peptide after administration of the preparation, and/or in case that an unstable active peptide or a derivative thereof is used as an active ingredient, or in case that an active peptide is adsorbed at the wall of the vessel used in the mixing procedure of the components, if necessary. Such animal protein and vegetable protein are preferably ones conventionally used in food, cosmetics, or pharmaceutical compositions.

The animal protein includes albumin (e.g. bovine serum albumin, human serum albumin, etc.), lecithin, casein, gelatin, etc. The vegetable protein includes gluten, zein, soybean protein, lecithin, etc. The animal protein and the vegetable protein can be used alone or can be used together in the form of a combination thereof of an appropriate ratio.

The amount of the animal protein and/or the vegetable protein in the present intravaginal preparation varies according to the kind of the peptide to be stabilized by them, but it is in the range of 0.001 to 25 w/w % to the total weight of the preparation.

The preparation form of the present intravaginal preparation may be liquid preparations, gel preparations (gel preparation having high viscosity is more preferably), suppositories, films, tablets, soft capsules, tampons, creams, etc., all comprising a physiologically active peptide, an organic acid, a sucrose fatty acid ester, and if necessary, an animal protein and/or vegetable protein.

The present intravaginal preparation may be prepared by mixing directly a physiologically active peptide, an organic acid and a sucrose fatty acid ester, and if necessary, an animal protein and/or vegetable protein, or dissolving or mixing them in purified water or physiological saline solution, and then, followed by mixing the resulting solution or mixture with a conventional base for intravaginal preparation in a conventional manner.

The pH value of the present intravaginal preparation is preferably a pH value closest to that of the vagina. After dissolving an organic acid in a diluent where said diluent is used in an amount as small as possible but necessary for dissolving the organic acid, the pH value of the organic acid solution is adjusted to 3 to 7, preferably 3 to 5 by adding a basic compound into said organic acid solution. The basic compound used for adjusting the pH value may be a conventional one but the resulting final solution should be non-toxic and non-irritative to humans. Suitable examples of the basic compound are bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, etc. Subsequently, a physiologically active peptide, a sucrose fatty acid ester, and if necessary, an animal protein and/or vegetable protein are added into said organic acid solution and dissolved or mixed.

The gel preparation having high viscosity may be prepared by adding a conventional thickening agent into the above solution, if necessary, and suitable examples of the thickening agent are cellulose lower alcohol ether, PVA (polyvinyl alcohol), PVP (polyvinylpyrrolidone), polyoxyethyleneoxy-propylene glycol block copolymer (PLURONIC.TM.), etc.

The present intravaginal preparation may contain one or more additives such as vehicles, isotonic agents, preservatives, antioxidants and coloring agents. For example, vehicles (e.g. starch, dextrin, D-mannitol, cyclodextrin, tragacanth, etc.); isotonic agents (e.g. sodium chloride, potassium chloride, sodium carbonate, etc.); benzoic acid and p-hydroxy-benzoic acid esters (e.g. methyl p-hydroxybenzoate, propyl p-hydroxy-benzoate, etc.); preservatives (e.g. benzyl alcohol, sorbic acid, etc.); antioxidants (e.g. butyl hydroxyanisol, sodium hydrogen sulfite, etc.); coloring agents (e.g. .beta.-carotin, Food red No. 2, Food blue No. 1, etc.), etc. may be used.

Claim 1 of 2 Claims

1. A method of administering a preparation containing a physiologically active peptide to a patient in need thereof, wherein the preparation comprises a physiologically active peptide, a sucrose fatty acid ester and an organic acid which is selected from the group consisting of malic acid, lactic acid and citric acid, or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier or diluent, and which preparation has a pH value of 3 to 7; said method comprising administering the preparation to the patient intravaginally.

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