JPS6236498B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to calcitonin formulations for rectal administration. More specifically, the present invention relates to a calcitonin preparation for rectal administration, which comprises calcitonin and a surfactant intimately dispersed in a suppository base. Calcitonin is secreted from the thyroid gland in mammals such as rats, guinea pigs, rabbits, dogs, sheep, goats, pigs, cows, monkeys, and humans, and is also found in fish such as salmon, trout, eel, carp, flounder, and sea bream, and birds such as chickens. In amphibians, it is a single-chain polypeptide hormone consisting of 32 amino acids secreted from the postbranchial gland. Although the amino acid composition and amino acid sequence differ somewhat depending on the animal species, its physiological effects are the same regardless of the animal species, and it is said to act on bones, intestinal tracts, kidneys, etc., and lower calcium ions and inorganic phosphorus in the blood. ing. Particularly in bones, it inhibits bone mineral elution, which is thought to be the main cause of lowering blood calcium ions.This effect of calcitonin prevents excessive calcium loss from bones during pregnancy and childbirth. Calcium mobilization in the bones of old animals is said to be suppressed. In the kidney, calcitonin increases the urinary excretion of sodium ions, potassium ions, and inorganic phosphorus, and the direction of calcium ion excretion decreases when the amount of calcitonin is small and increases when the amount of calcitonin is large, and the direction is reversed depending on the amount of calcitonin. It is said. It also has many other physiological effects, including inhibition of absorption of calcium and phosphorus in the intestinal tract, inhibition of gastric acid release in the stomach, inhibition of parathyroid hormone release and activation of adenyl cyclase in the parathyroid glands, and inhibition of exocrine and endocrine (insulin) in the pancreas. It is being revealed. Along with this, as a clinical application of calcitonin,
hypercalcemia, bone bezied's disease, osteoarthritis, peptic ulcer with high gastrin production,
It is used to treat fractures, and is said to be particularly effective for bone pain associated with senile osteoporosis. The main types of calcitonin that are used clinically are calcitonin from pigs, salmon, and eel, or their derivatives, which are currently chemically synthesized. For example, JP-A-52-59178, JP-A-53-
A new synthetic calcitonin has been proposed in 59688. Conventionally, in any of these methods using calcitonin, the only dosage form available is an injection, which is not necessarily a satisfactory administration method. In other words, because it is an injectable drug, doctors cannot perform out-of-hospital treatment, and patients have the disadvantage of having to visit the hospital every time they take the medication. However, there is also the disadvantage that treatment cannot be continued until complete recovery is achieved. Therefore, it is an object of the present invention to provide a non-injectable calcitonin preparation that can efficiently absorb calcitonin. However, as mentioned above, calcitonin is a polypeptide and is said to be degraded by the action of proteolytic enzymes in the gastrointestinal tract, and because it has a high molecular weight, it is not normally absorbed from the gastrointestinal tract. In order to overcome these drawbacks, the present inventors conducted extensive research and surprisingly found that calcitonin and a surfactant were tightly dispersed in a suppository base, which was then administered into the rectum as a suppository. The inventors discovered that calcitonin was efficiently absorbed during the treatment and arrived at the present invention. That is, the present invention is a calcitonin preparation for rectal administration, comprising calcitonin and a surfactant tightly dispersed in a suppository base. The calcitonin used in the present invention is not particularly limited, and includes commonly used calcitonin with a pig, salmon, and eel structure, as well as calcitonin modified and synthesized based on animal-derived calcitonin, such as 1,7-suberic acid bonded calcitonin. Eel calcitonin and the like are used. In the present invention, the surfactants used include sorbitan fatty acid esters such as sorbitan monopalmitate, sorbitan tristearate, and sorbitan sesquioleate; Oxyethylene sorbitan fatty acid esters; glycerin fatty acid esters such as glycerin monostearate, glycerin/coconut oil fatty acid ester, glycerin monooleate, acetylated glyceryl monostearate, acetoacetylated glyceryl monostearate; propylene glycol monolaurate Propylene glycol fatty acid esters such as; polyoxyethylene glycerin fatty acid esters such as polyoxyethylene glycerin monostearate; polyoxyethylene fatty acid esters such as polyoxyethylene monostearate and polyoxyethylene olecoat; polyoxyethylene lauryl Polyoxyethylene alkyl ethers such as ether, polyoxyethylene cetyl ether, polyoxyethylene oleyl ether; polyoxyethylene alkyl phenyl ethers such as polyoxyethylene nonyl phenyl ether; polyoxyethylene hydrogenated castor oil, polyoxyethylene Polyoxyethylene derivatives such as lanolin; polyoxyethylene alkyl amines and amides such as polyoxyethylene stearylamine, polyoxyethylene oleate amine; sodium lauryl sulfate, triethanolamine lauryl sulfate, polyoxyethylene lauryl ether triethanol sulfate Alkyl sulfate ester salts such as amines and polyoxyethylene alkyl ether sulfate ester salts; pyridoxine fatty acid esters; ascorbic acid fatty acid esters such as ascorbyl dipalmitate; sucrose fatty acid esters such as sucrose laurate; Carboxylic acid salts; alkyl phosphates and polyoxyethylene alkyl ether phosphates such as sodium lauryl phosphate and sodium polyoxyethylene cetyl ether phosphate; sulfate ester salts such as sodium coconut oil fatty acid monoglyceride sulfate; soybean lecithin; Phospholipids such as kephalin and lipoinositol; saponins such as Senega saponin; cholic acid and its salts such as sodium ursodeoxycholate and sodium glycocholate; one or more of these may be used. . Among these, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene alkyl ethers, phospholipids, saponins , cholic acid and its salts are preferably used. In particular, cholic acids and their salts, saponins, phospholipids, polyoxyethylene alkyl ethers, glycerin fatty acid esters, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters are preferably used. By dispersing such a surfactant together with calcitonin in the suppository base described below, calcitonin can be efficiently absorbed when administered rectally. The amount of surfactant to be used is preferably 0.001 to 5 mg dispersed per 1 MRC unit of calcitonin. Note that 1 MRC unit means 1 MRC unit, which is obtained by intravenously injecting a sample into a male rat weighing 150 g after fasting for 24 hours.
An amount that lowers serum calcium by approximately 1% after hours.
I'm talking about 1000 times the amount. Suppository bases used in the present invention include cacao butter, palm oil, palm kernel oil, coconut oil,
Oils and fats mainly composed of triglycerides, such as fractionated coconut oil, lard, and uitepsol; Waxes, such as lanolin and reduced lanolin; Hydrocarbons, such as vaseline, squalene, and squalane; Medium-long chain fatty acids; Higher alcohols such as lauryl alcohol, cetanol, stearyl alcohol, and oleyl alcohol; Fatty acid esters such as butyl stearate and dilauryl malonate; Glycerin medium-long chain carboxylic acid esters such as triolein and tristearin; Glycerin esters such as glycerin-substituted carboxylic acid esters such as glycerin acetoacetate; polyethylene glycols such as macrogol and cetomacrogol, and one or two of these.
More than one species is used. In particular, one or more of cacao butter, oils and fats mainly composed of triglycerides such as Witepsol, glycerin esters, and polyethylene glycols are preferably used. The preparation of the present invention has the above-mentioned calcitonin and surfactant tightly dispersed in the above-mentioned suppository base. The term "intimate dispersion" as used herein refers to a state in which the components contained in the base are mutually dispersed as uniformly as possible, and some components are not localized in some areas. The amount of the surfactant dispersed in the suppository base is generally preferably in the range of 0.05 to 20% by weight, particularly preferably 0.1 to 10% by weight, based on the suppository base. The amount of calcitonin dispersed in the suppository base is usually up to 400 MRC units. The preparation of the present invention is produced by taking a predetermined amount of a suppository base, calcitonin, and surfactant, heating if necessary, using a stirrer or a crusher to thoroughly disperse each component, and then This is carried out by casting the dispersion into a mold and cooling it, or by filling and molding the dispersion into gelatin capsules using a rotary capsule filling machine. A preferred embodiment of the present invention is as follows. 100 parts cocoa butter, salmon calcitonin
Take 0.01 part and 5 parts of sodium glycocholate,
A calcitonin preparation for rectal administration is produced by tightly dispersing the dispersion using a crusher, heating it to 40°C, and pouring the dispersion into a mold and cooling it. As mentioned above, according to a preparation made by dispersing calcitonin and a surfactant, calcitonin is efficiently absorbed when administered rectally. This is extremely significant as a non-injectable calcitonin preparation that can overcome these drawbacks. Hereinafter, the present invention will be explained in detail with reference to Examples. Example 1 1.0 g of sodium glycolate was added to 20.0 g of cacao butter (manufactured by Yamada Pharmaceutical Co., Ltd.) and thoroughly kneaded in a mortar. 0.105 mg of salmon calcitonin (approximately 1500 RMC units/mg) was weighed out using an electric balance, and the above base was gradually added and mixed in a mortar to obtain a homogeneous suppository composition. This is heated slightly to make it fluid and placed in a container prepared for rat suppositories.
The solution was poured to a total concentration of 80 mg, and cooled and solidified to obtain a suppository with a diameter of 3 mm and a length of about 6 mm. This drug was administered rectally to male SD rats (body weight 190-210 g), and the plasma calcium concentration was measured at 1, 2, 3, 5, and 7 hours after administration. Absorption was investigated. Five rats were used for each blood sampling. Plasma calcium was measured using a calcium measurement kit (manufactured by Yatron). A blank suppository containing equivalent calcitonin but not sodium glycocholate was prepared in the same manner as above, administered in the same manner, blood was collected, and the plasma calcium concentration was measured to serve as a control. The results are shown in Table 1 as the degree of decrease (%) in calcium value relative to the control value.

[Table] Example 2 ^[ Asu ^1.7 ] - Suppositories containing 0.6 MRC units of eel calcitonin and approximately 3% of the base weight of the surfactant as shown below were prepared and prepared in the same manner as in Example 1. It was administered rectally to SD male rats (body weight 190-210 g), and the plasma calcium concentration was compared with that of a blank suppository containing no surfactant one hour after administration. degree of decrease (%)
It is shown in Table 2 as follows.

【table】

Claims (1)

[Scope of Claims] 1. A calcitonin preparation for rectal administration, comprising calcitonin and a surfactant tightly dispersed in a suppository base. 2 The surfactant is cholic acids and their salts,
Claim 1 is a surfactant selected from the group consisting of saponins, phospholipids, polyoxyethylene alkyl ethers, glycerin fatty acid esters, sorbitan fatty acid esters, and polyoxyethylene sorbitan fatty acid esters. Calcitonin formulation for rectal administration as described. 3. The calcitonin preparation for rectal administration according to claim 1 or 2, wherein the suppository base is selected from the group consisting of triglyceride-based oils and fats, glycerin esters, and polyethylene glycols. 4. The calcitonin preparation for rectal administration according to any one of claims 1 to 3, wherein 0.001 to 5 mg of a surfactant is dispersed per 1 MRC unit of calcitonin.