JPS6236499B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to calcitonin formulations for oral administration. More specifically, calcitonin and one selected from the group consisting of ascorbic acids, acidic amino acids, citric acids, unsaturated fatty acids, and salicylic acids.
The present invention relates to a calcitonin preparation for intraoral administration, which has improved absorbability of calcitonin from the oral mucosa, and is characterized by containing one or more types of calcitonin. 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, osteoporosis,
It is used to treat peptic ulcers and fractures that exhibit high levels of gastrin production, 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 disadvantages such as having to go to the hospital every time they take the medication, which results in them not having to go to the hospital mid-way through treatment. This also has the disadvantage that treatment cannot be continued until complete recovery is achieved. Therefore, if a non-injectable calcitonin preparation that can efficiently absorb calcitonin can be provided, it would surely be good news for both patients and doctors. However, as mentioned above, calcitonin is a peptide compound 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. Therefore, as a result of intensive research in order to overcome such drawbacks, the present inventors surprisingly found that calcitonin, ascorbic acids, acidic amino acids,
Calcitonin is efficiently released when an intraorally administered preparation containing one or more selected from the group consisting of citric acids, unsaturated fatty acids, and salicylic acids is prepared and administered intraorally. The present invention was developed based on the discovery that it is absorbed. That is, the present invention provides calcitonin for oral administration, which comprises calcitonin and one or more selected from the group consisting of ascorbic acids, acidic amino acids, citric acids, unsaturated fatty acids, and salicylic acids. It is a formulation. There are no particular restrictions on the calcitonin used in the present invention, and in addition to commonly used calcitonin with a pig, salmon, or eel structure, calcitonin modified and synthesized based on animal-derived calcitonin, such as 1,7-sperate-linked calcitonin. Eel calcitonin and the like are used. Examples of the ascorbic acids used in the present invention include ascorbic acid, sodium ascorbate, ascorbic palmitate, ascorbic acid phosphate, ascorbic acid sulfate and its salts, dehydroascorbic acid, and especially ascorbic acid and/or ascorbic acid. Sodium chloride is preferably used. Acidic amino acids used in the present invention include glutamic acid, sodium glutamate,
Potassium glutamate, monosodium N-lauroylglutamate, monosodium N-palmitoylglutamate, glutamine, pyroglutamic acid, sodium pyroglutamate, potassium pyroglutamate, aspartic acid, sodium aspartate, potassium aspartate, monosodium N-lauroyl aspartate, N - Monosodium palmitoyl aspartate, asparagine, etc., and particularly glutamic acid, sodium glutamate, monosodium N-lauroylglutamate, sodium pyroglutamate, aspartic acid, and sodium aspartate are preferably used. Examples of citric acids used in the present invention include citric acid, sodium citrate, and potassium citrate, with citric acid and sodium citrate being particularly preferably used. The unsaturated fatty acids used in the present invention include oleic acid, sodium oleate, potassium oleate, linoleic acid, sodium linoleate, potassium linoleate, linolenic acid, sodium linolenate, potassium linolenate, arachidonic acid, and arachidonic acid. Examples include sodium, potassium arachidonic acid, etc., and oleic acid, sodium oleate, linoleic acid, and sodium linoleate are particularly preferably used. Salicylic acids used in the present invention include salicylic acid, sodium salicylate, acetylsalicylic acid, salicylsalicylic acid, aluminum acetylsalicylate, choline salicylate, methyl salicylate, salicylamide, ethenzamide, difunisal, acetylsalicylic acid lysine salt, and para-aminosalicylic acid. One or more of these may be used within a pharmaceutically acceptable range. In particular, sodium salicylate, acetylsalicylic acid, and para-aminosalicylic acid are preferably used. Calcitonin is efficiently absorbed when the above-mentioned compounds are dispersed and contained together with calcitonin in a formulation base for oral administration as described below and administered into the oral cavity. The usage amount of these compounds is calcitonin 1MRC
It is preferable to use 0.001 to 100 ft for the unit. Note that 1 MRC unit is the amount of 1,000 MRC units that will reduce serum calcium by approximately 1% one hour after intravenously injecting the sample into a male rat weighing 150 g after fasting for 24 hours.
I'm talking about double the amount. The preparations for oral administration used in the present invention include troches, capsule tablets, sublingual tablets, chewable tablets, drops, etc. In particular, sublingual tablets, capsule tablets, troches, and intraoral mucosal tablets as described below. Preferably, a formulation is used that is adapted to adhere to the surface. Examples of excipients used in the oral preparation used in the present invention include glucose, starch, crystalline cellulose, dextrin,
Lactose, mannitol, sorbitol, anhydrous calcium phosphate, sucrose, talc (natural hydrated magnesium silicate), kaolin, precipitated calcium carbonate, titanium oxide, light anhydrous silicic acid, etc. Adhesive/binding agents include starch, dextrin, tragacanth gum, gelatin, Polyvinylpyrrolidone, polyvinyl alcohol, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropyl starch, crystalline cellulose, pectin, polypectic acid, sodium polypectate, polyacrylic acid, sodium polyacrylate, polyacrylic acid copolymer,
Polymethacrylic acid, polysodium methacrylate, polyhydroxyethyl methacrylate,
Carboxymethylcellulose, sodium carboxymethylcellulose, gum arabic, sodium alginate, etc., and examples of disintegrants include starch, crystalline cellulose, calcium carboxymethylcellulose, agar powder, mannan, etc.
Disintegration regulators include oil, fat, wax, paraffin, stearic acid, magnesium stearate, etc. Colorants include, for example, tar pigments that can be used in pharmaceuticals as specified by the Ministry of Health and Welfare Ordinance, and flavoring agents include Examples of lubricants include fumaric acid, tartaric acid, menthol, loin oil, eucalyptus oil, lemon oil, citrus flavor, etc. Lubricants include, for example, talc, starch, magnesium and calcium stearate, boric acid, paraffin, cocoa butter, macrogol , leucine, sodium benzoate, etc. The formulation of the present invention includes the above-mentioned formulation base, the above-mentioned calcitonin, and one or two selected from the group consisting of the above-mentioned ascorbic acids, acidic amino acids, citric acids, unsaturated fatty acids, and salicylic acids. It contains the above. The preparation of the preparation of the present invention includes a preparation base, calcitonin and ascorbic acids, acidic amino acids,
A predetermined amount of one or more selected from the group consisting of citric acids, unsaturated fatty acids, and salicylic acids is taken, uniformly dispersed, and made into tablets using an ordinary tablet machine. This can be done either by forming a two-layer tablet with a non-adhesive layer so that only one side of the tablet adheres to the oral mucosa, or by forming it into a powder, powder, or granules as necessary. In the case of an oily product, it can be used as a powder by encapsulating and adsorbing it in an excipient or an adsorbent such as magnesium aluminate metasilicate. When carrying out the present invention, the amount of calcitonin to be contained and dispersed in the calcitonin preparation for oral administration varies depending on age, body weight, and indication, but it cannot be generalized, but is usually 1 to 4000 MRC units, preferably
It is 10~2000 MRC units. In addition, in the present calcitonin preparation for oral administration,
Compounds used as calcitonin absorption enhancers, i.e. ascorbic acids, acidic amino acids,
The total amount of one or more compounds selected from the group consisting of citric acids, unsaturated fatty acids, and salicylic acids is preferably 0.01 to 50% by weight, particularly preferably 0.1 to 20% by weight of the oral calcitonin preparation. Weight%. A preferred embodiment of the present invention is as follows. hydroxypropyl cellulose
85 parts, polyacrylic acid copolymer (Carbopol
Take 15 parts of salmon calcitonin (approximately 1500 MRC units/mg), 0.59 parts of ascorbic acid, and 0.5 parts of magnesium stearate, use a mixer to obtain a homogeneous powder, and use this as an adhesive layer for oral mucosa. A powder consisting of 92.5 parts of lactose and 7.5 parts of carboxymethylcellulose calcium was used as a powder for a non-adhesive layer to the oral mucosa, and an adhesive layer containing about 120 MRC units of calcitonin weighed 15% using a two-layer tablet machine.
Mucoadhesive bilayer tablets for oral administration are produced, consisting of 40 mg non-adhesive weight. As mentioned above, when the preparation of the present invention is administered into the oral cavity, calcitonin is efficiently absorbed,
Therefore, such a preparation is extremely significant as a non-injectable calcitonin preparation that can overcome the drawbacks of injectable calcitonin preparations. Hereinafter, the present invention will be explained in detail with reference to Examples. Example 1 As a base for sublingual tablets, 0.3 g of polyacrylic acid copolymer (Carbopol 934), 1.7 g of hydroxypropyl cellulose, and magnesium stearate
10 mg was placed in an agate mortar and kneaded well in the mortar. To this, 0.302 mg of salmon calcitonin (approximately 1500 MRC units/mg) weighed using an electric balance and 200 mg of ascorbic acid were added, and the salmon calcitonin and ascorbic acid were mixed with the base in a mortar to form a compact calcitonin sublingual tablet. A powder was obtained. By compressing this into tablets using a normal tablet machine, the weight of approximately 20
mg, and sublingual tablets for rats with a diameter of about 5 mm were obtained. This drug was administered sublingually to male SD rats (body weight 190-210 g), and the serum calcium concentration was measured at 1, 2, 3, 5, and 7 hours after administration. We investigated the absorption from Five rats were used for each blood sampling. Serum calcium was measured using a calcium measurement kit (manufactured by Yatron). A blank sublingual tablet containing equivalent calcitonin but no ascorbic acid was prepared in the same manner as above, administered in the same manner, blood was collected, and the serum 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 1.0 g of hydroxypropyl cellulose was dissolved in 10 ml of physiological saline to form a 10% (W/V) viscous base solution. [Asu ¹ , ⁷ ]-eel calcitonin (approx.
0.153 mg (3000 MRC units/mg) and 300 mg of sodium ascorbate were added and completely dissolved to obtain a transparent and uniform solution for calcitonin sublingual administration. In the same manner as in Example 1, 0.1 ml of this drug was intravenously administered sublingually to male SD rats (body weight 190-210 g) within 10 minutes, and the serum calcium concentration was measured 1, 2, and 3 hours after administration. Table 2 shows the degree of decrease (%) in serum calcium levels compared to the administration of a blank formulation solution containing no sodium ascorbate.

[Table] Example 3 As a base for sublingual tablets, 0.4 g of polyacrylic acid copolymer (Carbopol 934), 1.6 g of hydroxypropylcellulose, and magnesium stearate
10.2 mg was taken in an agate mortar and kneaded well. Weighed using an electric balance [Asu ¹ , ⁷ ] - eel calcitonin 0.250 mg and sodium glutamate 300 mg
mg was taken and thoroughly mixed with the base in a mortar to obtain a compact powder for calcitonin sublingual tablets. The powder for calcitonin sublingual tablets obtained in this way is compressed using a normal tablet machine for single-layer tablets, and the weight is approximately 20.
A sublingual tablet for rats with a diameter of about 5 mm was obtained. In the same manner as in Example 1, SD male rats (body weight 190~
210g) sublingually, and after administration 1, 2, 3,
The serum calcium concentrations at 5 and 7 hours are shown in Table 3 as the degree of decrease (%) in serum calcium values compared to the blank preparation containing no monosodium glutamate.

[Table] Example 4 Sublingual tablets containing 8.0 MRC units of salmon calcitonin and about 10% of the base weight of acidic amino acids as shown below were prepared and administered to SD male rats in the same manner as in Example 1. (body weight 190-210g) sublingually,
The serum calcium concentrations 1 hour and 2 hours after administration are shown in Table 4 as the degree of decrease (%) in serum calcium values compared to the blank formulation containing no acidic amino acids.

[Table] Example 5 1 ml of base solution prepared in the same manner as Example 2
Then, take 1.0 mg of porcine calcitonin (approximately 60 MRC units/mg) weighed using an electric balance and 50 mg of citric acids as shown below, and completely dissolve them to obtain a transparent and uniform calcitonin preparation solution for sublingual administration. I got it. In the same manner as in Example 1, 0.1 ml of this drug was instilled sublingually into SD male rats (body weight 190-200 g) over a period of 10 minutes, and the serum calcium concentration was measured 1, 2, and 3 hours after administration. Table 5 shows the degree of decrease (%) in serum calcium value compared to the case of administering a blank formulation solution containing no citric acids.

[Table] Example 6 [Asu ¹ , ⁷ ] - Eel calcitonin at 10.0 MRC
Sublingual tablets containing approximately 3% of the base weight of unsaturated fatty acids as shown below were prepared in the same manner as in Example 1, and administered to male SD rats (body weight 190-200 g).
The serum calcium concentration 2 hours after administration is shown in Table 6 as the degree of decrease in serum calcium value (%) compared to the blank formulation containing no unsaturated fatty acids. Ta.

[Table] Example 7 Sublingual tablets containing 5.0 MRC units of salmon calcitonin and approximately 8% of the base weight of salicylic acids as shown below were prepared in the same manner as in Example 1, and were administered to male SD rats (body weight 190-210g) was administered sublingually, and the serum calcium concentration was measured 2 hours after administration.
Table 7 shows the degree of decrease (%) in serum calcium values compared to the blank formulation containing no salicylic acids.

[Table] Example 8 [Asu ¹ , ⁷ ] - Example of a sublingual tablet containing 6.0 MRC units of eel calcitonin, ascorbic acid at 5% of the base weight, and sodium citrate at 3% of the base weight It was prepared in the same manner as in 1 and administered sublingually to SD male rats (body weight 190-200 g).
The serum calcium concentration at 1, 2, 3, 5, and 7 hours after administration was compared with the blank preparation containing no ascorbic acid and sodium citrate as the degree of decrease in serum calcium value (%). Shown in the table.

[Table] Example 9 Sublingual tablets containing 5.0 MRC units of salmon calcitonin and 2, 3, and 2% of the base weight of sodium glutamate, sodium citrate, and sodium ascorbate, respectively, were prepared in the same manner as in Example 1. SD male rats (body weight 190~
Administer 210g) sublingually, and after administration 1, 2,
Table 9 shows the serum calcium concentration at 3, 5, and 7 hours as the degree of decrease (%) in serum calcium value compared to the case of a blank suppository that does not contain sodium glutamate, sodium citrate, and sodium ascorbate. It was shown to.

【table】

Claims (1)

[Claims] 1. It is characterized by containing calcitonin and one or more selected from the group consisting of ascorbic acids, acidic amino acids, citric acids, unsaturated fatty acids, and salicylic acids. A calcitonin preparation for oral administration. 2 Ascorbic acids are ascorbic acid and/or
or sodium ascorbate, the calcitonin preparation according to claim 1. 3 Acidic amino acids include glutamic acid, sodium glutamate, sodium pyroglutamate,
The calcitonin preparation according to claim 1 or 2, which is one or more selected from the group consisting of monosodium N-lauroylglutamate, aspartic acid, sodium aspartate, and potassium aspartate. 4 Claims 1 to 3, wherein the citric acids are citric acid and/or sodium citrate
The calcitonin preparation according to any one of paragraphs. 5. Any one of claims 1 to 4, wherein the unsaturated fatty acids are one or more selected from the group consisting of oleic acid, sodium oleate, linoleic acid, and sodium linoleate. The calcitonin preparation according to item 1. 6. The calcitonin preparation according to any one of claims 1 to 5, wherein the salicylic acids are one or two selected from the group consisting of sodium salicylate, acetylsalicylic acid, and para-aminosalicylic acid.