JPH0383917A - Enteric preparation and its preparation - Google Patents

Abstract

PURPOSE:To provide a preparation enabling to exhibit depressed decomposition absorbability in stomachs and small intestines and subsequently release a solid drug in large intestines on the oral administration of the preparation by coating the surface of the solid drug with an aliphatic polyester which is a biodegradable, absorbable polymer. CONSTITUTION:An enteric preparation is prepared by coating a solid drug with a biodegradable, absorbable polymer (preferably having a mol.wt. of 6000-200000, especially preferably 10000-100000) such as polylactic acid, polyglycolic acid, lactic acid/glycolic acid copolymer, polymalic acid, poly epsilon- caprolactone, lactic acid or glycolic acid/caprolactone copolymer or poly beta- hydroxybutyrate. The preparation is suitable for active peptides such as insulin and human interferon readily decomposed with enzymes in the small intestines and further suitable for contrast media such as barium sulfate and magnesium sulfate used for examinational diagnoses.

Description

[Detailed description of the invention]

[Field of application of ML] The present invention relates to an enteric-coated preparation for solid drugs, and a method for producing the same. [Prior art] From the viewpoint of cost and convenience, there have been many advantages over single-administration drugs that patients can take with their bare hands.Therefore, the development of oral preparations↓ However, many of the drugs are inactivated by the antiseptic solution in the clay pipe, so 1M molten bamboo preparation is used. It has the following advantages: ■Protects drugs/?1 that are decomposed by acids from %7 liquids. ■It f+6beJU due to drug Il!!Igeki
I-Preventing qi, (3) No. 1 in the intestines. ) to expect a partial effect. (4) We expect that it will be absorbed in the intestine at the highest δ degree. Conventionally, shellac, cellulose acetate phthalate, hydroxyzolobyl methylcellulose phthalate, methylcellulose succinate, hydroxypropyl methylcellulose succinate, and the like are known as enteric coating agents. These i-soluble substances are insoluble under acidic conditions. Soluble in neutral region and under alkaline conditions. Therefore. By using these enteric-coated substances-・Treasure drug 1
For example, erythromycin, sodium salicylate, aminovirine, aspirin or enteric disinfectants were suitable. However, if the in-vivo kinetics of the drug after oral administration of L1 were investigated, conventional Il! 3 Soluble drugs often undergo considerable deactivation through hydrolysis and metabolism before they can be effectively absorbed, resulting in low bioavailability.Especially in the gastrointestinal tract of the small intestine, e.g. In most cases, it is an administration route that facilitates drug metabolism. On the other hand, in the large intestine, the 9 elements of digestion are J-J/)', and the intestinal lining is responsible for the 1 metabolism, and various metabolic modes are known. So 11. A new drug delivery system (DO3) has been proposed that has targeting properties to the large intestine as a polymeric carrier that dissolves or decomposes after reaching the large intestine without being dissolved or degraded in the small intestine. (Ai, 5arfran, el al. 5science, Vol, 2:13.1081.InF
+6) This utilizes a vinyl polymer bridged with an M/f group adiazo group, but since compounds with azo groups have a safety problem in terms of striping, it is not suitable for use as a pharmaceutical preparation. isn't it. [Problems that 91 Ming attempts to solve] These known enteric-coated substances are DDS that have certain effects.
&W provides active peptides. For example, insulin, interferon, somatomedin, calcitonin, etc., are degraded by digestive enzymes in the small intestine no matter how soluble they are, so no efficacy can be expected from oral Jp. Therefore, the present invention was developed by intensively studying the formulation of a formulation that has a relatively simple preparation method and a stable sustained release of the drug in the large intestine. , 8゛6min-f. By coating with aliphatic polyester, it does not decompose at all in the blue, but after decomposition starts in the small intestine, the coated aliphatic polyester rapidly decomposes in the large intestine, and its As a result, we have completed the present invention by discovering that it is possible to formulate enteric-coated formulations that have never been seen before, in which the drug is released in a sustained manner. [Means for solving the IfI problem] The present invention By coating the surface of a solid drug with aliphatic polyester, which is a molecule, the drug is released in the large intestine after passing through the mouth and small intestine in the oral stage.

The present invention proposes an enteric-coated formulation that is targeted to the large intestine and has an 0f-capability. Di aliphatic polyester, which is a biodegradable and absorbable polymer, was used as a sustained release JJF of S, 1! It has been actively researched since the 1970s and even in 1981/E.
83), L, and Kashi, all of which are intended for use as injectables or injectables, and no studies have been found regarding oral administration. The present inventor has discovered that the hydrolyzability of polylactic acid, which is one of the representative aliphatic polyesters, is largely dependent on the atmosphere, that is, the temperature, Pt, and is hardly decomposed in the acidic region of P II 1 to 5. PI! Although hydrolysis occurs in the neutral region of 6 to 7, it takes a long time. 51. In the alkaline range of pH 8-9, it will be hydrolyzed in a short time. I started using it. This knowledge constitutes one aspect of the present invention)1. ea. That is, the human digestive tract consists of three parts: YI, small intestine, and large intestine.
The small intestine is further divided into three parts: the adipose intestine, the jejunum, and the ileum.
part,! ! Ta. The large intestine is composed of three parts: the caecum, the colon, and the ri''ij horse.The Pl■ of -Il is.The gastric juice itself is around 1.0, but it is diluted by water and changed by 47% of the food. And empty Bl#, 1゜2 for de
~1.81 at mealtimes ranges from 3.0 to 5.0. Further, P11 of the small intestine is 5.-7, and around 8 in the large intestine. If you administer 11 drugs, the passage route will consume 1 ph,
It passes through the small intestine and then into the large intestine. Therefore. ]) II in the transit route shifts from acidity to alkalinity, and it can be seen that it is related to the influence of P II on the hydrolyzability of polylactic acid described above. The solid agent in the present invention includes a polypeptide or protein drug, an antibacterial drug, an anti-Ml ulcer agent, an antipyretic and antiinflammatory analgesic, an antitussive expectorant, an antidepressant, a muscle relaxant, an antiulcer agent, and an antiallergic agent. , 7E diuretic, mm disease treatment agent 9 cardiotonic agent, vasodilator, arrhythmia treatment agent, anticoagulant, hemostatic agent, narcotic antagonist, hormonal agent, immunostimulant, antiepileptic agent, antihistamine agent, or diagnostic agent And so on. Among these drugs, active peptides that are small and easily degraded by enzymes in the intestine, such as insulin, interferon, somatomedin, and calhitonin, are particularly suitable. Furthermore, it is suitable for contrast agents such as barium sulfate and magnesium sulfate for examination and diagnosis. Furthermore, mixed micelles of lipids such as linoleic acid or oleic acid and a surfactant, or medium-chain fatty acid capric acid, etc., can be added as an absorption promoting agent that acts in the large intestine. Aliphatic polyesters, which are biodegradable and absorbable polymers used in the present invention, include polylactic acid (including 1-body, D-body, TRI, and L-body), polyglycolic acid, lactic acid/glycolic acid copolymer, polymalic acid, lactic acid/ Malic acid copolymer, glycolic acid/malic acid copolymer, poly-ε-caprolactone, lactic acid/caprolactone copolymer, glycolic acid/caprolactone copolymer, poly-β-hydroxybutyrate, hydroxybutyrate/valerate copolymer Polymer, polydepsipeptide, poly-α-cyanoacrylate. These are polyacid anhydrides, polyethylene glycol/lactic acid copolymers, sebacic acid/ethylene glycol copolymers, or other aliphatic polyesters. The molecular weight of the aliphatic polyester is about 2000 to about 60
Although a wide range of 0000 is available. Although any molecular weight is suitable in relation to the desired sustained release properties, those having a molecular weight in the range of 1oooo to 1ooooo are particularly preferred. The enteric preparation coating base of the present invention is a polylactic acid homopolymer or copolymer alone, or a plasticizer suitable for softening the coating film, such as triacetin, sugar ester, phthalate ester, and polyethylene glycol. Propylene glycol, triethyl citrate, diethyl tartrate, glycerin, etc. are used. The above-mentioned aliphatic polyester alone or mixed with a plasticizer can be coated on the surface of a solid drug using, for example, an organic solvent 1 which is a solvent for the aliphatic polyester. Acetone, methylene chloride, ethyl acetate, ethanol, tetrahydrofuran, toluene, xylene. A coating liquid can be obtained by dissolving a 1M aliphatic polyester in a mixed solvent of one or more of dioxane, acetonitrile, trichloroethane, chloroform, acetic acid, formic acid, acetic anhydride, dimethylformamide, dimethylacetamide, etc. In this case, the concentration is preferably 1 to 30% by weight.The coating liquid obtained in this way may contain various additives, such as colorants, flavoring agents, fragrances, or absorbing agents. A promoter or the like may be added. The solid dosage form applicable to the present invention is one tablet or pill. Examples include granules and capsules, and as a coating method, devices such as a pan coating device, a drum type coating device, or a fluid coating device can be used. still. 1lf8 formulation of the present invention as well as the solid formulation described in E. It can also be applied to encapsulation of syrups and oils into liquid formulations. Furthermore, it can be applied not only to the coating and encapsulation of a solid drug as described in 1- above, but also as granules, rondos, and pellets by uniformly dispersing the drug in a polylactic acid matrix. Effects of the Invention The wQfB drug obtained by the present invention has a drug that is biodegradable and absorbable in the small intestine by coating it with a polylactic acid polymer, which is a hydrophobic polymer that is biodegradable and absorbable. This is a new type of enteric-coated preparation in which the drug is released when it reaches the large intestine.
l! Oral administration of the active peptide that could not be expressed was i+7.
It became Noh. The present invention will be explained in detail by giving examples below. Example] A coating solution was prepared by dissolving poly-〇,L-lactic acid having a quantitative amount of 46,000 min'F in methylene chloride to a concentration of 10'R%. Next, lactose/starch tablets (:l OOtag /tablet) were coated with this coating solution by a spray method until Coating 15 was 10 g per #2 to obtain coated tablets. The test results for coated tablets were as follows. Disintegration properties of tablets in Mcllvaini 9 buffer solution: PH3.0 Not disintegrated 5.02-3 hours 7.0 0.5-1 hour 8.0 10-20 minutes Comparison fit Commercially available hydroxypropyl methylcellulose (90SH
-4000) in water and apply a coating solution with a concentration of 5) It M% to X*t.Similarly to Example 1, this coating solution was sprayed onto lactose/starch tablets (300 μ/tablet) to coat the tablets. Coated tablets were obtained by coating until each tablet contained 10 sweetfish. The test results for coated tablets were as follows. M o ] l v a i n loose FI! Disintegration of tablets in solution 11: PTR 3.0 1-2 hours 5.0 30-60 minutes 7.01-2 minutes 8.0 Instantaneous Example 2 Molecular weight 52000 1], L-lactic acid/glycolic acid synergism The combined product (m-acid ratio 75:25 mol%) was dissolved in methylene chloride to a concentration of 5% to prepare a coating solution. Separately, 2 u tt of commercially available insulin was mixed with lactose and starch in advance and tablets (200 Akira/
Tablets) were prepared. These tablets were coated with the above coating liquid by a spray method so that the coating amount was Log per tablet to obtain coated tablets. In addition, diabetic rats were prepared by administering 75 g/g of streptocytosine into the peritoneal cavity of female Wistar rats. This tablet was orally administered to rats, and blood was collected from the tail vein every few hours to determine the blood glucose level. ) method (glucose B
Test, Wako Pure Chemical Industries, Ltd.). Blood glucose levels following oral administration of enteric-coated insulin tablets in diabetic rats began to decrease 5 hours after administration, and after 1 hour.
A 5-hour period of depression was observed. Comparative Example 2 An experiment was carried out in the same manner as in Example 2, except that commercially available hydroxypropyl methylcellulose (90SH-4000) was used as the coating substrate, and no decrease in blood sugar levels in rats was observed.

Claims (1)

[Scope of Claims] 1) An enteric-coated preparation characterized in that an aliphatic polyester, which is a biodegradable and absorbable polymer, is used as an enteric-coated coating base. 2) Aliphatic polyesters which are biodegradable and absorbable polymers include polylactic acid, polyglycolic acid, lactic acid/glycolic acid copolymer, polymalic acid poly-ε-caprolactone, lactic acid/caprolactone copolymer, glycolic acid/caprolactone copolymer. A patent characterized in that it is a polymer, poly-β-hydroxybutyrate, hydroxybutyrate/valerate copolymer, polydepsipeptide, poly-α-cyanoacrylate, polyacid anhydride, polyethylene glycol/lactic acid copolymer The enteric-coated preparation according to claim 1. 3) A method for producing an enteric-coated preparation, which comprises coating a solid preparation with a film of an enteric-coated coating base. 4) The solid agent is a polypeptide or protein drug, an antibacterial drug, an antitumor drug, an antipyretic and antiinflammatory analgesic, an antitussive expectorant, an antidepressant, a muscle relaxant, an antiulcer agent, an antiallergic agent,
Antihypertensive diuretics, antidiabetic agents, inotropes, vasodilators, antithermal pulse agents, anticoagulants, hemostatic agents, narcotic antagonists, antituberculous agents,
4. The method for producing an enteric-coated preparation according to claim 3, which is a hormonal agent, an immunostimulant, an antiepileptic agent, an antihistamine, or a contrast agent. 5) The enteric coating base film is formed by extrusion molding, calendar molding, or casting molding using aliphatic polyester alone, a biodegradable and absorbable polymer, or a solution or powder mixed with a plasticizer. A method for producing an enteric-coated preparation according to claim 3, which is obtained by a method. 6) The intestine according to claim 4, wherein the plasticizer is one or a mixture of two or more of triacetin, sugar ester, phthalate ester, polyethylene glycol, propylene glycol, triethyl citrate, jetyl tartrate, and glycerin. Method for producing soluble preparations.