JPH04327531A - Taste-improving oral drug composition - Google Patents

Abstract

PURPOSE:To provide an oral drug composition improved in unpleasant tastes thereof such as a bitter taste and capable of readily absorbed from digestive tracts by compounding the acid adduct of a basic beta-lactam antibiotic with a pharmacologically acceptable weakly alkaline substance. CONSTITUTION:An oral drug composition produced by compounding an antibiotic with a pharmacologically acceptable weakly alkaline compound selected from organic acid alkaline metal salts, organic acid alkaline earth metal salts, amino acids and alkali metal salts thereof, antacids and weakly alkaline inorganic compounds except the antacids preferably in a weight ratio of 100:20-300 in order to improve the unpleasant tastes such as bitter taste of the ester type prodrug basic beta-lactam antibiotic acid adduct having a pKa of 4-11. The improved oral drug composition is readily taken by children sensitive to the bitter taste, has good absorbability in digestive tracts, and exhibits good bio- availability.

Description

Detailed Description of the Invention [0001] [Industrial Application Field] The present invention relates to an ester prodrug type basic β-lactam antibiotic with a pKa of 4 to 11 (hereinafter simply referred to as "basic β-lactam antibiotic"). The present invention relates to an oral pharmaceutical composition that has improved unpleasant tastes such as bitterness of acid addition salts of antibiotics. [Prior Art] Conventionally, acid addition salts of basic β-lactam antibiotics such as cefcaneldaloxate hydrochloride, cefotiamhexetil hydrochloride, renampicillin hydrochloride, and bacampicillin hydrochloride generally have unpleasant tastes such as bitterness. Therefore, when administering drugs containing them orally, there are problems such as bitterness and difficulty in swallowing. This was an even more serious problem in children who were sensitive to bitter tastes. On the other hand, an acid addition salt of a basic β-lactam antibiotic is coated with a binder, a masking agent, etc.
Attempts have been made to improve bitterness, etc., but these preparations have thick coating layers and poor solubility, resulting in poor absorption of the acid addition salt of the basic β-lactam antibiotic from the gastrointestinal tract. However, there were problems such as low bioavailability. [0004] Therefore, attempts have been made to develop easy-to-drink oral preparations that have improved unpleasant tastes such as bitterness of acid addition salts of basic β-lactam antibiotics, but a fully satisfactory preparation has not been obtained. Therefore, the development of such a formulation is eagerly awaited. SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide an oral pharmaceutical composition in which the unpleasant taste such as bitterness of acid addition salts of basic β-lactam antibiotics is improved. It is to be. [Means for Solving the Problems] As a result of extensive research to achieve the above object, the present inventors have found that the acid addition salts of basic β-lactam antibiotics are pharmacologically acceptable. The present invention was completed based on the discovery that unpleasant tastes such as bitterness can be improved by blending a weakly alkaline compound with a weakly alkaline compound, and that absorption from the digestive tract is facilitated. The present invention has been completed based on such new findings, and has been developed to provide a pharmacologically acceptable acid addition salt of an ester prodrug type basic β-lactam antibiotic with a pKa of 4 to 11. This is an oral pharmaceutical composition with improved bitterness, which contains a weakly alkaline drug. Acid addition salts of basic β-lactam antibiotics related to the present invention include cefcaneldaloxate hydrochloride, cefothiamhexetil hydrochloride, renampicillin hydrochloride, bacampicillin hydrochloride, talampicillin hydrochloride, pivmecillinam hydrochloride, sultamicillin tosylate, etc. Preferred examples include cefcaneldaloxate hydrochloride, cefotiamhexetil hydrochloride, renampicillin hydrochloride, and bacampicillin hydrochloride. Examples of acid addition salts include mineral acid salts such as hydrochloric acid and sulfuric acid, and organic acid salts such as acetic acid, tosylic acid, and maleic acid. The basic β-lactam antibiotic according to the present invention has a pKa of 4 to 11, preferably 5 to 1.
0, more preferably 6 to 9.5. [0010] The pharmacologically acceptable weakly alkaline compound according to the present invention is not particularly limited as long as it can convert the acid addition salt of the basic β-lactam antibiotic into a free basic drug; % aqueous solution pH is usually 7-11,
Particularly preferred are those having a molecular weight of 7 to 10. Examples of weakly alkaline compounds include alkali metal salts of organic acids, alkaline earth metal salts of organic acids, amino acids, alkali metal salts thereof, antacids, and weakly alkaline inorganic compounds other than antacids. Specifically, examples of alkali metal salts of organic acids and alkaline earth metal salts of organic acids include citric acid, maleic acid, fumaric acid, tartaric acid, succinic acid, malic acid, malonic acid, etc. Examples of amino acids and their alkali metal salts include glycine, potassium salt, magnesium salt, calcium salt, etc.
Alanine, leucine, isoleucine, valine, serine,
Amino acids such as threonine, aspartic acid, glutamic acid, asparagine, glutamine, lysine, arginine, and histidine, and their sodium salts and potassium salts are used as antacids, aluminum silicate, aluminum hydroxide, magnesium aluminate silicate, and hydrotalcitate. , magnesium aluminate metasilicate, magnesium oxide, magnesium hydroxide, magnesium carbonate, calcium carbonate, sodium hydrogen carbonate, etc.; weakly alkaline inorganic compounds other than antacids include potassium phosphate, potassium carbonate, potassium hydrogen carbonate, phosphoric acid. Examples include sodium and soda carbonate. The weakly alkaline compound in the oral pharmaceutical composition of the present invention is usually 5 to 800 parts by weight, preferably 10 to 500 parts by weight, per 100 parts by weight of the acid addition salt of the basic β-lactam antibiotic. More preferably 20-30
It is blended in a proportion of 0 parts by weight. The oral pharmaceutical composition of the present invention may optionally contain additives (such as binders, masking agents, excipients, flavoring agents, etc.).
(fragrance, lubricant, disintegrating agent, buffering agent, antioxidant, etc.) may be contained. Binders and masking agents used in this case include starches, dextrin, gum arabic, gelatin, sodium carboxymethylcellulose (CM
C-Na), methylcellulose (MC), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP)
, hydroxypropyl methylcellulose (HPMC),
Hydroxypropyl cellulose (HPC), macrogols, ethyl cellulose (EC), vinyl acetate resin, aminoalkyl methacrylate copolymer (Euragid RS), aminoalkyl methacrylate copolymer (Euragid E), polyvinyl acetal diethylene amino acetate (AEA), cellulose Acetate phthalate (CAP), methacrylic acid-alkyl methacrylate copolymer (Euragid L), hydroxypropyl methyl cellulose phthalate (HPMCP), hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, crystalline cellulose, hydroxypropyl starch, dimethylaminoethyl meth Examples include acrylic acid methyl methacrylic acid copolymer, methyl vinyl pyridine methyl acrylate acrylic acid copolymer, wax, higher fatty acid, triglyceride, and preferably PVP, HPMC, EC, AEA, and Euragid E. Excipients include lactose, starch, sugar, calcium carbonate, calcium phosphate, crystalline cellulose, etc., flavoring agents include sucrose, mannitol, saccharin, salt, etc., and flavoring agents include lemon oil, orange oil, vanillin, etc. However, as a lubricant, magnesium stearate, talc, calcium stearate, sucrose fatty acid ester, etc. are used, as a disintegrant, carboxymethyl cellulose calcium, talc, starch, hydroxypropyl cellulose, hydroxypropyl starch, etc. are used, and as a buffer agent, amino acid is used. Examples of antioxidants include acetic acid, sodium alginate, sodium benzoate, and the like, and sodium hydrogen sulfite and the like are examples of antioxidants. The oral pharmaceutical composition of the present invention comprises basic β-
By blending a weakly alkaline compound with the acid addition salt of a lactam antibiotic, for example, a pharmacologically acceptable weakly alkaline compound can be powdered, suspended, or emulsified with the acid addition salt of a basic β-lactam antibiotic. Alternatively, it can be produced by mixing in a solution state using a fluidized bed granulator, rotary type granulator, spray drying granulator, high-speed mixing granulator, microencapsulation method machine, etc., but preferably as follows. Manufactured by The acid addition salt of the basic β-lactam antibiotic is prepared in a solution or suspension of the above-mentioned excipients, binders or masking agents (for example, a methylene chloride solution, a methylene chloride-ethanol mixture, an ethanol- Aqueous mixture, aqueous solution, etc.) is mixed and kneaded, and dried to obtain a powder. Next, this powder is coated and granulated using a fluidized bed granulator or the like, preferably using a masking agent or the like, to obtain elementary granules. It is produced by mixing a weakly alkaline compound with this elementary granule as it is, or as a granulated product thereof, or as a suspension in the presence of a binder. The granules thus obtained may be made into capsules, fine granules, granules, dry syrups, etc. according to methods known per se, and other additives may be added as desired. It may also be used as a formulation as described above. Examples of additives include the binders, masking agents, excipients, flavoring agents, fragrances, lubricants, and disintegrants exemplified above. [Examples] Examples and comparative examples are given below to explain the present invention in detail, but the present invention is not limited by these in any way. Example 1 45 g of cefcaneldaloxate hydrochloride, 100 g of lactose and 50 g of Avicel were mixed and placed in a fluidized bed granulator, and granulated with an aqueous solution of 5 g of polyvinylpyrrolidone to obtain fine granules. These fine particles were coated with 1000 ml of a methylene chloride-ethanol mixture of 50 g of ethyl cellulose and 10 g of talc to obtain fine particles. 35 in this fine grain
g of trisodium citrate powder were mixed to obtain bitter taste-masked cefcaneldaloxate hydrochloride fine granules. Separately, a mixture of 4 g of saccharin sodium and 300 g of sucrose was granulated in a conventional manner using a 2% aqueous solution of hydroxypropyl cellulose to obtain flavoring granules. Granules of cefcaneldaloxate hydrochloride, flavoring granules, and a small amount of lemon oil are mixed so that the cefcaneldaloxate hydrochloride content is 100 mg per 1 g to produce fine granules with improved bitterness and easy to take. Obtained. Example 2 250 g of bacampicillin hydrochloride and 3 g of ethyl cellulose
A fine powder was obtained by spray drying the ethanol-methylene chloride mixture. This fine powder was mixed with 25 g of stearic acid, 50 g of tristearic acid glyceride, and 5 g of ethyl cellulose.
Coating was performed with 0 g of a methylene chloride-ethanol mixture to obtain fine particles. Mix 125g of trisodium citrate and saccharin with these fine particles, add sucrose,
The mixture was mixed so that the content of bacampicillin hydrochloride was 100 mg per gram to obtain fine granules with improved bitterness and easy to take. Example 3 According to Example 2, easy-to-take fine granules with improved bitterness and a content of renampicillin hydrochloride of 100 mg per gram were obtained. Example 4 According to Example 1, easy-to-take fine granules with improved bitterness and a content of cefotiamhexetil hydrochloride of 100 mg per gram were obtained. Example 5 According to Example 2, by using sodium tartrate in place of trisodium citrate, easy-to-take fine granules with improved bitterness and a cefcaneldaloxate hydrochloride content of 100 mg per gram were obtained. . Example 6 According to Example 2, disodium phosphate was used in place of trisodium citrate to obtain fine granules with improved bitterness and an easy-to-take granule containing 100 mg of bacampicillin hydrochloride per gram. Example 7 According to Example 1, by using sodium glutamate in place of trisodium citrate, fine granules with improved bitterness and an easy-to-take granule containing 100 mg of cefotiam hexetyl hydrochloride per gram were obtained. Example 8 90 g of cefcaneldaloxate hydrochloride, 100 g of lactose and 90 g of cornstarch were mixed and placed in a fluidized bed granulator, and granulated with 200 ml of an aqueous ethanol solution in which 15 g of polyvinylpyrrolidone was dissolved to obtain granules. . This granule 400
g was coated with 500 ml of a methylene chloride-ethanol mixture of 10 g of ethyl cellulose to obtain fine particles. Granules of 50 g of sodium tartrate (containing an appropriate amount of excipients) were mixed with the fine particles to obtain fine particles of cefcaneldaloxate hydrochloride whose bitter taste was masked. Hereinafter, according to Example 1, the cefcaneldaloxate hydrochloride content was 10 per gram.
The powder was mixed to give a concentration of 0 mg to obtain fine granules with improved bitterness and easy to take. Example 9 According to Example 8, trisodium citrate was used in place of sodium tartrate to obtain fine granules with improved bitterness and easy-to-administer cefcaneldaloxate hydrochloride content of 100 mg per gram. . Example 10 According to Example 8, sodium succinate was used in place of sodium tartrate to obtain fine granules with improved bitterness and an easy-to-take granule containing 100 mg of cefcaneldaloxate hydrochloride per gram. Comparative Example 100 g of cefcaneldaloxate hydrochloride, 3 g of saccharin sodium, a trace amount of orange oil and mannitol were added.9
After weighing 50 g, the mixture was granulated with a 2% aqueous solution of hydroxypropyl cellulose using a fluidized bed granulator to obtain fine granules containing 100 mg of cefcaneldaloxate hydrochloride per gram. Test Example Using the fine particles of Examples 8 to 10 and Comparative Example as samples, a bitterness test and an oral absorption comparison test were conducted by a panel of 10 people. [0031] [Table 1] [Table 2] [0033] From the above results, the cefcaneldaloxate hydrochloride fine granules obtained in Example 9 have no unpleasant taste such as bitterness and are very easy to take. It was clear that the drug exhibited good oral absorption (bioavailability). Effects of the Invention The oral pharmaceutical composition of the present invention has basic β
- The unpleasant taste of acid addition salts of lactam antibiotics has been improved, making it easier to take even for children who are sensitive to bitter tastes, and having good absorption in the gastrointestinal tract and good bioavailability. shows.

Claims (3)

[Claims] Claim 1: An oral product with improved bitterness, which is prepared by adding a pharmacologically acceptable weakly alkaline compound to an acid addition salt of an ester prodrug type basic β-lactam antibiotic with a pKa of 4 to 11. Pharmaceutical composition. 2. The pharmacologically acceptable weakly alkaline compound is an alkali metal salt of an organic acid, an alkaline earth metal salt of an organic acid, an amino acid and its alkali metal salt, an antacid,
The oral pharmaceutical composition according to claim 1, which is at least one selected from weakly alkaline inorganic compounds other than antacids. 3. The oral pharmaceutical composition according to claim 1, wherein the basic β-lactam antibiotic is cefcaneldaloxate hydrochloride, cefotiamhexetil hydrochloride, renampicillin hydrochloride, or bacampicillin hydrochloride.