JPH04327529A - Taste-improving oral agent - Google Patents

Abstract

PURPOSE:To provide a taste-improving oral agent improving unpleasant tastes such as bitter tastes, readily administered to children, having good absorbability in digestive tracts and exhibiting good availability by coating a nucleus containing the acid adduct of a basic drug with a weakly alkaline compound. CONSTITUTION:An oral agent having an improved bitter taste and produced by coating a nucleus containing the acid adduct (e.g. hydrochloride, sulfate, acetate or citrate) of a basic drug with a pharmacologically acceptable weakly basic alkaline inorganic compound such as an organic acid alkali(ne earth) metal salt, an amino acid or an alkali metal salt thereof, an antacid, or a weakly alkaline inorganic compound except the antacid. The basic drug includes antibiotics (e.g. beta-lactams), anti-histaminic agents (e.g. promethazine hydrochloride), depressants (e.g. tannic acid oxeladin salt), platelet agglutination-inhibiting agents (e.g. ticlopidine hydrochloride) and ataractics (e.g. promethazine hydrochloride) and has a pKa of 4-11, especially 6-9.5.

Description

[Detailed description of the invention]

0001

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to oral preparations that have improved unpleasant tastes such as bitterness of acid addition salts of basic drugs.

0002

[Prior Art] Conventionally, acid addition salts of basic drugs such as cefcaneldaloxate hydrochloride, cefothiam hexetyl hydrochloride, renampicillin hydrochloride, and bacampicillin hydrochloride have unpleasant tastes such as bitterness, so drugs containing these have been used. When administered as an oral formulation, there were problems such as it being bitter and difficult to swallow. This was an even more serious problem in children who were sensitive to bitter tastes.

On the other hand, attempts have been made to improve bitterness by coating acid addition salts of basic drugs with binders, masking agents, etc., but these preparations have thick coating layers and have poor solubility. This has led to problems such as poor absorption of the acid addition salt of the basic drug from the gastrointestinal tract and low bioavailability.

[0004] Therefore, attempts have been made to develop easy-to-drink oral preparations that have improved unpleasant tastes such as the bitterness of acid addition salts of basic drugs, but a fully satisfactory preparation has not been obtained.
The development of such formulations is eagerly awaited.

[0005]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide an oral preparation that has improved unpleasant taste such as bitterness of acid addition salts of basic drugs.

[0006]

[Means for Solving the Problems] As a result of intensive research to achieve the above object, the present inventors have developed a method for converting a core containing an acid addition salt of a basic drug into a pharmacologically acceptable weakly alkaline compound. The present inventors have completed the present invention by discovering that unpleasant tastes such as bitterness can be improved by covering the skin with water, and that absorption from the gastrointestinal tract is facilitated.

The present invention was completed based on such new findings, and consists of a core containing an acid addition salt of a basic drug covered with a pharmacologically acceptable weakly alkaline compound. It is an oral preparation with improved bitterness.

Acid addition salts of basic drugs related to the present invention include mineral acid salts (hydrochlorides, sulfates, etc.), organic acid salts (acetates, tartrates, tosylates, maleates, etc.) of basic drugs. citrate, etc.), and specific examples include antibiotics (
For example, ester prodrug type β-lactam antibiotics such as cefcaneldaloxate hydrochloride, cefothiamhexetil hydrochloride, renampicillin hydrochloride, bacampicillin hydrochloride, talampicillin hydrochloride, pivmecillinam hydrochloride), antihistamines (e.g. promethazine hydrochloride, etc.),
Antitussives (e.g., oxelazine tannate, clobutinol hydrochloride, etc.), antidiarrheal agents (e.g., berberine hydrochloride, etc.),
Antispasmodics (e.g., bropaterine bromide, papaverine hydrochloride, etc.), platelet aggregation inhibitors (e.g., ticlopidine hydrochloride, etc.), tranquilizers (e.g., chloropromazine hydrochloride, promethazine hydrochloride, etc.), preferably cefcanelda hydrochloride. Examples include loxate, cefotiamhexetil hydrochloride, renampicillin hydrochloride, bacampicillin hydrochloride, and sultamicillin tosylate. The pKa of the basic drug is preferably 4 to 4.
11, more preferably 5-10, even more preferably 6-10
It is 9.5.

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 drug into a free basic drug, and the pH of its 1% aqueous solution is Usually 7 to 11, particularly 7 to 10 is preferred. 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 amount of the weakly alkaline compound in the oral preparation of the present invention is 5 parts by weight based on 100 parts by weight of the acid addition salt of the basic drug.
It is used in a proportion of ~800 parts by weight, preferably 10-500 parts by weight, more preferably 20-300 parts by weight.

The core containing an acid addition salt of a basic drug according to the present invention may contain at least an acid addition salt of a basic drug, and may optionally contain additives (such as a binder, a masking agent, an excipient, etc.). additives, flavoring agents, fragrances, lubricants, disintegrants, buffering agents, antioxidants, etc.).

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. These may be incorporated into the core containing the acid addition salt of the basic drug or may be coated on the core, but it is preferable that the core is coated.

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.

[0015] In the oral preparation of the present invention, the core containing the acid addition salt of the basic drug may be directly coated (coated) with the weakly alkaline compound, or may be coated with a void therebetween. good. Further, it may be covered with a weak alkaline compound alone or with a composition consisting of a weak alkaline compound and other components (for example, a binder or a masking agent).

[0016] The oral preparation of the present invention includes, for example, a powder or a weakly alkaline compound on a core containing an acid addition salt of a basic drug.
It is manufactured by coating it as a suspension or solution and making it into granules. Here, the core may be a powder of the acid addition salt of the basic drug itself having an unpleasant taste such as bitterness, and preferably the acid addition salt of the basic drug and the binder or masking agent as described above. solutions or suspensions of agents (e.g.
(methylene chloride solution, methylene chloride-ethanol mixture, ethanol-water mixture, aqueous solution, etc.) and then drying the resulting powder, which is then processed into a fluidized bed granulator, rotary type granulator, or spray drying granulator. It may also be a granule (core) obtained by granulation using a machine, a high-speed mixing granulator, a microcapsule machine, or the like. Moreover, the core may be a microcapsule manufactured by a conventional method.

The granules thus obtained may be made into capsules, fine granules, granules, dry syrups, etc., as they are, or by adding other additives, according to known methods. Examples of additives include the same binders, masking agents, excipients, flavoring agents, fragrances, lubricants, and disintegrants as exemplified above.

[0018]

[Examples] The present invention will be specifically explained below with reference to Examples and Comparative Examples, but the present invention is not limited thereto. 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. Add 100 g of methylene chloride-ethanol mixture of 50 g of Euragid E100 and 10 g of talc to the fine particles.
Coating was performed with 0 ml to obtain fine particles. Using a fluidized bed granulator, 40g of fine powder of monosodium glutamate and Euragit E100 were added to 250g of the fine particles.
30 g of mixture methylene chloride-ethanol suspension 6
Coating was performed with 00 ml to obtain cefcanel daloxate hydrochloride 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 content of cefcaneldaloxate hydrochloride is 100 mg per gram to produce fine granules with improved bitterness and easy to take. Obtained.

Example 2 100 g of bacampicillin hydrochloride in 200 ml of methylene chloride
After 100 g of ethyl cellulose was added to the suspension and sufficiently kneaded, 90 g of light anhydrous silicic acid was added, kneaded, powdered, and dried to obtain fine particles. Using a fluidized bed granulator, 10 g of ethyl cellulose and 2 g of talc were added to the fine granules.
Coating was performed with 500 ml of a methylene chloride-ethanol mixture of 100 g to obtain fine particles. 75g of trisodium citrate fine powder and 5g of ethyl cellulose are added to the fine particles.
The mixture was coated with 500 ml of a methylene chloride solution to obtain bacampicillin hydrochloride granules. Hereinafter, according to Example 1, the content of bacampicillin hydrochloride is 100 m per 1 g.
Fine granules with improved bitterness and easy to take were obtained.

Example 3 90 g of cefcaneldaloxate hydrochloride, 360 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. The fine grains were coated with 50 g of fine powder of sodium tartrate and 10 g of ethyl cellulose in a methylene chloride-ethanol mixture to obtain fine grains of cefcaneldaloxate hydrochloride with masked bitterness. Hereinafter, according to Example 1, the content of cefcaneldaloxate hydrochloride is 100 m per 1 g.
Fine granules with improved bitterness and easy to take were obtained.

Example 4 According to Example 3, trisodium citrate was used in place of sodium tartrate to obtain fine granules with improved bitterness and easy to take, containing 100 mg of cefcaneldaloxate hydrochloride per gram. .

Example 5 According to Example 3, sodium phosphate 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.

Example 6 According to Example 3, magnesium carbonate 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.

Example 7 300 g of the elementary granules obtained in Example 1 were coated with 1000 ml of a methylene chloride-ethanol mixture of 100 g of aluminum hydroxide and 20 g of ethyl cellulose to obtain cefcaneldaloxate hydrochloride granules. . Hereinafter, according to Example 1, fine granules with improved bitterness and easy to take were obtained containing 100 mg of cefcaneldaloxate hydrochloride per gram.

Example 8 According to Example 2, easy-to-take fine granules with improved bitterness and cefotiamhexetil hydrochloride content of 100 mg per gram were obtained.

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 grains of Examples 3 to 6 and Comparative Example as samples, Panel 1
A bitterness test and oral absorption comparison test were conducted by 0 people.

[0028]

[Table 1]

[0029]

[Table 2]

[0030] From the above results, the fine granules of cefcaneldaloxate hydrochloride obtained in Example 4 have no unpleasant taste such as bitterness, are very easy to take, and exhibit good oral absorption (bioavailability). became clear.

[0031]

[Effects of the Invention] The flavor-correcting oral preparation of the present invention has improved unpleasant tastes such as the bitterness of acid addition salts of basic drugs, so it is easy to take even for children who are sensitive to bitter tastes, and it is easy to take in the gastrointestinal tract. It is well absorbed and shows good bioavailability.

Claims (2)

[Claims] 1. An oral preparation with improved bitterness, comprising a core containing an acid addition salt of a basic drug and coated with a pharmacologically acceptable weakly alkaline compound. 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 preparation according to claim 1, which is at least one selected from weakly alkaline inorganic compounds other than antacids.