KR20040023167A - Taste masking pharmaceutical composition for oral administration - Google Patents

Abstract

PURPOSE: Provided is an oral administration medicament which conceals its bitter taste, and heightens the patient compliance thereto with enhanced treatment effect. CONSTITUTION: The oral administration pharmaceutical composition comprises amorphous cefuroxime axetil as an active component, and surfactant as a wetting agent. Micro particles are formed by water, and coated with an enteric-coated film containing a film coating material and an acidic material. The amorphous cefuroxime axetil involves a low melting point of 75-95 deg.C. The surfactant is selected from glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan mono laureate, polyoxyethylenepolyoxypropylene block copolymer, polysorbate, sodium laurylsulfate, or sucrose fatty acid ester.

Description

Pharmaceutical composition of cefuroxime axetyl formulation concealing bitter taste and its preparation {Taste masking pharmaceutical composition for oral administration}

Cefuroxime axetil is a cephalosporin-based oral antibiotic that exhibits high activity against a wide range of Gram-positive and Gram-negative microorganisms. This is increased by the very high stability of the compound against β-lactamase produced by various gram-negative microorganisms. The presence of the 1-acetoxyethyl ester group allows the compound to be absorbed significantly in the gastrointestinal tract, since the esterification group is hydrolyzed by enzymes present in serum and body tissues, and cefuroximeaxetyl is used in amorphous form. It is advantageous to. There are three types of polymorphysm in cepuroxime axetyl, crystalline with a melting point of about 180 ° C, a high melting point like amorphous with a melting point of about 135 ° C, and a low melting point of about 70-95 ° C. There is a melting point-like amorphous. The compositions of the present invention preferably contain a crystalline form as described in British Patent No. 2,127,401, more suitably amorphous cefuroxime axetyl.

In spite of its excellent antimicrobial activity, cefuroxime axetyl forms gelatinous gel-like form by contact with water-soluble media due to the poorly soluble, crystalline form and amorphous form of the drug substance itself. There is a problem that the absorption of is lowered. This gelation phenomenon is temperature dependent but occurs at a temperature of about 37 ° C., ie at the physiological temperature at which disintegration of the administered agent in the body occurs. When cefuroxime axetyl is ingested relatively slowly into the surrounding aqueous medium, the elution of cefuroxime axetyl present in the composition is lowered, and thus absorption in the digestive tract is lowered, resulting in low bioavailability. In the case of paticulates, it is preferable to use small diameter and high surface area particles to prevent the gelation.

When formulating cefuroximeaxetyl in granules, it is important to prevent the drug from eluting into any liquid suspension used or orally. This problem can be minimized by formulating cefuroximexetyl as polymer coated particles with limited permeability to water.

Accordingly, the present inventors have found that the very bitter taste of cefuroxime axetyl can be overcome by completely coating the cefuroxime axetyl particles with a polymeric material that is substantially insoluble in water but readily dispersed and dissolved in the body. The formulated coated particles can be eluted by disintegrating in the digestive tract while not releasing the bitter taste of cefuroximexetyl in the oral cavity.

A convenient means of providing antibiotics for oral administration is in the form of granules which may be administered as suspensions or suspensions or taken together with a batch of water. Solutions and suspensions of granules, for example syrups, are particularly convenient for oral administration of antibiotics to young children. However, the bitter taste of unshielded cefuroxime axetyl lasts a long time and has a very bitter taste that cannot be adequately masked by the sweetening and flavoring agents generally added to the formulation.

The present invention relates to pharmaceutical formulations of cepuroximeaxetyl, in particular formulations which mask the flavor of oral administration agents, methods of preparing such formulations and methods of masking the flavor of oral administration agents. Oral dosage forms, such as tablets, in solid form often have dosage problems, depending on the patient, especially for children or the elderly. To address this problem, other forms of pharmaceutical formulations, for example, chewable tablets, single dosage forms in which the tablets and contents rapidly disintegrate in the mouth or in a spoonful of water are dissolved or suspended in a glass of water. A sachet of is required.

Unfortunately, as mentioned above, cefuroximeaxetyl needs to be masked because the taste is unpleasant, bitter or irritating. To mask this flavor, the particles of the drug are coated with a membrane to prevent the drug from being released into the water and to prevent the drug from being released into the cavity of the oropharyngeal cavity while taking the drug, but after taking the drug. The drug may be released from the digestive tract. In order to cover the bitter taste, the pH dependence, that is, coated with a polymer that is dissolved at a pH of 5 or above, or the acid treatment of the surface to find that it can effectively conceal the bitter taste to complete the present invention.

The most suitable coatings for this purpose are membranes which are impermeable to water and saliva, but dissolve by the action of gastrointestinal pH. The most common membranes are membranes made of polymers which are insoluble under water and acidic environments but soluble at pH above 5 as in the intestinal tract. However, since the pH of saliva is above 5, the membrane may be partially dissolved in the oral cavity, and thus the bitter taste of cepuroximeaxetyl may be released. Thus, by adding acidic substances to pharmaceutical formulations for oral administration, these acidic substances are dissolved to create a microenvironment around the coated particles to prevent the polymer constituting the membrane from dissolving or minimizing the aforementioned problems. Turned out to be.

Cepuroxime axetyl is a cephalosporin-based antibiotic that acts on Gram-positive bacteria and Gram-negative bacteria, and its taste is so great that it is very necessary to conceal its taste in dry syrup, suspension tablets and chewable tablets.

In the present invention, in order to shield the bitter taste of cefuroxime axetyl is a method of coating the cefuroxime axetyl with a pH-dependent dissolved material, insoluble or poorly soluble material. Specifically, a low melting point amorphous cefuroximexetyl powder and a humectant are formed, and the fine granules are formed by wet granulation, and then injected into a coater to obtain a coating by dispersing or dissolving a pH dependent dissolving material. It is preferable that 590 micrometers or less occupy 60% or more of particle | grains, and a particle | grains of 590 micrometers or less can also be obtained by passing a 590 micrometer sieve as needed.

Plasticizers such as pharmaceutically acceptable glycerin, polyethylene glycols, phthalate esters, triacetin, citrate esters, etc. may be added to the coating solution alone or in combination of two or more thereof.Antifoaming agent, colorant, lubricant, preservative, etc. It can be used individually or in mixture of 2 or more types.

pH dependent dissolving materials include cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, copolymers of methacrylic acid with methacrylic acid methyl ester or methacrylic acid ethyl ester, polyvinyl acetate phthalate, shellac, hydroxypropylmethylcellulose acetate succinate Nate, carboxymethyl cellulose, etc. can be used individually or in mixture.

Sepuroxime axetyl is extremely poorly soluble in physicochemical properties, and its wettability is extremely low. Therefore, it is advantageous to improve surface properties as well as to stably obtain particles of 590 μm or less. Therefore, in order to improve the surface properties, cefuroxime axetyl may be added to the coalescer, and the liquid obtained by dispersing or dissolving the surfactant is added to the purified water, and then fed through a sieve of 297 μm or less. Surfactants for improving surface properties include glycerin monostearate, sorbitan monostearate, sorbitan monopalmitinate, sorbitan monolauryl, polyoxyethylene polyoxypropylene block copolymers, polysorbates, sodium lauryl sulfate, sucrose Osfatty acid ester can be used individually or in mixture of 2 or more types.

When the cefuroxime axetyl particles concealing bitterness using the pH dependent soluble substance used in the present invention are applied to the dry syrup, the saliva pH may be 5 or more, so that the membrane may be partially dissolved in the oral cavity. Unpleasant flavors may be released. It has been found that by adding an acidic substance to the coating surface, these acidic substances are dissolved to create a microenvironment around the coated particles to prevent the polymer constituting the film from dissolving, thereby overcoming or minimizing the above problems. lost. It is thus possible to mask the flavor in the oral cavity by coating the agent and the present invention provides an acidic agent which reduces or prevents the dissolution of the membrane in the oral cavity and the core containing the agent, which is coated with a polymerizable membrane which is soluble only at pH 5 or above. Provided are pharmaceutical formulations for oral administration containing a compound.

In addition, when the dry syrup is suspended by adding water, the final surface of the particle covering the bitter taste is coated with a pharmaceutically acceptable acidic substance in order to prevent the film surface of the coated surface from being damaged by an increase in pH around the surface of the particle. If used, it can mask the bitter taste more effectively.

To this end, by spraying the liquid prepared by dissolving or dispersing the bitter taste concealed particles prepared above in the coating machine to the pharmaceutically acceptable acidic material to the surface to maintain the acidity. Along with the acid can also be sprayed with the addition of pharmaceutically acceptable excipients and polymers.

Pharmaceutically acceptable excipients and polymers that can be used herein include polymethacryl compounds such as carbomer, cellulose acetate phthalate, ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose phthalate, and Eudragit alone or in combination of two or more thereof. Examples of the acid compound include, but are not limited to, dried acid, fumaric acid, citric acid and tartaric acid.

The formulation of the present invention may be a pharmaceutical formulation that can be easily taken by children, the elderly or patients with difficulty in taking it. Examples thereof are tablets or single doses of Shashay formulations. Examples of tablets are chewable, dissolved in the mouth, or disintegrated rapidly (eg within 1 minute) in a small amount (about 1 minute) of water: suspended in a small amount of water (eg 20-50 ml) or taken directly It is a single dose Shasha that can.

The following examples are intended to illustrate the invention in detail.

Example 1.

300 g of cefuroxime axetyl are added to the coalescer, and 5 g of polysorbate 80 is dissolved in 250 g of water. The association is sieved through a No. 70 sieve and placed in a fluidized bed granulator. The solution of the following composition is sprayed onto a flowing drug to coat and dry to prepare cefuroxime axetyl particles concealing bitter taste.

<Coating solution 1>

Eudragit L 30 D 55 500 g

30 g of talc

500 g of water

<Coating solution 2>

Eudragit L 100 150 g

30 g of talc

15 g of polyethylene glycol # 6000

100 g of purified water

Ethanol 1,400 g

The bitter taste was remarkably concealed when the obtained sypuroxime axetyl particles were prepared by the following formulation to evaluate the degree of concealment of the bitter taste.

Sepuroximexetyl Particles 42.0 g

10.0 g of hydroxypropyl methyl cellulose

10.0 g of microcrystalline cellulose

1.0 g of citric acid

Shimechikon 1.0 g

1.0 g of sodium benzoate

64.5 g per bag

Add purified water to make 500.0 ml total.

Example 2.

Sepuroximexetyl particles prepared according to Example 1 were injected into a fluidized bed granulator while flowing, and the solution of the following composition was sprayed onto the flowing granules to cover and dry to conceal bitter taste and to coat the surface with an acidic substance. Til particles are prepared.

<Injection amount>

200.0 g citric acid

300.0 g per bag

1000.0 g of water

The bitter taste was remarkably concealed when the obtained sypuroxime axetyl particles were prepared by the following formulation to evaluate the degree of concealment of the bitter taste.

Sepuroximexetyl Particles 62.5 g

10.0 g of hydroxypropyl methyl cellulose

10.0 g of microcrystalline cellulose

1.0 g of sodium benzoate

69.5 g per bag

Purified water is added to prepare a total of 500.0 ml.

Example 3.

300 g of cefuroxime axetyl is first introduced into the coalescing machine, and then a solution in which 20 g of polyethylene glycol 4000 and 5 g of polysorbate 80 is dissolved is added to 250 g of purified water. The association is sieved through a No. 70 sieve and placed in a fluidized bed granulator. The solution of the following composition is sprayed onto a flowing drug to coat and dry to prepare cefuroxime axetyl particles concealing bitter taste.

<Injection amount>

<Coating solution 1>

Eudragit L 30 D 55 500 g

30 g of talc

500 g of water

<Coating solution 2>

Eudragit L 100 150 g

30 g of talc

15 g of polyethylene glycol # 6000

100 g of purified water

Ethanol 1,400 g

The bitter taste was remarkably concealed when the obtained sypuroxime axetyl particles were prepared with the following formulation to evaluate the degree of concealment of the bitter taste.

Sepuloximexetyl Particles 45.0 g

1.0 g of citric acid

Shimechikon 1.0 g

1.0 g of sodium benzoate

64.5 g per bag

Add purified water to make 500.0 ml total.

Example 4

Add 300 g of cefuroxime axetyl to the coalescer, and add 3 g of sodium lauryl sulfate in 250 g of water. The association is sieved through a No. 70 sieve and placed in a fluidized bed granulator. The solution of the following composition is sprayed onto a flowing drug to coat and dry to prepare cefuroxime axetyl particles concealing bitter taste.

<Coating solution 1>

Eudragit L 30 D 55 500 g

30 g of talc

500 g of water

<Coating solution 2>

Eudragit L 100 150 g

30 g of talc

15 g of polyethylene glycol # 6000

10 g citric acid

100 g of purified water

Ethanol 1,400 g

The bitter taste was remarkably concealed when the obtained sypuroxime axetyl particles were prepared by the following formulation to evaluate the degree of concealment of the bitter taste.

Sepuroximexetyl Particles 42.0 g

5.0 g of gellan gum

Avicel RC 581 10.0 g

1.0 g of citric acid

1.0 g of simethicone emulsions

1.0 g of sodium benzoate

64.5 g per bag

Add purified water to make 500.0 ml total.

The drug for oral administration in which the bitter taste is masked by the present invention and the pharmaceutical stability is secured in the aqueous solution is intended to increase the therapeutic effect of the drug by conveniently administering to the patient by increasing the compliance of the patient.

Claims (9)

Oral medicaments coated with an enteric coating agent containing amorphous cefuroximexetyl as an active ingredient and a surfactant as a humectant, forming particles as water, and containing the fine coating particles and acidic substances To a composition and a method for producing the same. The amorphous according to claim 1, wherein the cefuroxime axetyl is amorphous, characterized by a low melting point of 75 to 95 ℃. The surfactant according to claim 1, wherein the surfactant is glycerin monostearate, sorbitan monostearate, sorbitan monopalmitinate, monolauryl sorbitan, polyoxyethylene polyoxypropylene block copolymer, polysorbates, sodium lauryl sulfate, sucrose Sepuroxime axetyl composition concealing bitterness used alone or in combination with osfatty acid ester. The composition according to claim 3, wherein the surfactant is included in the range of 2 to 30 parts by weight based on 100 parts by weight of cefuroxime axetyl. The method of claim 1 wherein the enteric polymeric material is cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, copolymers of methacrylic acid with methacrylic acid methyl ester or methacrylic acid ethyl ester, polyvinyl acetate phthalate, shellac, hydroxypropyl Formulations comprising methylcellulose acetate succinate. 6. The composition according to claim 5, wherein the enteric polymer material is used alone or in combination to fall within the range of 2 to 70% w / w relative to cefuroxime axetyl. The formulation of claim 1, wherein the acidic substance is citric acid, ascorbic acid, succinic acid, dried acid, fumaric acid, tartaric acid, or a mixture of one or more of these acids. Pharmaceutical composition, characterized in that the pH of the aqueous solution is 2.5 to 5.0 when included in the 5% w / v aqueous solution as a cepuroxime when prepared according to the composition and method of claim 1. An oral drug composition prepared by oral administration of a powder, granules, capsules, suspension tablets, effervescent tablets, dry syrups or suspension syrups using the cefuroxime axetyl particles of claim 1.