KR101469326B1 - Pharmaceutical preparation comprising bepotastine or phamaceutical acceptable salt thereof and water-insoluable basic material - Google Patents

Abstract

The present invention relates to pharmaceutical preparations comprising bevotastine or a pharmaceutically acceptable salt thereof and a water-insoluble basic substance. The present invention also relates to pharmaceutical preparations comprising bevotastine or a pharmaceutically acceptable salt thereof, a water-insoluble basic substance and a sustained-release carrier. The pharmaceutical preparation according to the present invention contains a water-insoluble basic substance in the preparation to effectively maintain the optical stability of bepotastine by adjusting the pH to 7 or more, and further includes a sustained-release carrier, This has the advantage.

Description

[0001] The present invention relates to pharmaceutical preparations comprising bepotastine or a pharmaceutically acceptable salt thereof and a water-insoluble basic substance and to a pharmaceutical preparation comprising bepotastine or phamaceutical acceptable salt thereof and a water-insoluble basic material,

The present invention relates to pharmaceutical preparations comprising bevotastine or a pharmaceutically acceptable salt thereof and a water-insoluble basic substance. The present invention also relates to pharmaceutical preparations comprising bevotastine or a pharmaceutically acceptable salt thereof, a water-insoluble basic substance and a sustained-release carrier.

Allergic rhinitis is a symptom of runny nose, sneezing, or nasal congestion as a result of an antigen-antibody reaction by an allergen. Many people worldwide suffer from allergic rhinitis. Allergic rhinitis is not a life-threatening fatal disease, but it must be a disease that is a burden to public health in terms of prevalence, quality of life, or health economics.

Various drugs have been used to treat allergic rhinitis, and antihistamines are widely used as a first line therapy. However, the above-mentioned antihistamines temporarily alleviate symptoms, do not affect the underlying allergic reaction process, and cause side effects such as sleepiness, thereby deteriorating the quality of life of the patients. In addition, topical steroid preparations commonly used for allergic rhinitis cause child growth inhibition or local side effects. Nasal decongestants are limited in their use due to side effects such as insomnia, elevated blood pressure, and nasal congestion.

On the other hand, new selective antihistamines such as bepotastine not only inhibits the expression of symptoms of allergic rhinitis but also does not pass through the blood brain gates and does not exhibit the side effects of existing antihistamines and is useful for multi-annual and seasonal allergic rhinitis .

Bephotastine has been disclosed for the first time as a racemic compound in JP-A No. 2-25465 as an antihistamine agent exhibiting excellent clinical efficacy and rapid drug efficacy and having little side effects of drowsiness and little interaction with other drugs .

Japanese Patent Laid-Open No. 1998-237070 discloses that the S-configuration of bevetastine is far superior to the isomer of the corresponding R-configuration. However, S-bepotastine is a very poorly crystallized compound, and since it is usually obtained as a syrup, it is difficult to secure and maintain a high quality, and there is a limitation in using it as a direct medicine.

The chemical stability of the pharmaceutical composition is very important in the field of pharmaceuticals, which must ensure high purity and maintain it during long-term storage. In particular, when the pharmacologically active ingredient is composed of one of the optical isomers, optical stability must be secured and maintained.

For example, in Japanese Patent Laid-Open No. 2001-261553, when beportastine is formulated together with additives such as conventional excipients and binders, the water in the additive causes the S-configuration of bevetastine to form isomers of the corresponding R-configuration There is a problem that racemization occurs due to conversion, so that it is necessary to secure the beptapastin with high optical purity, and a formulation which does not cause racemization is required.

Japanese Patent Application Laid-Open No. 2000-198784 and Korean Patent Registration No. 10-0515227 disclose a method for producing a polyurethane resin by adding hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, fumaric acid, maleic acid, mandelic acid, succinic acid, There have been disclosed examples in which bephatastinic acid addition salts are prepared using various pharmaceutically acceptable acids such as lactic acid and malic acid. Thus, in order to obtain beatifastine having a stable crystalline form, research for developing an acid addition salt of bepotastine has been carried out continuously.

However, the majority of conventional bepotastine acid addition salts are obtained in the form of oily, syrupy or hygroscopic crystalline forms. Examples of the beptaustin salt known as a relatively stable and non-hygroscopic crystalline form include benzenesulfonic acid salts and benzoic acid salts disclosed in Japanese Patent Application Laid-Open No. 10-237070. Other Leone ^TM (Talion ^TM), which are commercially available from Tanabe (Tanabe) of Japan is that the anti-histamine drugs chopping Porta sustaining benzene sulfonate as the active ingredient.

However, the above-mentioned bepotastine benzenesulfonic acid salt has not sufficient stability for use. For example, when beportastine benzenesulfonate is exposed to ordinary severe conditions (40 DEG C, 75% relative humidity), the isomer of R- The formation of degradation products and a significant increase in moisture content have been observed.

Therefore, there is a demand for a bevitalustine preparation capable of maintaining optical purity even under various conditions such as high temperature and high humidity during storage and distribution, as well as the formulation process.

On the other hand, 10 mg of veczanobentastine (Tari onion) is currently marketed by oral administration twice a day in Korea. The mean serum concentration of Vesicobanthastine shows a rapid disappearance trend after reaching the highest concentration 1 hour after the administration of the drug, and exhibits a pharmacokinetic characteristic that the blood concentration also increases proportionally as the dose increases. Therefore, it is necessary to develop a sustained-release formulation in order to increase the antihistamine effect of bepotastine by maintaining a constant blood concentration through sustained drug release, and to improve tolerance and compliance with medicines.

However, if beportastine is to be developed as a western dosage form, sustained-release carrier has a high water content and is highly likely to absorb moisture in the air during storage, There is a difficult problem.

Therefore, the inventors of the present invention have conducted intensive studies to develop a formulation capable of effectively maintaining the optical stability even in the case of the sustained-release preparation of bevitalastine, as a result of the above problems and circumstances. As a result, , It was confirmed that the optical stability of bepotastine could be effectively maintained, and furthermore, a method of administration once a day was possible by including a sustained-release carrier, and the present invention was completed.

The present invention provides a pharmaceutical preparation comprising bevapastastin or a pharmaceutically acceptable salt thereof and a water-insoluble basic substance.

The present invention also provides a pharmaceutical preparation comprising bevapastastin or a pharmaceutically acceptable salt thereof, a water-insoluble basic substance and a sustained-release carrier.

In order to solve the above problems, the present invention provides a pharmaceutical preparation comprising bevapastastin or a pharmaceutically acceptable salt thereof and a water-insoluble basic substance.

The pharmaceutical preparations of the present invention include a therapeutically effective amount of bevapastastin. The beptoustin according to the present invention includes a drug which is pharmacologically effective or which is pharmacologically effective or which is pharmacologically effective by an in-body chemical or enzymatic method, specifically, the bevitalustine drug itself, a pharmaceutically acceptable salt or ester thereof And its precursor may be used.

As used herein, the term "bepotastine" refers to a salt of ((S) -4- [4- (4-chlorophenyl) -2-pyridylmethoxy] piperidin- And specifically refers to a selective antihistamine agent represented by the following formula 1 and having little side effects such as drowsiness and arrhythmia.

[Chemical Formula 1]

The above-mentioned bepotastine inhibits the histamine H1 receptor antagonism and the release of leukotrienes and cytokines, thereby suppressing the allergic inflammatory reaction and alleviating the symptoms of runny nose or sneezing. In addition, IL-5 is inhibited by peripheral blood monocytes (PBMC) in human peripheral blood mononuclear cells, thereby suppressing eosinophil function against allergic inflammation. Common allergies to bepotastine are allergic rhinitis, urticaria, pruritus, nasal obstruction, dermatitis, and eczema.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared according to methods conventional in the art, and such methods of preparation are known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic and organic acids and bases which are pharmacologically or physiologically acceptable. Examples of suitable acids include hydrochloric acid, hydrobromic acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium or potassium, alkaline earth metals such as magnesium.

Preferably, the salt of bepotastine according to the present invention may be bepotastine bevacillate or bepapastine tosylate.

The term " water insoluble "as used in the present invention means a property that is hardly soluble in water or dissolves in a very small amount, and the term" basic substance "Quot; means a substance which is controlled to exhibit a neutral or alkaline pH of 7 or higher.

The water-insoluble basic substance maintains the optical stability of the unstable bepotastine in the acidic environment in the preparation by keeping the ambient pH environment at 7.0 or higher among the preparations combined with bepotastine.

The water-insoluble basic material according to the present invention may be calcium carbonate, precipitated calcium carbonate, hard magnesium oxide, or fine magnesium oxide. In the case of calcium carbonate, the solubility is 0.0013 g / 100 ml and the magnesium oxide is 0.0086 g / 100 ml, which is almost water insoluble.

In one specific example, formulations comprising bevetastatin tosylate and precipitated calcium carbonate or magnesium oxide were prepared (Examples 1 and 2) and the pH of the formulations was measured to be pH 7.16 and pH 9.62, respectively And maintained the basicity of pH 7 or more.

The preparation comprising the water-insoluble basic substance according to the present invention has an effect of keeping the pH at least 7 basic and significantly reducing the content of the soft substance.

Bepotastine is preferably included in the formulation as an S-isomer effective pharmacological component because the effect of the S-isomer is significantly superior to that of the R-isomer. However, it is not easy to maintain the S-isomer in the preparation due to various environmental factors such as moisture, and there is a problem that the S-isomer is converted into the R-isomer during preparation and storage of the preparation. Therefore, it is very important to maintain the optical stability. The present invention, by including the water-insoluble basic substance in the preparation, significantly lowers the content of the flexible substance and the R-isomer, and ultimately can effectively maintain the optical stability have.

In a specific experimental example, the content of R-isomer and the content of the flexible substance in the preparation containing bevetastatin tosylate and precipitated calcium carbonate or magnesium oxide were measured (Experimental Example 1). As a result, the content of the R-isomer of the preparation containing precipitated calcium carbonate was 1.0%, the content of the softener was 2.8%, the content of the R- Was significantly lowered to 0.15%.

Preferably, the water-insoluble basic substance may be contained in an amount of 1 to 30% by weight based on the total weight of the preparation. More preferably, the water-insoluble basic substance may be contained in an amount of 5 to 10% by weight based on the total weight of the preparation.

Also preferably, the beportantine or a pharmaceutically acceptable salt thereof and the water-insoluble basic substance are contained in a weight ratio of 1: 0.1 to 1.

In another aspect, the present invention provides a pharmaceutical formulation comprising bevapastastin or a pharmaceutically acceptable salt thereof, a water-insoluble basic substance, and a sustained-release carrier.

The term "sustained-release carrier" as used herein refers to a substance that causes the pharmacologically active ingredient, particularly beportastine or a pharmaceutically acceptable salt thereof, to be released or eluted slowly from the formulation. For example, the sustained-release carrier may be at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, polyethylene oxide, hydroxypropylcellulose, colloid SR, Eudragit RS, Eudragit L 100-55, carrageenan, sodium alginate and xanthan gum , But is not limited thereto.

Preferably, the hydroxypropyl methylcellulose has a viscosity of 100 mPa.s to 100,000 mPa.s, and is contained in an amount of 5 to 50% by weight based on the total weight of the preparation.

Also preferably, the polyethylene oxide has an average molecular weight of 600,000 to 7,000,000 and is contained in an amount of 5 to 50% by weight based on the total weight of the preparation.

Also, preferably, said bevatastin or its pharmaceutically acceptable salt and sustained-release carrier are contained in a weight ratio of 1: 1 to 4:

The pharmaceutical preparations of the present invention can be prepared using any standard technique and a suitable preparation method generally known in the art, and an exemplary preparation method of the preparation is described as follows: a mixture of bevetastin and a water-insoluble basic substance ≪ / RTI >

(1) mixing beportastine or a pharmaceutically acceptable salt thereof and a water-insoluble basic substance, a sustained-release carrier and certain other excipients together;

(2) The components of the mixture before mixing, or the mixture itself, are sieved by passing through a mesh screen, for example, a 400-700 탆 mesh sieve, and then added to the mixture until the homogeneous mixture is obtained ; And

(3) a dry granulation method in which the obtained mixture is compressed into tablets, or

(1 ') bepotastine or a pharmaceutically acceptable salt thereof and a water-insoluble basic substance, a sustained-release carrier and any other excipient;

(2 ') granulating the powder mixture with a small amount of binding liquid, and drying and granulating the granules; And

(3 ') excipient and a sustained-release carrier and a lubricant residue to the milled granules, and compressing the resulting homogeneous mixture into tablets. The pharmaceutical granules of the present invention A preparation can be prepared.

The dry mixing and wet granulation methods, including the order of addition of the constituents in the above methods and their mixing prior to compression by screening and tableting, can be freely modified in accordance with the principles known in the art.

The preparation of the pharmaceutical preparations according to the present invention can be prepared according to the above methods or other methods apparent to those skilled in the art, and then administered without further formulation, or further formulated in a manner obvious to a person skilled in the art.

Alternatively, the coating can be further effected, for example the tablet coating can be spray coated with an aqueous film coating formulation. The coating composition may comprise lactose, hydroxypropyl methylcellulose, triacetin, titanium dioxide and ferric oxide.

Preferably, the coating may be included in an amount of 0.5 to 10% by weight, preferably 1 to 6% by weight, more preferably 2 to 3% by weight based on the total weight of the tablet. The coating of tablets is particularly preferred for beportastine preparations which are sensitive to moisture.

The pharmaceutical preparations comprising the sustained-release carrier according to the present invention exhibit a zero-order release pattern and can be dosed once a day since the release takes place slowly over a long period of time.

In one specific experimental example, the dissolution profiles of tablets containing bepotastine tosylate, precipitated calcium carbonate or magnesium oxide, and hydroxypropylmethylcellulose were analyzed. As a result, Taroon, a commercially available drug, was completely released within 1 hour to 2 hours at a high speed, whereas the pharmaceutical preparation containing the sustained-release carrier according to the present invention had almost zero-order release (Fig. 1 and Fig. 2 of Experimental Example 3).

In a specific experimental example, the dissolution profiles of the pharmaceutical preparations according to the present invention were analyzed by pH. As a result, it was confirmed that all of the portions of pH 1.2, which means stomach, pH 4.0, which means the large intestine, and pH 6.8, which means the small intestine, exhibited a zero-order release pattern lasting more than 10 hours 3 and 4). Thus, it can be seen that the pharmaceutical preparation containing the sustained-release carrier according to the present invention has the characteristics of a sustained-release preparation which continuously releases the drug at the same or similar level without being affected by any pH condition in the body there was.

The pharmaceutical preparations according to the invention may additionally be formulated together with one or more pharmaceutically acceptable excipients. As used herein, the term "excipient" is used as a carrier or medium for the delivery of beportantine, or it may be added to the formulation to improve handling or storage, or the formulation of the dosage unit may be formulated into capsules or tablets ≪ / RTI > and the like. Excipients include, but are not limited to, diluents, disintegrants, binders, tackifiers, wetting agents, lubricants, lubricants, perfumes, surfactants and inclusion compounds.

The diluent is for the formulation of oral solid preparations, and any diluents commonly used in the pharmaceutical field can be used. For example, lactose, sucrose, starch, modified starch, mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g., microcrystalline cellulose, cellulose), calcium sulfate, xylitol and lactitol can be used.

These binders are for the formulation of oral solid preparations, and any of those generally used in the pharmaceutical field can be used. A starch, modified starch, sucrose, acacia rubber, tragacanth gum, guar gum, pectin, wax binder, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose , Hydroxyethyl cellulose, hydroxypropyl cellulose, copolyvidone, gelatin and sodium alginate.

The lubricant is for the formulation of oral solid preparations, and any of those generally used in the pharmaceutical field can be used. For example, sodium stearyl fumarate, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, hydrogenated vegetable oil, mineral oil, polyethylene glycol and the like.

The contents of beportastine or a pharmaceutically acceptable salt thereof, a water-insoluble basic substance and other excipients in the pharmaceutical preparation according to the present invention may be exemplarily as follows:

The betapastin or a pharmaceutically acceptable salt thereof may be 1 to 20% by weight, preferably 10 to 20% by weight, based on the total weight of the preparation.

Water insoluble basic substances such as precipitated calcium carbonate or magnesium oxide may be present in an amount of 1 to 20% by weight based on the total weight of the preparation.

The sustained-release carrier may be from 1 to 90% by weight based on the total weight of the preparation.

The diluent may be 30-90 wt% based on the total weight of the formulation.

The binder may be from 2 to 90% by weight, based on the total weight of the formulation.

The lubricant may be 0.5 to 3% by weight, preferably 1 to 2% by weight, based on the total weight of the preparation.

The pharmaceutical preparations of the present invention can be administered via any conventional route so long as they can reach the target tissue. The formulations of the present invention may be administered intraperitoneally, intravenously, intramuscularly, subcutaneously, intradermally, orally, intranasally, intracorally, rectally, but not exclusively, as desired. The agent may also be administered by any device capable of transferring the active agent to the target cell.

The pharmaceutical preparation according to the present invention contains a water-insoluble basic substance in the preparation to effectively maintain the optical stability of bepotastine by adjusting the pH to 7 or more, and further includes a sustained-release carrier for once-a-day administration There are advantages.

1 is a graph showing the dissolution profiles of Examples 12 to 14 according to an experimental example of the present invention.
2 is a graph showing the dissolution profiles of Examples 15 to 17 according to an experimental example of the present invention.
3 is a graph showing the elution profile of Example 18 and the tarrying method according to one experimental example of the present invention.
FIG. 4 is a graph showing the elution profile of Example 19 and the tarrying method according to an experimental example of the present invention. FIG.
FIG. 5 is a graph showing changes in plasma concentration of the tarrying jig and Example 18 according to an experimental example of the present invention.
FIG. 6 is a graph showing changes in plasma concentration of the tarrying jig according to an experimental example of the present invention and the plasma concentration according to Example 19. FIG.

Hereinafter, the present invention will be described in detail with reference to Examples. However, the scope of the present invention is not limited by these examples. Embodiments of the invention are provided to more fully describe the present invention to those skilled in the art.

Comparative Example  One

10 mg of a commercially available beportantine bevic acid preparation, Intionate, was used as Comparative Example 1.

Comparative Example  2

As a composition to which no stabilizer was added, tablets were prepared in a composition as shown in Table 1 below (unit mg) as a composition containing bevetastatin tosylate, a sustained-release carrier, a diluent, and a lubricant.

Furtherance Comparative Example 2 Bepotastine tosylate 20.51 Hydroxypropylmethylcellulose 80.0 Mannitol 95.49 Silicon dioxide 2.0 Sodium stearyl fumarate 2.0 Gross weight 200.0

Comparative Example  3 to 12

Tablets were prepared by adding various kinds of salts to evaluate the degree of stability of formulations according to kinds of stabilizers added to bepotastine. Specifically, water-soluble salts such as sodium chloride, potassium chloride and calcium chloride were used, and sodium citrate, meglumine, sodium hydrogen phosphate, calcium hydrogen phosphate, potassium carbonate, sodium carbonate and sodium hydrogen carbonate were used as water- Tablets were prepared in the same composition (unit mg).

The amount of the stabilizer was about 10% by weight in the formulation. The preparation method is as follows. First, the tablet of bevapastin tosylate is mixed with a stabilizer, hydroxypropylmethylcellulose and mannitol. Then, Aerosil 200, sodium stearyl fumarate Were sieved with 20 mesh and mixed. This mixture was tableted at 9 to 11 kp to prepare a white tablet, 200 mg per unit tablet.

Furtherance Weight (mg) Comparative Example 3 Comparative Example 4 Comparative Example 5 Bepotastine tosylate 20.51 20.51 20.51 Sodium chloride 20.0 - - Potassium chloride 20.0 - Calcium chloride 20.0 Hydroxypropylmethylcellulose 80.0 80.0 80.0 Mannitol 75.49 75.49 75.49 Silicon dioxide 2.0 2.0 2.0 Sodium stearyl fumarate 2.0 2.0 2.0 Gross weight 200.0 200.0 200.0

Furtherance Weight (mg) Comparative Example 6 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Comparative Example 12 Bepotastine
Tosylate 20.51 20.51 20.51 20.51 20.51 20.51 20.51 Calcium hydrogen phosphate 20.0 Sodium citrate - 20.0 - - - - - Meglumine - - 20.0 - - - - Sodium hydrogen phosphate - - - 20.0 - - - Potassium carbonate - - - - 20.0 - - Sodium carbonate - - - - - 20.0 - Sodium hydrogencarbonate - - - - - - 20.0 Hydroxypropylmethylcellulose 80.0 80.0 80.0 80.0 80.0 80.0 80.0 Mannitol 75.49 75.49 75.49 75.49 75.49 75.49 75.49 Silicon dioxide 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Sodium stearyl fumarate 2.0 2.0 2.0 2.0 2.0 2.0 2.0 Gross weight 200.0 200.0 200.0 200.0 200.0 200.0 200.0

Example  1 to 4

Tablets were prepared (unit mg) using the same method as in Comparative Examples 3 to 12, except that precipitated calcium carbonate and magnesium oxide were used as water-insoluble basic substances.

Furtherance Weight (mg) Example 1 Example 2 Example 3 Example 4 Bepotastine tosylate 20.51 20.51 Bepotastine acetate 20.51 20.51 Precipitated calcium carbonate 20.0 - 20.0 - Magnesium oxide (fine grain) - 20.0 - 20.0 Hydroxypropylmethylcellulose 80.0 80.0 80.0 80.0 Mannitol 75.49 75.49 75.49 75.49 Silicon dioxide 2.0 2.0 2.0 2.0 Sodium stearyl fumarate 2.0 2.0 2.0 2.0 Gross weight 200.0 200.0 200.0 200.0

Example  5 to 11

Tablets were prepared with the compositions shown in Tables 5 and 6 below in order to confirm the effect of stabilization of the precipitated calcium carbonate and magnesium oxide (hard and fine) according to their contents in the preparation.

Examples 5 and 6 used precipitated calcium carbonate, Examples 7 to 9 used magnesium oxide (fine granules), Examples 10 and 11 used magnesium oxide Tablets were prepared using magnesium oxide (hard) (unit mg).

Specifically, a mixture of bepotastine tosylate and a stabilizer (precipitated calcium carbonate, magnesium oxide (hard), or magnesium oxide (fine granule)), hydroxypropylmethyl cellulose and mannitol are mixed, then Aerosil 200, sodium stearyl fumarate 20 mesh and mixed. This mixture was tableted to prepare a white tablet, 200 mg per unit tablet.

Furtherance Weight (mg) Example 5 Example 6 Example 7 Example 8 Example 9 Bepotastine tosylate 20.51 20.51 20.51 20.51 20.51 Precipitated calcium carbonate 10 20 - - - Magnesium oxide (fine grain) - - 2 10 20 Hydroxypropylmethylcellulose 80 80 80 80 80 Mannitol 85.49 75.49 93.49 85.49 75.49 Silicon dioxide 2 2 2 2 2 Sodium stearyl fumarate 2 2 2 2 2 Gross weight 200 200 200 200 200

Furtherance Weight (mg) Example 10 Example 11 Bepotastine tosylate 20.51 20.51 Magnesium oxide (hard) 10.0 20.0 Hydroxypropylmethylcellulose 80.0 80.0 Mannitol 85.49 75.49 Silicon dioxide 2.0 2.0 Sodium stearyl fumarate 2.0 2.0 Gross weight 200.0 200.0

Example  12-14

Magnesium oxide (fine particles) and hydroxypropylmethylcellulose as a sustained-release carrier were prepared as shown in Table 7 according to viscosity, to prepare a stabilized beatifastine tosylate sustained release tablet which can be taken once a day.

Specifically, a mixture of bepotastine tosylate, magnesium oxide, mannitol, and hydroxypropylmethylcellulose was mixed with silicon dioxide and sodium stearyl fumarate, and the mixture was tableted at 9 -11 kp to prepare a white tablet of 200 mg per unit tablet. The prepared tablets were filled in a coating pan (-coater, Freund) and maintained at a discharge air temperature of about 30-40 ° C. Opaque Dry 200 White (polyvinyl alcohol 35.0%, titanium oxide 25.0%, polyethylene glycol 3500 12.0%, methacrylic acid copolymer TYPE C 4.0%, sodium bicarbonate 0.12%) 10 g of the coating agent was dissolved in 40 g of water to prepare a coating solution After spraying the dried tablet with a sprayer operated by air pressure, the air supply was continued to dry for about 10 minutes. The coating amount of the tablets obtained here was 8.0 mg relative to the tablets.

Furtherance Weight (mg) Example 12 Example 13 Example 14 Bepotastine tosylate 20.51 20.51 20.51 Magnesium oxide (fine grain) 20.51 20.51 20.51 Hydroxypropylmethylcellulose
(4,000 cps) 80.0 40.0 - Hydroxypropylmethylcellulose
(100 cps) - 40.0 80.0 Mannitol 72.98 72.98 75.49 Silicon dioxide 3.0 3.0 2.0 Sodium stearyl fumarate 3.0 3.0 2.0 Opa Dry 200 White 8.0 8.0 8.0 Gross weight 208.0 208.0 208.0

Example  15 to 17

Magnesium oxide was used to prepare a stabilized beatifastine tosylate sustained release tablet which can be taken once a day, and hydroxypropyl methylcellulose and / or Eudragit L100-55 or hydrofilpropyl methylcellulose Acetate succinate was used to prepare tablets (unit mg) with the composition shown in Table 8 below.

Specifically, bevetastatin tosylate is mixed with precipitated calcium carbonate or magnesium oxide with lactose hydrate, microcrystalline cellulose, hydroxypropylmethylcellulose and / or Eudragit L 100-55 or hydroxypropylmethylcellulose acetate succinate, The granules were granulated with ethanol and dried at 60 DEG C for 2 hours. The obtained granules were sieved to 20 mesh and then mixed with sodium stearyl fumarate and tableted at 9-11 kp to prepare a white tablet having 200 mg per unit tablet. The tablet coating was carried out in the same manner as described in Examples 12 to 14.

Furtherance Example 15 Example 16 Example 17 Bepotastine tosylate 20.51 20.51 20.51 Magnesium oxide 20.0 15.0 10.0 Hydroxypropylmethylcellulose 60.0 60.0 20.0 Eudragit L100-55 - 20.0 - Hydroxypropylmethylcellulose acetate succinate - - 40.0 Lactose baggage 46.49 61.49 46.49 Microcrystalline cellulose 50.0 20.0 60.0 Sodium stearyl fumarate 3.0 3.0 3.0 Opa Dry 200 White 8.0 8.0 8.0 Gross weight 208.0 208.0 208.0

Example  18 to 19

Precipitated calcium carbonate or magnesium oxide was used to prepare a stabilized beatifastine tosylate sustained release tablet which can be taken once a day, and hydroxypropyl methylcellulose as a sustained-release carrier was added to Table 9 Tablets were prepared with the same composition (unit: 200 mg).

Specifically, bevetastatin tosylate and precipitated calcium carbonate or magnesium oxide were mixed with lactose hydrate, microcrystalline cellulose and hydroxypropylmethylcellulose, granulated with a certain amount of ethanol, and dried at 60 ° C for 2 hours. The obtained granules were sieved to 20 mesh and then mixed with sodium stearyl fumarate and tableted at 9-11 kp to prepare a white tablet having 200 mg per unit tablet. The tablet coating was carried out in the same manner as described in Examples 12 to 14.

Furtherance Example 18 Example 19 Bepotastine tosylate 20.51 20.51 Precipitated calcium carbonate 20.0 - Magnesium oxide - 20.0 Hydroxypropylmethylcellulose 60.0 60.0 Lactose baggage 40.0 46.49 Microcrystalline cellulose 56.49 50.0 Sodium stearyl fumarate 3.0 3.0 Opa Dry 200 White 8.0 8.0 Gross weight 208.0 208.0

Example  20

Tablets were prepared with the compositions of Table 10 below using the same method as in Examples 18 and 19.

Furtherance Example 20 Bepotastine tosylate 20.51 Magnesium oxide 20.0 Hydroxypropylmethylcellulose 60.0 Lactose baggage 40.0 Microcrystalline cellulose 56.49 Polyethylene oxide 40.0 Sodium stearyl fumarate 3.0 Opa Dry 200 White 8.0 Gross weight 208.0

Experimental Example  1: Stability test

To demonstrate the effect of the present invention, the optical isomer (R-bepotastine) and the content (%) of the flexible substance in the severe conditions for temperature and humidity for the final formulation were confirmed by the following method.

The packs prepared in Comparative Examples 1 to 12 and Examples 1 to 4 were packaged in HDPE bottles and stored for 2 weeks under severe conditions (60 ° C, 80% RH), and each optical isomer (R-bepotastine) (%) And the content (%) of the flexible material were measured. 10 tablets of each tablet were taken, and each one of the tablets was taken out of the powder. One equivalent of each tablet was taken into a 10 ml volumetric flask, and the diluted solution was added to dissolve the tablets. The tablets were mixed and analyzed by filtration. Separately, 10 mg of RS- Was precisely weighed, placed in a 25-ml volumetric flask, and dissolved by adding a dilution solution. The resulting mixture was mixed and mixed with a marking line, followed by filtration to obtain S-bepotastine and R-bepotastine in the sample solution.

10 μl of the standard solution and the test solution were subjected to the liquid chromatography method in the general test method of the Korean Pharmacopoeia under the following analysis conditions and the peak areas of R-bepotastine and S-bepotastine in the sample solution were determined. HPLC analysis was carried out under the following chromatographic conditions, and the results are shown in Table 11. < tb > < TABLE >

<Analysis condition>

Column: Daicel, Chiralpac IC (250 mm L x 4.6 mm I.D. 5 m)

- Column temperature: 35 ° C

- Detector: Exothermic absorptiometer (measuring wavelength: 260 nm)

- Flow rate: 1.0 ml / min

- Analysis time: 25 minutes

- Mobile phase: 1 L of ethanol / n-hexane (60:40) mixture, add 1 mL of triethylamine.

- Diluent: pH 3.0 A mixture of phosphate buffer and acetonitrile (7: 3)

<Calculation>

The amount (%) of the optical isomer (R-bepotastine)

= (Peak area of R-bepotastine / (peak area of R-bepotastine + peak area of S-bevapastastin)) x 100

Optical isomer
(R-bepotastine) Content (%) Content of soft materials (%) Formulation composition pH Test commencement Two weeks Test commencement Two weeks Test commencement Comparative Example 1 0.0 5.6 0.20 8.2 Comparative Example 2 0.0 3.3 0.02 0.41 3.83 Comparative Example 3 0.0 3.3 0.05 0.32 3.84 Comparative Example 4 0.0 5.7 0.01 0.37 3.86 Comparative Example 5 0.0 3.9 0.04 0.66 3.78 Comparative Example 6 0.0 4.1 0.02 0.39 4.52 Comparative Example 7 0.0 8.0 0.02 1.01 6.35 Comparative Example 8 0.0 0.7 0.02 8.53 9.50 Comparative Example 9 0.0 0.0 0.00 1.55 7.62 Comparative Example 10 0.0 3.1 0.00 0.46 7.10 Comparative Example 11 0.0 0.6 0.00 0.47 10.3 Comparative Example 12 0.2 0.7 0.00 0.61 7.56 Example 1 0.0 1.0 0.00 0.15 7.16 Example 2 0.0 1.4 0.00 0.11 9.62 Example 3 0.6 0.37 0.06 0.10 7.17 Example 4 0.6 1.16 0.04 0.20 9.60

As a result, in all of the comparative examples in which the water-insoluble basic substance was not used as the stabilizer, after two weeks, the content of R-bevapastastin was remarkably increased and the content of the substance was also remarkably increased.

On the other hand, all of the preparations of Examples 1 to 4 in which the water-insoluble basic substance was added retained the basicity of the pH of the composition of 7.0 or more, and the content of R-bepotastine and the content of the flexible substance were remarkably lower , Indicating excellent stability.

Experimental Example  2: Stability test

In order to demonstrate the effect of the present invention, Examples 5 to 11 were subjected to the determination of the optical isomer (R-bevaporustine) and the content (%) of the flexible substance under severe conditions for temperature and humidity for the final formulation. The test method was the same as that described in Test Example 1.

Optical isomer
(R-bepotastine) Content (%) Content of soft materials (%) Formulation composition pH Test commencement Two weeks Test commencement Two weeks Test commencement Example 5 0.0 1.4 0.00 0.09 7.3 Example 6 0.0 1.2 0.00 0.11 7.75 Example 7 0.0 1.6 0.00 0.10 9.16 Example 8 0.0 0.0 0.00 0.08 10.18 Example 9 0.0 0.0 0.08 0.08 10.42 Example 10 0.0 3.6 0.00 0.27 9.19 Example 11 0.0 2.5 0.00 0.06 9.54

As a result, as shown in Table 12, it was found that as the content of water-insoluble basic substance increased, the content of R-bepotastine and the softening material decreased.

Experimental Example  3: Dissolution test

The sustained release tablets prepared in Examples 12 to 19 and 10 mg of fasted purified intrathecic tablets of commercially available bepotastine besylate were subjected to a dissolution test according to the paddle method under the following conditions, The release pattern of the active ingredient, bepotastine, was measured.

- Elution test apparatus: paddle method

- eluent: pH 1.2, 4.0, 6.8, water

- Temperature of eluent: 37 ° C ± 0.5 ° C

- Amount of discharged liquid: 900 ml

- Agitation speed: 50 rpm

<Analysis method>

Column: Xterra RP18 (length 150 mm, inner diameter 3.9 mm, particle 5 um) or equivalent column

Column temperature: constant temperature around 40 캜

Mobile phase: pH 3.0 Phosphate buffer: acetonitrile (70:30, v / v)

Flow rate: 1.0 ml / min

<Formula>

(%) = Peak area of bepotastine in the chromatogram of the sample solution / Peak area of bepotastine in the chromatogram of the standard solution x (Concentration (mg / mL) of the standard solution of bevapastatin tosylate / 20.51) x Amount (mL) × Purity (%) of beptapastin tosylate standard

The measurement results are shown in Figs.

As a result, as shown in FIG. 1, as the viscosity of hydroxypropylmethylcellulose, which is a sustained-release carrier, was increased, the release rate of the drug was gradually delayed, and the release time was a pattern of continuous release over 10 hours .

Further, as shown in FIG. 2, it is also possible to use the aqueous solutions of Examples 15 to 16 containing hydroxypropylmethylcellulose, which is a sustained-release carrier, and / or Eudragit L100-55 or hydroxypropylmethylcellulose acetate succinate, 17 had an effect of sustaining release of the drug up to 10 hours, and in particular, Examples 16 and 17 containing the sustained-release carrier exhibiting pH-dependent solubility had the effect of accelerating the release rate of the drug in the latter half of Example 15 .

As shown in FIGS. 3 and 4, the release of the drug was completed within one hour in the comparative example. However, the preparation of Example 18 and Example 19 using hydroxypropylmethylcellulose as the sustained-release carrier showed 6 to 10 hours Over time, the drug was released continuously. In particular, the tablets of Examples 18 and 19 were released at the same rate of release in all pH buffer conditions (pH 1.2, pH 4.0, color: large, pH 6.8, respectively) Indicating the zero-order release rate which is released by the drug concentration.

Experimental Example  4: Stability test

In order to demonstrate the effect of the present invention, the final sustained release formulation was stored for 2 weeks under severe conditions of temperature and humidity, and the content of the optical isomer (R-bepotastine) and the content of the flexible substance was confirmed. The test method was the same as the method described in Experimental Example 1.

Optical isomer
(R-bepotastine) Content (%) Content of soft materials (%) Test commencement Two weeks Test commencement Two weeks Comparative Example 1 0.0 5.6 0.20 8.2 Example 18 0.16 0.45 0.06 0.36 Example 19 0.12 0.11 0.00 0.27 Example 20 0.07 0.09 0.00 0.26

As a result, as shown in Table 13, magnesium oxide and calcium hydroxide were mixed with magnesium oxide and precipitated calcium carbonate, and magnesium oxide with Examples 18 and 19 using hydroxypropylmethylcellulose as a sustained-release carrier, hydroxypropylmethylcellulose and polyethylene (R-bepotastine) and the preparation of the flexible material exhibited excellent stability as compared with the comparative example 1 of the present invention.

Experimental Example  5: Beagles  Pharmacokinetic study

In Example 18 and Comparative Example 19, 10 mg tablets of control drug were each administered to each of six beagles at a dose of 1 tablet each time, and then cephalic vein was administered 0.25, 1.5 mL of blood was collected at 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 12.25, 12.5, 12.75, 13, 13.5, 14, 15, , 1.5 ml of blood was collected before and after administration at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15, 18 and 24 hours. The collected blood was centrifuged to separate the plasma and stored in the freezer until analysis. After a sufficient 7-day withdrawal period, cross-testing was conducted in the same manner. The drug concentrations in plasma were analyzed by LC-MS / MS.

LC / MS / MS was used for the analysis of plasma isofutaine in the evaluation of pharmacokinetic absorption, and cetirizine was used as an internal standard substance. LC conditions were a column -ACQUITU UPLCBEH C18 (2.0 x50mm, 1.7 m m); mobile phase -MeOH: 5mM Ammonium formate = 65: 35; Flow rate -0.25 ml / min; injection amount -10 l; sample temperature -4 [deg.] C; And a column temperature of 25 ° C. MS conditions were ionization method - Electrospray ionization (ESI) in Positive ionmode; MRM (Multiple Reaction Monitoring) - bepotastine [M + H] + 388.8 → 201.9, cetirizine + 388.8 → 200.9. The comparative evaluation items (AUCt, Cmax) of the comparative example and the example were log-transformed and statistically processed.

Tari warmth 10mg (CV%) Example 18 (CV%) Tmax (hr) Primary administration: 1.5 ± 0.316 (21.1) 3.7 ± 1.059 (28.6) T _1/2 (hr) Primary dose: 4.668 ± 0.313 (6.7) 6.862 + - 3.446 (50.2) Cmax (ng / mL) 1149.005 + 148.739 (12.9) 1268.947 + - 354.927 (28.0) AUCt (ng.hr / mL) 12429.578 + - 1561.009 (12.6) 12365.641 + - 2629.077 (21.3) Ln Ratio (90% C.I) - Cmax 104.58%
AUCt 95.32%

Tari warmth 10mg (CV%) Example 19 (CV%) Tmax (hr) Primary dose: 1.54 +/- 0.89 (57.8) 4.25 + - 1.60 (37.7) T _1/2 (hr) Primary dose: 4.53 + 0.41 (9.1) 5.89 ± 1.28 (21.7) Cmax (ng / mL) 1226.29 + - 175.49 (14.3) 1191.86 + -447.97 (37.6) AUCt (ng.hr / mL) 13212.09 + - 1564.17 (11.8) 13192.53 + - 3297.34 (25.0) Ln Ratio (90% C.I) Cmax: 91.98%
AUCt: 97.79%

As a result, through FIGS. 5 and 6 and Tables 14 and 15, it was confirmed that both of Examples 18 and 19 maintained a high blood concentration of the active ingredient, bepotastine, in the beagle dog for a certain period of time, Cmax and AUC of the same level were secured as compared with the administered Tari warmth and Tmax was delayed so that the sustained-release carrier of the present invention, hydroxypropyl methylcellulose or polyethylene oxide, or a sustained-release tablet in which the two were mixed, can be taken once a day It was confirmed that the formulation had an effect.

Claims (14)

Bepotastine or a pharmaceutically acceptable salt thereof; And a water-insoluble basic substance selected from the group consisting of carbonates of magnesium and calcium and oxides of magnesium.
Bepotastine or a pharmaceutically acceptable salt thereof; A water-insoluble basic substance selected from the group consisting of carbonates of calcium and magnesium, and oxides of magnesium; And a sustained-release carrier.
delete 3. The preparation according to claim 1 or 2, wherein the beatifastine or a pharmaceutically acceptable salt thereof and a water-insoluble basic substance are granulated.
3. The formulation according to claim 1 or 2, wherein the formulation exhibits a pH of 7 or higher.
The preparation according to claim 1 or 2, wherein the water-insoluble basic substance is contained in an amount of 1 to 30% by weight based on the total weight of the preparation.
3. The preparation according to claim 1 or 2, wherein the water-insoluble basic substance is contained in an amount of 5 to 10% by weight based on the total weight of the preparation.
3. The preparation according to claim 1 or 2, wherein said beatifastine or a pharmaceutically acceptable salt thereof and a water-insoluble basic substance are contained in a weight ratio of 1: 0.1 to 1.
The sustained-release carrier according to claim 2, wherein the sustained-release carrier is at least one selected from the group consisting of hydroxypropylmethylcellulose, hydroxyethylcellulose, polyethylene oxide, hydroxypropylcellulose, collondol SR, Eudragit RS, Eudragit L 100-55, Sodium chloride, and xanthan gum.
The pharmaceutical preparation according to claim 9, wherein the hydroxypropylmethylcellulose has a viscosity of 100 mPa.s to 100,000 mPa.s and 5 to 50% by weight of the total weight of the preparation.
The preparation according to claim 9, wherein the polyethylene oxide has an average molecular weight of 600,000 to 7,000,000, and is contained in an amount of 5 to 50% by weight based on the total weight of the preparation.
3. The preparation according to claim 2, wherein the beatifastine or a pharmaceutically acceptable salt thereof and the sustained-release carrier are contained in a weight ratio of 1: 1 to 4: 1.
The formulation of claim 2, wherein the formulation exhibits a zero order release profile in pH buffer conditions (pH 1.2: up, pH 4.0: large intestine, pH 6.8: small intestine).
3. The formulation according to claim 2, wherein the formulation is administered once a day.

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