WO2018043850A1 - Pharmaceutical formulation of d-cycloserine and method for producing same - Google Patents

Abstract

The present invention relates to a pharmaceutical formulation of d-cycloserine and a method for producing same, and can provide an oral preparation of d-cycloserine by producing d-cycloserine by coating, with a Kollicoat^® Protect coating material, a mixture comprising d-cycloserine and a pH adjuster selected from magnesium hydroxide and calcium hydroxide, which has improved stability against pH, water and heat, saves the production cost by providing a common, ordinary packaging form without special packaging such as moisture-proof packaging, and shows improved stability by allowing long-term storage and drug activity maintenance.

Description

Pharmaceutical Formulations of D-Cycloserine and Methods for Making the Same

The present invention relates to a pharmaceutical formulation of D-cycloserine and a method for preparing the same, and more particularly, to a D-cyclocerine coated with a Kollicoat ^® Protect coating base, a mixture comprising a pH adjusting agent selected from magnesium hydroxide or calcium hydroxide. A pharmaceutical formulation of cycloserine and a method for preparing the same.

D-cycloserine is a type of antibiotic that exhibits antimicrobial effects by inhibiting the synthesis of bacterial cell walls by competitively binding to D-alanine in the cell wall during bacterial cell wall synthesis. In particular, antimicrobial activity against the Gram-negative Escherichia coli strain and Staphylococcus aureus strains has antibacterial effects, and it also shows antimicrobial effects against Mycobacteria strains that cause tuberculosis. It is also used as. In particular, D-cycloserine is one of the most widely used drugs in the treatment of tuberculosis in infants or children. In some cases, as a drug that can effectively treat toxic or resistant bacteria expressed after the use of a primary tuberculosis treatment, it may be used in multi-drug therapy.

In addition, D-cycloserine is used as a contra-indicator of patients with severe kidney defects caused by alcoholism, or mental disorders such as depression and epilepsy, and D-cycloserine and the L-cyclosomer, which is a mirror isomer. Serine has been reported to be effective in the treatment of Gaucher's disease. In addition, D-cycloserine is a drug for the central nervous system has been studied as a drug for treating dementia or increasing memory. Therefore, research on the preparation of precursor pro-drug forms for increasing the drug efficacy while increasing the stability of the cycloserine has been actively conducted.

D-cycloserine is water soluble, neutral and acid labile and stable in alkaline environments. As a result, moisture-proof packaging is required because it easily decomposes in wet conditions, low pH, and above temperature conditions, and rapidly decomposes when exposed to heat in the presence of moisture. Therefore, to stably formulate this drug, it is essential to improve the stability to the above conditions.

The commercially available D-cycloserine formulation is packed with aluminum at a capacity of 250 mg, which requires a high cost and special packaging equipment for its manufacture. In addition, when it is opened and stored, it is rapidly decomposed under heat or moisture conditions and stored for a period of time. As a result, problems may occur that do not achieve the desired therapeutic effect.

D-cycloserine is prepared by various methods, of which, according to the preparation method disclosed in British Patent No. 1,223,887, hydroxylamine based on D-α-amino-β-chloropyropionic acid methyl ester hydrochloride as a starting material. After reacting with hydrochloride to prepare D-α-amino-β-chloro propiohydramic acid, and then cyclized in a caustic soda solution to prepare D-cycloserine, and then a large amount to separate and purify D-cycloserine A method of using 8-hydroxyquinoline is disclosed. However, this method is not economical and is not suitable as a mass production method because a large amount of expensive 8-hydroxyquinoline must be used, and a method for improving the stability of D-cycloserine is not disclosed.

It is an object of the present invention to provide a pharmaceutical formulation of D-cycloserine characterized by coating a mixture comprising D-cycloserine and a pH adjusting agent selected from magnesium hydroxide or calcium hydroxide with a Kollicoat ^® Protect coating base.

Another object of the present invention is to prepare a first mixture by i) mixing D-cycloserine and a pH adjusting agent selected from magnesium hydroxide or potassium hydroxide, ii) mixing a pharmaceutically acceptable additive into the first mixture. Preparing a second mixture by mixing by dry granulation, wet granulation, or direct mixing, iii) preparing a pharmaceutical oral formulation with the second mixture, and iv) applying the oral formulation to a Kollicoat ^® Protect coater. It provides a method for producing a pharmaceutical formulation of D-cycloserine, characterized in that it comprises a step of coating zero.

In order to achieve the above object, the present invention provides a pharmaceutical formulation of D-cycloserine characterized by coating a mixture comprising D-cycloserine and a pH adjusting agent selected from magnesium hydroxide or calcium hydroxide with Kollicoat ^® Protect coating base. .

In addition, the present invention comprises the steps of i) mixing D-cycloserine and a pH adjusting agent selected from magnesium hydroxide or potassium hydroxide to prepare a first mixture, ii) mixing the pharmaceutically acceptable additives into the first mixture to dry granules. Method, wet granulation, or direct mixing to prepare a second mixture, iii) preparing a pharmaceutical oral formulation with the second mixture, and iv) coating the oral formulation with a Kollicoat ^® Protect coating. It provides a method for preparing a pharmaceutical formulation of D-cycloserine, characterized in that it comprises a step of.

The present invention is made in the cycle D- serine coated relates to pharmaceutical formulations and methods for their preparation of D- serine cycle, the mixture comprising a pH adjusting agent selected from cyclo D- serine and magnesium hydroxide or calcium hydroxide agent Kollicoat ^® Protect coater This improves the stability to pH, moisture and heat, and provides a common general packaging form without special packaging, such as moisture-proof packaging, to reduce the manufacturing cost, and to maintain long-term storage and drug activity.

Therefore, due to the disadvantages of the conventional D-cycloserine which is rapidly decomposed at pH, moisture and thermal conditions, it solves the problem that the desired therapeutic effect may not be obtained depending on the storage conditions during the administration period, and provides an oral preparation that can maintain drug activity. can do.

FIG. 1 evaluates the suitability by comparing the D-cycloserine containing the pH adjusting agent of Examples 1 to 9 with the D-cycloserine powder containing no pH adjusting using differential scanning calorimetry.

FIG. 2 compares the dissolution patterns of D-cycloserine of Examples 22, 24, 25, and 27-31 using the dissolution test method of D-cycloserine of a commercial product.

The inventors of the present invention coated a mixture containing D-cycloserine and a pH adjusting agent selected from magnesium hydroxide or calcium hydroxide with a Kollicoat ^® Protect coating base to prepare D-cycloserine to improve stability against pH, moisture and heat, and to provide moisture-proof packaging. By providing a general packaging form without special packaging such as to reduce the manufacturing cost, while completing the present invention while confirming that long-term storage and drug activity is maintained.

The term “Kollicoat ^® Protect” used in the present invention is a product commercialized by BASF, and consists of polyvinyl alcohol-polyethylene glycol copolymer and polyvinyl alcohol (PVA). And represented by the following Chemical Formula 1. Kollicoat ^® Protect consists of 55 to 65% by weight of polyvinyl alcohol-polyethylene glycol copolymer and 35 to 45% by weight of polyvinyl alcohol and serves as a protective coating in the manufacture of film coatings.

[Formula 1]

The present invention provides a pharmaceutical formulation of D- serine cycle, it characterized in that the coating mixture comprising a pH adjusting agent selected from cyclo D- serine and magnesium hydroxide or calcium hydroxide agent Kollicoat ^® Protect coater.

Preferably, the mixture may comprise a pharmaceutically acceptable additive. The mixture may further improve the preparation, flowability and physical properties of the pharmaceutical composition by further comprising at least one pharmaceutically acceptable additive.

In the art, all additives other than the main ingredient, which are active ingredients, are collectively referred to as additives or excipients, and preferably, the pharmaceutical composition may further include any one or more of excipients, binders, disintegrants, lubricants, and diluents.

Excipients may be included to ensure uniform volume and uniformity of the desired tableting and content depending on the dose of the main drug, D-cycloserine. Examples of excipients include lactose, mannitol, starch, powdered white sugar, calcium phosphate, microcrystalline cellulose, colloidal silicon dioxide, and the like, and can be appropriately selected and used by those skilled in the art in consideration of cost and compatibility with active ingredients. Other kinds of additives may also serve as excipients in addition to their primary use.

The binder acts to improve adhesion between the granules and to maintain the form of the formulation after the compression process. Examples of the binder may include, but are not limited to, maltose, natural gum (gum), cellulose derivatives (methylcellulose, carboxymethylcellulose, microcrystalline cellulose), gelatin, povidone, and the like.

Disintegrants may be added to promote disintegration or disintegration of the final prepared formulation, specifically to expand upon contact with moisture and serve to disrupt the tablet in the gastrointestinal tract. Examples of disintegrants include starch derivatives (corn starch, potato starch, sodium starch glycolate, croscarmellose), cellulose derivatives (sodium carboxymethylcellulose, polyvinylpyrrolidone), crospovidone, and cation exchange resins. It may be, but not limited to.

Glidants improve the fluidity during granule production, prevent adhesion in devices such as punches and rollers, and reduce resistance when withdrawing granules from the device. It serves to facilitate the filling in the formulation. Examples of lubricants include, but are not limited to, talc, hydrogenated castor oil, magnesium stearate, calcium stearate, silicon dioxide, stearic acid, magnesium stearate, or mixtures thereof.

In addition, microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salts, diluents such as clay, polyethylene glycol and dicalcium phosphate, and conventionally used desiccants, sweeteners or desiccants do not impair the effects of the present invention. It may be included in the range, the preferred type and content of the additive may be appropriately selected and applied in consideration of the nature, dosage and formulation properties of the ingredients used in conjunction with those skilled in the art according to techniques known in the art.

Preferably, the mixture may consist of 35 to 60% by weight of D-cycloserine, 30 to 60% by weight of pH adjuster and 0.1 to 10% by weight of talc.

Preferably, the pH adjusting agent may be included in an amount of 6 to 100 parts by weight in 100 parts by weight of D-cycloserine. More preferably, it may be contained in 12.5 to 100 parts by weight, when the pH adjusting agent is added to 12.5 parts by weight or less relative to 100 parts by weight of D-cycloserine, the pH control ability is sharply lowered, is added to 100 parts by weight or more In this case, there may be a problem in that there is no big difference in pH adjusting ability and difficulty in formulating, which may be undesirable.

The pH adjusting agent is magnesium hydroxide, calcium hydroxide, calcium silicate, calcium carbonate, dicalcium phosphate, tricalcium phosphate, magnesium carbonate, magnesium silicate, magnesium oxide, magnesium aluminate, aluminum hydroxide, lithium hydroxide, potassium hydroxide, sodium bicarbonate, borate It may be selected from, but is not limited to, sodium, sodium carbonate, sodium hydroxide, meglumine, arginine and mixtures thereof.

The pH adjusting agent serves to adjust the microenvironmental pH of the pharmaceutical composition of D-cycloserine. More specifically, as a pH adjuster, calcium salts (calcium silicate, calcium carbonate, calcium hydroxide, dicalcium phosphate, tricalcium phosphate), magnesium salts (magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium oxide, magnesium aluminate, aluminum hydroxide ), Alkaline metal salts such as lithium salt (lithium hydroxide), potassium salt (potassium hydroxide) and sodium salt (sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide). In addition, basic additives such as meglumine, arginine, and mixtures thereof can also be used. It is noted that the pH adjusting agent may be, but is not limited to, one or two or more selected from the group of pH adjusting agents listed above. Preferably, it may be one or more selected from the group consisting of magnesium hydroxide and calcium hydroxide. Such a pH adjuster may be used to adjust the microenvironment pH of the pharmaceutical composition to 7 or more, such as pH 7 to 11, more preferably to adjust the microenvironment pH to 9 or more.

Preferably, the coating base may be included in an amount of 2 to 8 parts by weight based on 100 parts by weight of D-cycloserine.

The pharmaceutical formulation may be film coated with a pharmaceutically acceptable coating base. The coating base may be Kollicoat ^® Protect, Opadry ^® AMB, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, xanthan gum, natural rubber, carboxymethyl cellulose, alginic acid, polyvinyl alcohol and its derivatives, methacrylic acid derivatives, polyacrylic acid derivatives. It may be one or two or more selected from the group consisting of ethyl cellulose and methyl cellulose, but is not limited thereto. More preferably, the coating base may be Kollicoat ^® protect.

Preferably, the pH adjusting agent and the coating agent may improve the stability of D-cycloserine against pH, moisture, and heat.

Preferably, the pharmaceutical formulation may be an oral preparation, but is not limited thereto.

The present invention comprises the steps of i) mixing D-cycloserine and a pH adjusting agent selected from magnesium hydroxide or potassium hydroxide to prepare a first mixture, ii) mixing a pharmaceutically acceptable additive to the first mixture to dry granules, step was mixed by a wet granulation method or the direct mixing method for producing a second mixture, iii) phase and iv) the step of coating the preparations for the oral agent Kollicoat ^® Protect coating machine for producing a pharmaceutical oral preparation for a second mixture It provides a method for producing a pharmaceutical formulation of D-cycloserine comprising a.

Preferably, the oral preparation in step iii) may be selected from the group consisting of granules, capsules, powders, tablets and film coated tablets, but is not limited thereto.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. .

Example 1-9 Preparation of a 1: 1 Mixture of D-Cycloserine with Various pH Control Agents

D-cycloserine and pH regulators meglumine, magnesium hydroxide, sodium bicarbonate, sodium citrate, calcium hydroxide, precipitated calcium carbonate, magnesium aluminate silicate, magnesium carbonate and calcium silicate, respectively, as shown in Table 1 below. The mixture was prepared by direct mixing with.

(Unit: g)

division	Example
	One	2	3	4	5	6	7	8	9
D-cycloserine	One	One	One	One	One	One	One	One	One
Meglumine	One	-	-	-	-	-	-	-	-
Magnesium hydroxide	-	One	-	-	-	-	-	-	-
Sodium bicarbonate	-	-	One	-	-	-	-	-	-
Sodium citrate	-	-	-	One	-	-	-	-	-
Calcium hydroxide	-	-	-	-	One	-	-	-	-
Precipitated Calcium Carbonate	-	-	-	-	-	One	-	-	-
Magnesium Aluminate	-	-	-	-	-	-	One	-	-
Magnesium carbonate	-	-	-	-	-	-	-	One	-
Calcium silicate	-	-	-	-	-	-	-	-	One

Example 10-21 Preparation of a Mixture According to the D-Cycloserine and pH Control Concentrations

The mixture was prepared by directly mixing D-cycloserine and magnesium hydroxide and calcium hydroxide, which are pH adjusting agents, at different concentrations of the pH adjusting agent as shown in Table 2 below.

(Unit: g)

division	Example
	10	11	12	13	14	15	16	17	18	19	20	21
D-cycloserine	One	One	One	One	One	One	One	One	One	One	One	One
Magnesium hydroxide	4	0.25	0.125	0.0625	0.032125	0.01	-	-	-	-	-	-
Calcium hydroxide	-	-	-	-	-	-	2	0.25	0.125	0.0625	0.032125	0.01

Example 22-27 Preparation of D-Cycloserine Formulations Containing pH Control Agents

D-cycloserine and a pH regulator, magnesium hydroxide and calcium hydroxide, microcrystalline cellulose, talc were directly mixed in a composition as shown in Table 3 below to prepare a D-cycloserine tablet by a direct method.

(Unit: g)

division	Example
	22	23	24	25	26	27
D-cycloserine	25	25	25	25	25	25
Magnesium hydroxide	25	15	5	-	-	-
Calcium hydroxide	-	-	-	25	15	5
Microcrystalline cellulose	-	10	20	-	10	20
Talc	0.75	0.75	0.75	0.75	0.75	0.75

<Examples 28-31> film-coated tablets of D- serine cyclo formulations containing a pH controlling agent Article

In Examples 22 and 23, D-cycloserine, a pH regulator, magnesium hydroxide, a microcrystalline cellulose as a diluent, and talc as a lubricant are mixed directly, and the coating base is different from the D-cycloserine tablet prepared by the direct method. As shown in each of the three coating bases (Kollicoat ^® protect, Opardry ^® , Oparday ^® AMB) to prepare a film coated tablet, respectively.

(Unit: g)

division	Example
	28	29	30	31
Example 22	10	10	10	-
Example 25	-	-	-	10
Kollicoat ® protect	0.5	-	-	0.5
Opardry ®	-	0.5	-	-
Oparday ® AMB	-	-	0.5	-

Comparative Example 1-5 Preparation of D-Cycloserine Formulation Without pH Adjusting Agent

Cyclo D- serine, was prepared in D- Serine cyclo preparation of a composition such as to use the magnesium hydroxide, calcium hydroxide, a binding agent is povidone, talc, and Kollicoat ^® protect and Table 5. The

Comparative Example 1 prepared D-cyclocerine tablets using the raw material itself, Comparative Examples 2 and 3 prepared the granules by dry granulation method with a composition excluding talc, and then mixed the talc after the D-cyclocerine tablet. Was prepared. Comparative Examples 4 and 5 were prepared by first mixing the D-cycloserine and the pH adjusting agent, and then preparing granules by wet granulation using a solution of povidone dissolved in ethanol as a binding solution, followed by drying at 40 ° C. and post-talc mixing. To prepare a D-cycloserine tablet. Comparative Example 6 Preparation of D- serine cycle to obtain the mixture after the povidone and the liquid was dissolved in ethanol to prepare a binding solution granules by a wet granulation method and then dried at 40 ℃ and talc in D- Serine cycle and Kollicoat ^® protect It was prepared as a coated tablet using a coating base.

(Unit: g)

division	Comparative example
	One	2	3	4	5	6
D-cycloserine	25	25	25	25	25	25
Magnesium hydroxide	-	25	-	25	-	-
Calcium hydroxide	-	-	25	-	25	-
Povidone	-	-	-	4	4	4
Talc	-	0.75	0.75	0.5	0.5	0.5
Kollicoat ® protect	-	-	-	-	-	1.475

<Experimental Example 1> CAB by differential scanning calorimetry of the cyclo D- serine and pH control agents (differential scanning calorimetry, DSC)

Each sample was analyzed by differential scanning calorimetry to analyze the compatibility of the drug of Example 1 to Example 9 with the pH adjuster. Differential scanning calorimetry analyzes the temperature difference between the reference material and the sample at a constant rate of temperature rise at the same time, and the endothermic or exothermic due to phase change and pyrolysis of the sample. It is a way.

As a result, referring to Figure 1 it was confirmed that after the characteristic endothermic peak of the D-cycloserine powder at 145 ° C corresponding to the melting point of the D-cycloserine powder is rapidly decomposed to show an exothermic peak. Differential scanning calorimetry was used to evaluate the suitability of D-cycloserine and pH regulators to determine the suitability of D-cycloserine in the mixtures of Examples 2 to 5 containing magnesium hydroxide, sodium bicarbonate, sodium citrate, and calcium hydroxide, respectively. The same changes as the powder were observed to confirm that there was no change in the properties of the drug, but Examples 1 and 6 to 6 containing meglumine, precipitated calcium carbonate, magnesium metasilicate aluminate, magnesium carbonate and calcium silicate In the mixture of 9, it was confirmed that the melting of the drug floated and appeared to affect the drug stability. Therefore, it was confirmed that pH adjusting agents such as magnesium hydroxide and calcium hydroxide did not change the stability of the drug.

Experimental Example 2 Severity Stability Evaluation of a D-Cycloserine-Containing Formulation

60 ° C., 75% relative humidity (DH), unpackaged open the D-cycloserine containing the pH adjusting agent of Examples 1 to 21 and the D-cycloserine containing no pH adjusting agent of Comparative Example 1 Severity stability was assessed by measuring high-performance liquid chromatography (HPLC) content of D-cycloserine over time in storage.

HPLC conditions for quantification of D-cycloserine

Column: C18 column or similar column (25 cm X 0.46 cm, I.D., particle size 5.0 μm)

Injection volume: 10 μl

Detector: ultraviolet absorbance photometer (wavelength 219 nm)

Flow rate: 1.0 ml / min

Column temperature: 25-35 ° C.

Mobile phase: 0.5 g of 1-decanesulfonate is dissolved in 800 ml of water, then 50 ml of acetonitrile and 5 ml of glacial acetic acid are added. Adjust to pH 4.4 with 1 N sodium hydroxide and filter to 0.45 μm

As a result of comparing Examples 1 to 21 and Comparative Example 1 at 60 ° C., 75% RH, and unpackaged open storage at 1 day, as shown in Table 6, magnesium hydroxide and calcium hydroxide as pH regulators were shown. It was confirmed that the formulation containing this, that is, excellent thermal and moisture stability in Example 2 and Example 5. In addition, when looking at the changes in the D-cycloserine content according to the concentration of magnesium hydroxide and calcium hydroxide as shown in Examples 10 and 16, there was no significant change in the ratio of 1: 1 or more, but the ratio of 1: 1 or less. In it was confirmed that the amount of D-cycloserine also decreases as the amount of pH adjuster decreases.

division		content(%)
Changes in D-cycloserine content after 1 day at 60 ° C and 75% RH
Example	One	15.12 ± 4.51
	2	38.94 ± 7.29
	3	8.14 ± 3.27
	4	0
	5	54.24 ± 8.44
	6	0
	7	0
	8	3.24 ± 1.21
	9	8.64 ± 2.25
	10	41.25 ± 3.01
	11	20.32 ± 2.54
	12	10.18 ± 1.02
	13	6.09 ± 0.34
	14	3.21 ± 0.15
	15	1.62 ± 0.06
	16	56.84 ± 7.61
	17	27.06 ± 1.15
	18	13.38 ± 0.75
	19	7.54 ± 0.31
	20	4.05 ± 0.18
	21	2.13 ± 0.08
Comparative example	One	0

<Experimental Example 3> microenvironmental pH of the formulation containing D- serine cyclo (microenvironmental pH) evaluation

400 mg of each of Examples 1 to 21 and Comparative Example 1 at 60 ° C., 75% RH, and unpackaged open storage at the time of one day elapsed, and 4 ml of water were added thereto, followed by mixing, followed by a pH meter. Microenvironment pH was measured. Separately, only 40 mg of the pH adjuster was added to 50 ml of water, mixed, and the pH of the pH adjuster was measured.

When the pH of the solution containing only the pH adjuster was measured, as shown in Table 7, meglumine, magnesium hydroxide, calcium hydroxide, and magnesium carbonate showed a pH of 10, but in a mixture of 1: 1 mixed with D-cycloserine, magnesium hydroxide and calcium hydroxide This pH was maintained at 9 or higher.

(Unit: g)

	* Theory	Measured value (40 mg / 50 ml)	receptivity
Meglumine	10.5	10.7	receptivity
Magnesium hydroxide	10.3	10.9	Very weak water soluble
Sodium bicarbonate	8.3	8.4	receptivity
Sodium citrate	7.0-9.0	8.2	receptivity
Calcium hydroxide	12.4	12.4	Weak water solubility
Precipitated Calcium Carbonate	9.0	9.9	Insoluble
Magnesium Aluminate	9.0-10.0	7.8	Insoluble
Magnesium carbonate	-	10.2	Insoluble
Calcium silicate	8.4-10.2	9.5	Insoluble

* Theoretical Value: Handbook of Pharmaceutical Excipient 6 ^th edition.

As a result of comparing Examples 1 to 21 and Comparative Example 1 1 day after storage, as shown in Table 8, the formulation containing magnesium hydroxide and calcium hydroxide as a pH regulator, that is, Example 2 and Example It was confirmed in 5 that the microenvironmental pH remains unchanged. In addition, when looking at the pH change according to the concentration of magnesium hydroxide and calcium hydroxide as shown in Examples 10 and 16, there was no significant change in the ratio of 1: 1 or more, but the amount of the pH regulator at the ratio of 1: 1 or less As a result, the microenvironment pH of D-cycloserine could not be maintained as a result similar to the decrease in the content of D-cycloserine.

division		Microenvironmental pH
		At the start	PH after 1 day at 60 ° C and 75% RH
Example	One	7.38 ± 0.27	9.42 ± 0.33
	2	9.30 ± 0.31	9.37 ± 0.29
	3	6.94 ± 0.25	9.08 ± 0.27
	4	6.31 ± 0.33	7.36 ± 0.29
	5	9.25 ± 0.21	9.32 ± 0.31
	6	6.37 ± 0.25	7.59 ± 0.21
	7	6.26 ± 0.19	7.9 ± 0.28
	8	7.10 ± 0.13	9.52 ± 0.26
	9	6.76 ± 0.29	8.38 ± 0.18
	10	9.51 ± 0.34	9.56 ± 0.29
	11	7.91 ± 0.19	9.48 ± 0.39
	12	7.35 ± 0.25	9.31 ± 0.22
	13	6.68 ± 0.19	7.61 ± 0.28
	14	6.25 ± 0.28	7.31 ± 0.19
	15	6.11 ± 0.25	7.13 ± 0.23
	16	9.32 ± 0.26	9.33 ± 0.18
	17	7.78 ± 0.40	9.18 ± 0.38
	18	7.12 ± 0.43	9.23 ± 0.29
	19	6.52 ± 0.38	7.54 ± 0.34
	20	6.34 ± 0.28	7.38 ± 0.24
	21	6.01 ± 0.25	7.08 ± 0.23
Comparative example	One	6.03 ± 0.25	7.02 ± 0.30

Experimental Example 4 Dissolution Evaluation

Elution of the pharmacopeias by taking the corresponding amount in D-cycloserine and commercial preparations (Croserine capsules, Dong-A Pharmaceutical Co., Ltd.) 250 mg of Examples 22, 24, 25 and 31 Dissolution experiments were carried out according to the second test method. At this time, the eluate was 900 ml of distilled water, the temperature was 37 ℃, the rotation speed was 50 rpm. 1 ml of the sample was taken at a certain time, filtered, and quantified by high performance liquid chromatography (HPLC).

As a result, referring to FIG. 2, similar release patterns such as release of 90% or more within 15 minutes in Examples 22, 24, 25, 27-31, and all commercially available formulations over time were observed. By showing, it was confirmed that the formulation containing the pH adjuster does not affect the elution.

Experimental Example 5 Evaluation of Accelerated Stability of a D-Cycloserine-Containing Formulation

The D-cycloserine and the commercially available formulations (Crosserin capsule, Dong-A Pharmaceutical Co., Ltd.) D-cycloserine of Examples 22 to 31 and Comparative Examples 2 to 5 were used at 40 ° C., 75% RH, and high density polyethylene (HDPE). The content of D-cycloserine over time was measured by high performance liquid chromatography (HPLC) method while stored in bottle packaging.

As a result, as shown in Table 9 it was confirmed that the excellent stability compared to the commercially available in the D-cyclocerine content change. Example 22 to Example 27 showed a better stability as the amount of pH adjusting agent increases, especially Example 28 and Example 31 of Kollicoat ^® showed a better stability Jung a film coating to protect the coating. Comparing Example 22 and Example 26 with Comparative Examples 2 to 4, the tablets produced by the straight and the dry granules showed better stability than the tablets produced by the wet granules. It was confirmed that it affects. In addition, when comparing Example 28 and Example 31 and Comparative Example 6, the pH coating agent does not play a role in the stability of the D-cycloserine by confirming that the stability of the rapid decrease in the accelerated conditions in the case of the film coating agent does not contain a pH regulator It was confirmed that.

division		Content of D-cycloserine (%)
		0	1 month	2 months	4 months
Example	22	100	97.66 ± 1.95	45.54 ± 5.64	21.15 ± 8.11
	23	100	97.96 ± 1.24	35.58 ± 7.44	8.94 ± 6.48
	24	100	99.25 ± 0.98	27.54 ± 6.12	1.59 ± 3.51
	25	100	97.24 ± 1.10	67.64 ± 3.54	27.45 ± 5.64
	26	100	96.87 ± 0.97	41.18 ± 6.11	20.45 ± 4.48
	27	100	91.34 ± 1.11	22.32 ± 4.12	8.83 ± 5.94
	28	100	99.15 ± 1.64	95.45 ± 1.95	90.19 ± 1.54
	29	100	98.39 ± 1.05	66.35 ± 3.44	30.45 ± 4.65
	30	100	97.45 ± 1.65	88.23 ± 2.58	70.64 ± 6.45
	31	100	99.39 ± 1.35	99.45 ± 0.64	97.18 ± 1.14
Comparative example	2	100	98.10 ± 1.47	50.21 ± 6.61	23.64 ± 6.15
	3	100	98.25 ± 1.62	60.15 ± 7.12	28.18 ± 5.18
	4	100	97.45 ± 1.21	47.95 ± 5.59	8.12 ± 2.64
	5	100	96.45 ± 1.36	40.26 ± 7.31	3.54 ± 3.54
	6	100	99.39 ± 1.35	79.66 ± 6.35	32.28 ± 6.11
Commercial item		100	85.24 ± 3.14	13.24 ± 4.12	0.0 ± 0.0

From the above experimental results, as in the present invention, the preparation of D-cycloserine preparations containing pH adjusting agents such as magnesium hydroxide and calcium hydroxide shows better thermal and moisture stability than the conventional D-cycloserine preparations, thereby improving stability. It is thought to be able to provide.

As described above in detail certain parts of the present invention, it is apparent to those skilled in the art that these specific descriptions are merely preferred embodiments, and the scope of the present invention is not limited thereto. Thus, the substantial scope of the present invention will be defined by the appended claims and equivalents thereof.

The scope of the present invention is represented by the following claims, and it should be construed that all changes or modifications derived from the meaning and scope of the claims and their equivalents are included in the scope of the present invention.

Claims (9)

1. A pharmaceutical formulation of D-cycloserine characterized by coating a mixture comprising D-cycloserine and a pH adjusting agent selected from magnesium hydroxide or calcium hydroxide with a Kollicoat ^® Protect coating base.
2. The pharmaceutical formulation of D-cycloserine according to claim 1, wherein the mixture comprises a pharmaceutically acceptable additive.
3. The pharmaceutical composition of D-cycloserine according to claim 1, wherein the mixture consists of 35 to 60% by weight of D-cycloserine, 30 to 60% by weight of pH adjuster and 0.1 to 10% by weight of talc. Formulation.
4. The pharmaceutical formulation of D-cycloserine according to claim 1, wherein the pH adjusting agent is included in an amount of 6 to 100 parts by weight based on 100 parts by weight of D-cycloserine.
5. The pharmaceutical formulation of D-cycloserine according to claim 1, wherein the coating agent is included in an amount of 2 to 8 parts by weight based on 100 parts by weight of D-cycloserine.
6. The pharmaceutical formulation of D-cycloserine according to claim 1, wherein the pH adjusting agent and the coating agent improve the stability of D-cycloserine against pH, moisture and heat.
7. The pharmaceutical formulation of D-cycloserine according to claim 1, wherein the pharmaceutical formulation is an oral formulation.
8. i) mixing a D-cycloserine and a pH adjuster selected from magnesium or potassium hydroxide to prepare a first mixture;

   ii) mixing a pharmaceutically acceptable additive with the first mixture to dry granulate, wet granulate, or direct mix to prepare a second mixture;

   iii) preparing a pharmaceutical oral formulation from the second mixture; And

   iv) coating the oral formulation with a Kollicoat ^® Protect coating base;

   Method for producing a pharmaceutical formulation of D-cycloserine comprising a.
9. The method of claim 8, wherein the oral preparation in step iii) is selected from the group consisting of granules, capsules, powders, tablets and film coated tablets.

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