TW201036976A - Zaleplon pharmaceutical composition and the method for producing the same - Google Patents

Abstract

The present invention provides a zaleplon pharmaceutical composition, which comprises 5 to 15 %(w/w) of zaleplon, 45 to 90 %(w/w) of filler, 0.5 to 1.5 %(w/w) of lubricant, 1 to 10 %(w/w) of adhesive, 0.5 to 6 %(w/w) of surfactant and 2 to 30 %(w/w) of disintegrating agent. The zaleplon pharmaceutical composition provided by the present invention is advantageous of its constant releasing rate, fast and stable efficacy. The PK (pharmacokinetic) parameters of the zaleplon pharmaceutical composition of the present invention are better than those of the brand name drug SONATA ®. The present invention also provides a method for producing the zaleplon pharmaceutical composition of the present invention.

Description

201036976, '<> Description of the Invention: [Technical Field] The present invention relates to a Zalepler pharmaceutical composition and a method for producing the same, and more particularly to a Zalepler pharmaceutical composition having a stable dissolution rate . [Prior Art]

Ο Modern people are under increasing pressure. Sleeping at night and insomnia are long-standing problems for many people and one of the most common complaints for outpatients. According to the results of the “Large Insomnia Question” published by the University of the People's Republic of China in February 1993, the prevalence of insomnia in the country over 15 years old is the highest in the region. In addition, according to the Department of Health's Drug Administration, the Department of Insomnia 3, about 2 million people, each thousand people take 9 安 sleeping pills per day. After conversion, the amount of sleeping pills in Taiwan is about 65.7 million or more per year, and the market is about NT$100 million. And this data is still climbing up every year. Insomnia refers to difficulty falling asleep (sleeping latency > 3 minutes), easy to wake up in the middle of the night. ^ Can't sleep immediately, wake up too early to sleep, and sleep less than six hours a day. In the face of patients who have been sleeping for a long time and seriously affecting daily life and work, 'the use of sleeping sedatives is almost the only way to solve the symptoms of insomnia quickly and effectively. Wei Zhi can effectively improve the symptoms of insomnia; but long-term use of sleeping sedatives can produce dependence, withdrawal, drug resistance and the symptoms of rebound insomnia, and increase the risk of accidents, so the US food and medicine only approved sleep Sedatives are used for short-term treatment of insomnia. The most commonly used sleeping sedative in the past is benzodiazepine (Be brain Repines), and rum-Benzodiazepines sleeping pills have become popular in the past decade. Non-Benzodimamine 4 201036976 'The drug has lower side effects than traditional sleeping pills, and has no side effects such as anti-caries and muscle relaxation. Its effect is rapid, and the patient may go to sleep less than half an hour after taking the drug. Although the above-mentioned advantages of non-benzodiazepine sleeping pills, there are still possible adverse reactions of traditional sleeping pills, including headache, dizziness, gastrointestinal discomfort, transient amnesia, sleepwalking, etc., and their addiction and dependence are similar to those of traditional sleeping pills. Zaleplon is a new non-benzodiazepine sleeping pill with a half-life of about 1 hour and a potency of about 4 hours. Due to the short-acting properties of Zalepler, sleep latency can be shortened. It is more suitable for patients who have difficulty falling asleep. Because the residual effects of sleeping pills may affect daytime attention, sleeping pills are not recommended for the second time in the middle of the night, but Zalepler's ultra-short-term properties make it the only drug available for midnight use. Zaleple (N-[3-(3-cyanopi-pyrazolopyrimidinyl-7-yl)phenyl]-N-ethylacetamidamine (N-[3-(3-cyanopyrazol〇[l,5_a ]pyrimidin_7_yl) phenyl]-N-ethylacetamide), a molecular formula of c17H15N50, molecular weight 305.34 g/mol 'an effective drug for the treatment of insomnia. Zalepler was developed by Wyeth-Ayerst in the United States in 1985 (US 4,626,538). In 1999, it was marketed in I League and the United States, and the dosage forms were 5 mg and 1 〇mg capsules (trade name: SONATA®). Taiwan Patent Publication No. 200704410 discloses a two-stage administration of sleeping pills, and substances, taking The therapeutic time of the sleeping pills can be prolonged. Taiwan Patent Publication No. 1285118 provides a timed dual release dosage form of short-acting hypnotics or its salts, which can extend the release effect. U.S. Patent No. 6,485,746 B1 discloses a short half-life controlled release sleeping pill. a pharmaceutical composition characterized in that it achieves a bimodal (pulsed) release effect in a laboratory concentration; US 2005/0119281 A1 proposes a specific particle size powder group comprising Zaleple 5 5,036,976 distribution and pharmaceutical composition , 10% or less Leppler particles <0.5 μπι, 10/〇 or less of Zalepule particles>, the intermediate particle size is about 4-10 μιη; us 2007/0020333 A1 proposes a method comprising at least one delayed sustained release component ( Delay ed release element) and 扎莱普勒's pharmaceutical combination to achieve the effect of extended release, all of which are significantly different from the short-acting formulations of the present invention. ❹ 〇 θ below are descriptions of short-acting formulations, WO 2007/107878 A solid oral dosage form of Zaleple and a preparation process thereof comprising a pharmaceutical composition using stearic acid (lubricant) and other excipients to increase the dissolution effect thereof are proposed, and the disadvantages of the patent are: total weight It is heavier, and there is no wet type in the process, which is easy to cause delamination when filling capsules or tableting, resulting in uneven distribution of products and easy to cause dust. CN 13G6934C exposes an oral disintegration preparation containing St. This material is formulated as Zalepule 5mg, 35mg, povidone K3〇12mg, mannitol 88, ethyl cellulose short magnesium 矣 1mg, this formula can increase the concentration of blood in the body, the US is good, but this Total formula weight First, the surface is: t; the raw material and all the excipients are ground and scattered, but in the system: 22 f small 'to make the product easy to release and collapse process cold * drying takes a long time; in the system = cfN requires special packaging materials to prevent: product; == pharmaceutical combination 'but this patent has a high degree of rapidity' and cold green dry products in the production of m (four) the cost is more preventive products to absorb moisture, so the production Special packaging materials are required. It is not easy to store, and in terms of dosage form, this 6 201036976 is said to dissolve quickly in the mouth in 5 to 15 seconds without water assistance, but the main ingredient, Zalepler, has a bitter taste, so it dissolves quickly in the mouth and is prone to bitterness. Therefore, it will reduce the patient's acceptance, although the addition of sweeteners, but can not completely cover the bitterness. CN101239049A, this article is mainly for the dispersible tablet type' also emphasizes that the drug can be quickly dissolved in the oral cavity, and it is convenient for patients who have difficulty swallowing and inconvenient to take water. Therefore, it is also easy to have a bitter taste, and the patient acceptance is lowered, in terms of materials, The main component and the excipient are treated separately to make Ο

The particles are small, and the effect of easy release and disintegration is obtained, so the preparation process is complicated. Zale's lack of know-how is expected to develop a novel and simple pharmaceutical composition to improve the stability of drug release and to have an early process cost. SUMMARY OF THE INVENTION The purpose of the present invention is to provide a Zalepler pharmaceutical combination of good fruit. The Lai Poule pharmaceutical composition is stable and effective when it is effective and can be taken orally for patients with sleep disorders. The degree of drug administration helps the pharmacokinetics (ΡΚ) of the electrophoresis with the concentration of Lepler in the blood of the body. In addition, the "provided by the present invention is that the C process is simple" can greatly reduce the cost of the drug. Including: 5 to, the Zalepl pharmaceutical composition provided by the present invention is more than a filler: 503f than Zalepl; 45 to 90% by weight of the binder 0% by weight of the lubricant; 1 to 10 to 30 ca · to 6 weight percent of surfactant; and 2 percent of summer disintegration. Weight percent: Zlepler pharmaceutical composition comprises: 5 to 1: Zaleple; 70 to 87 weight percent filler; 〇. 201036976 to 0.8 weight J lubricant; i to 3 weight Percentage of binder; 0.5 to 5 weight percent of surfactant; and 2 to 8 weight percent of disintegrating agent. The above-mentioned filler of the invention can increase drug release property, and comprises lactose, palace powder, pre-gelatinized powder, maltodextrin, mannitol, powdered cellulose, microcrystalline cellulose, hydrogen-filled dance, Sorbitol or a mixture thereof. Preferably, the filler is starch or microcrystalline cellulose, and the content of the beans in the composition may be 45 to 90% by weight, more preferably 7 to 87% by weight. The adhesive of the present invention has the function of drug adhesion, and may include: a slurry, a syrup, a methyl cellulose, a propyl cellulose, a pre-gelatinized powder, a hydroxypropyl methyl cellulose, an ethyl fiber. , guar gum, magnesium aluminum silicate, gelatin, polyvinyl cyanohydrin, polyvinyl alcohol, dextran or a mixture thereof. Preferably, the binder is a pregelatinized starch which may be present in the composition in an amount of from 1 to 10% by weight, more preferably from 1 to 3% by weight. The aforementioned lubricant of the present invention can increase the surface of the preparation to be smooth, convenient for processing and for taking by a patient, and can include stearic acid, glyceryl palmitate, oxidized magnesium, poloxamer, polyethylene glycol. , polyvinyl alcohol, sodium phthalate, sodium lauryl sulfate, sodium stearyl sulfate, talc, magnesium stearate, sodium stearyl sulphate, hydrogenated vegetable oil, eucalyptus oil, light mineral oil or mixture. Preferably, the aforementioned lubricant is magnesium stearate in an amount of from 0.5 to 1.5% by weight, more preferably from 0.5 to 0.8% by weight. The aforementioned surfactant of the present invention can increase bioavailability, and includes trimethyl-di(tetradecylidene)-ammonium propane, dimethyl-bis(octadecane)-ammonium < odor, trimethyl - hexadecane-based recorded desert (CTAB), dimethyl-bis(d-decyl)-aminated bromine, cetylpyridinium quaternary gas, lauryl sulfate, polysorbate 酉 80 or Its mixture. Preferably, the aforementioned surfactant is a dodecapine 8 201036976: a content of 5% to 5% by weight, and a viscous oryzanol which provides a lysate to each component of the composition. It may contain microcrystalline Ο Ο Substituting: base fiber; base = sulfhydryl group, the aforementioned disintegrating agent, and the like. Preferably, the to-heavy (four) ratio is more preferably 'to 8 to 8 basis weight = or powder = type ΐ» The Zalepler pharmaceutical composition of the present invention is a key agent, a capsule Zalepl; 45 to 90 a lubricant that repeats a percentage of a hundred and eight hundred stars; i to 1 () to 1.5 weight percent of a surfactant; and a weight of 50 to 15 〇,; 2; a particle size of the second two is adjusted to = agent , adhesives, disintegrating agents and pure water or alcohols, into wet particles; (4) dry at the temperature of the war; and borrow::: dry:; state steps (4) dry particles plus release: force = 9 201036976 The drug wave in the blood 'helps the patient to quickly enter the sleep. The Zagura pharmaceutical composition provided has a simple process: low cost. [Embodiment] For example, the present invention is for treating a loss compound, which comprises: 5 to 15Re-inspected Zhalai Ri Le Medical Music, and Pandan Bai Ba μ·之埴古钿.Λ Hundred-knife ratio Zaleple; 45 to 90 Ο Ο 'Dan Baiyi this two went to 'people 5 to I .5 weight percent lubricant; 1 to 10 weight percent of the binder; 5 & 曰 W: sword; tongue 曰 7Γ \ . Reset percentage of surfactant and 2 to 30 weight 1 percentage of the collapse PowderIn a preferred embodiment, it is too respectful. The tongue and the tongue: The pharmaceutical composition of Zhalaipuer of the Maoyue. The weight of the hundred is the ratio of Zaleple; 45 to 90 weight. 1 S m tongue π weight percent magnesium stearate to 1 〇 replacement percentage of pregelatinized starch; 0.5 to 6 weight percent sodium undecy sulfate or polysorbate 8 〇 carboxymethyl starch sodium.久ζ主川置I百刀 The focus of the present invention is to use the ingredients in the pharmaceutical composition to reproduce the percentages to achieve the advantages of Daxian invention. The g formula of the present invention exemplifies the features of the present invention. The hunter will be hunted by the embodiment and the drawing, and the 贼 百分比 百分比 调 调 _ _ _ 调 调 调 调 调 调 调 调 调 调 调 调 调 调 调 调 调 调 调 调 调 调 ' ' ' ' ' ' ' ' ' ' The preparation process may be, for example but not limited to, the following: f preparation method t 10 201036976 Table 1 Component weight (mg) Zalepler 10 Starch 68 Pregelatinized starch 2 Sodium lauryl sulfate 3.5 Carboxymethyl group Starch Sodium 5.5 Magnesium Stearate 1 Total 90

The ingredients and weights of the materials used in the preparation method are listed in Table 1. The Zaleple and sodium lauryl sulfate are premixed in a rapid mixing granulator, then poured into starch, pregelatinized starch, sodium carboxymethyl starch, and mixed again in a rapid mixing granulator. The ingredients form a powder mixture, and then a solvent of water or an alcohol such as ethanol, n-propanol or isopropanol is added to the powder to form a wet particle mixture, and drying is carried out at a temperature of 50 ° C to 100 ° C. Dry granules were obtained which were sieved through a sieve to remove large particles. Magnesium stearate is then added to the granulated granules, followed by mixing, and finally the granules are filled to form capsules. Preparation method 2: Table 2 Ingredient weight (mg) Zalepler 5 Microcrystalline cellulose 72 Pregelatinized starch 2 Sodium oxalate sodium 5 Sodium carboxymethyl starch 5 11 201036976 Magnesium stearate 1 Total 90 Preparation The composition and weight of the materials used in the method are listed in Table 2. The Zalepler, sodium lauryl sulfate, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch are mixed in the rapid mixing granulator to form a powder mixture, and then added to the powder. A solvent of water or an alcohol such as ethanol, n-propanol or isopropanol is formed to form a wet granule mixture, and drying is carried out at a temperature of from 50 ° C to 100 ° C to obtain dry granules which are subjected to a sieve. Screen to remove large particles. Magnesium stearate is then added to the granulated granules, followed by mixing, and finally the granules are filled to form capsules. Preparation Method 3: Table 3 Ingredients Weight (mg) Zalepler 5 Microcrystalline cellulose 72 Pregelatinized starch 2 Polysorbate 80 5 Carboxymethyl starch sodium 5 Magnesium stearate 1 Total 90

The composition and weight of the materials used in the preparation method are listed in Table 3. Zaleple, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, mixed in the rapid mixing granulator to form a powder mixture, and the polysorbate 80 and water or alcohol Mix and dissolve evenly, then add water or alcohol (such as ethanol, n-propanol or isopropanol) and polysorbate 80 solvent to the powder to form a wet particle mixture, and carry out at 50 ° C to l〇〇 °C 12 201036976 The dry granules were obtained by drying at a temperature, which was sieved through a sieve to remove large particles. Magnesium stearate is then added to the granulated granules, followed by mixing, and finally the granules are filled to form a capsule package. Preparation method 4: Table 4 Component weight (mg) Zalepler 10 Microcrystalline cellulose 45 Pregelatinized starch 3 Polysorbate 80 3 Sodium lauryl sulfate 5 Carboxymethyl starch sodium 23 Magnesium stearate 1 Total 90

The composition and weight of the materials used in the preparation method are shown in Table 4. Pre-mixing Zalepler with sodium lauryl sulfate in a rapid mixing granulator, then pouring microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, again in a fast mixing granulator Mixing the above five components to form a powder mixture, mixing the polysorbate 80 with water or an alcohol to dissolve uniformly, and then adding water or an alcohol (such as ethanol, n-propanol or isopropanol) and polysorbate to the powder. The solvent of the alcohol ester 80 is used to form a wet particle mixture, and drying is carried out at a temperature of from 50 ° C to 100 ° C to obtain dry particles which are sieved to remove large particles. Magnesium stearate is then added to the granulated granules, followed by mixing, and finally the granules are filled to form a tablet package. Preparation method 5: 13 201036976 Table 5 Ingredient weight (mg) Zalepler 5 Starch 45 Pregelatinized starch 8 Polysorbate 80 3 Sodium decanoate 5 Carboxymethyl starch 23 Magnesium stearate 1 Total 90

The composition and weight of the materials used in the preparation method are shown in Table 5. The Zaleple and sodium lauryl sulfate are premixed in a rapid mixing granulator, then the starch, the pregelatinized starch is poured, and the above four components are mixed again in a rapid mixing granulator to form a powder mixture. The polysorbate 80 is mixed with water or an alcohol to dissolve uniformly, and then water or an alcohol (such as ethanol, n-propanol or isopropanol) and a solvent of polysorbate 80 are added to the powder to form wet granules. The mixture is subjected to drying at a temperature of from 50 ° C to 10 ° C to obtain dry granules which are sieved to remove large particles. Further, sodium carboxymethyl starch and magnesium stearate are added to the granules after sieving, followed by mixing, and finally the granules are filled into a tablet package. Preparation Method 6: Table 6 Ingredient Weight (mg) Zalepler 5 Starch 70 Pregelatinized Starch 1 14 201036976 Polysorbate 80 1 Sodium Lauryl Sulfate 2 Carboxymethyl Starch Sodium 10 Magnesium Stearate 1 Total The composition and weight of the materials used in the preparation method are listed in Table 6. The Zaleple and sodium lauryl sulfate are premixed in a rapid mixing granulator, then poured into starch, pregelatinized starch, sodium carboxymethyl starch, and mixed again in a fast idling mixing granulator. The above five components form a powder mixture, and the polysorbate 80 is mixed with water or an alcohol to dissolve uniformly, and then water or an alcohol (such as ethanol, n-propanol or isopropanol) and polysorbate are added to the powder. The solvent of the ester 80 is used to form a wet granule mixture, and drying is carried out at a temperature of from 50 ° C to 10 ° C to obtain dry granules which are sieved with a mesh to remove large particles. Sodium carboxymethyl starch and magnesium stearate are added to the granules after sieving, followed by mixing, and finally the granules are filled into a powder package. Preparation method 7: ❹ Table 7 Component weight (mg) Zalepler 10 microcrystalline cellulose 60 Pregelatinized starch 8 Polysorbate 80 5 Sodium decyl sulfate 4 Sodium carboxymethyl starch 2 Magnesium stearate 1 Total 90 15 201036976 The composition and weight of the materials used in the preparation method are listed in Table 7. Pre-mixing Zalepler, polysorbate 80 and sodium lauryl sulfate in a rapid mixing granulator, then pouring microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, again in fast The above six components are mixed in a mixing granulator to form a powder mixture, and then a solvent of water or an alcohol such as ethanol, n-propanol or isopropanol is added to the powder to form a wet particle mixture, which is carried out at 50 ° C. Dry granules were obtained by drying to a temperature of 100 ° C, which was sieved through a sieve to remove large particles. Magnesium stearate is then added to the granulated granules, which are then mixed and finally filled into granules for encapsulation. Preparation method 8: Table 8 Ingredient weight (mg) Zalepler 10 Starch 50 Microcrystalline cellulose 19 Pregelatinized starch 2 Polysorbate 80 1 Sodium decyl sulphate 3.5 Carboxymethyl starch sodium 3.5 Stea Magnesium Hydroxide 1 Total 90 The ingredients and weights of the materials used in the preparation method are listed in Table 8. Pre-mixing Zalepler with sodium lauryl sulfate in a rapid mixing granulator, then pouring starch, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, and again in rapid mixing granulation The above six components are mixed in the machine to form a powder mixture, and the polysorbate 80 is mixed with water or an alcohol to dissolve uniformly. 16 201036976 Then water or an alcohol (such as ethanol, n-propanol or isopropanol) is added to the powder. The solvent of polysorbate 80 is used to form a wet granule mixture, and drying is carried out at a temperature of from 50 ° C to 100 ° C to obtain dry granules which are sieved to remove large granules. Magnesium stearate is then added to the granulated granules, which are then uniformly mixed, and finally the granules are filled and packaged into capsules. Preparation method 9: Table 9 Ingredient weight (mg) Zalepler 5 Starch 52.5 Microcrystalline cellulose 25 Pregelatinized starch 3 Polysorbate 80 0.5 Sodium sulfonate sodium 1 Carboxymethyl starch sodium 2 Stearic acid Magnesium 1 Total 90 ❹ The composition and weight of the materials used in the preparation method are listed in Table 9. The Zaleple and Polysorbate 80 are premixed in a rapid mixing granulator, and then poured into starch, microcrystalline cellulose, pregelatinized starch, sodium lauryl sulfate, sodium carboxymethyl starch, The above seven components are mixed again in a rapid mixing granulator to form a powder mixture, and then a solvent of water or an alcohol such as ethanol, n-propanol or isopropanol is added to the powder to form a wet particle mixture, and Dry granules are obtained by drying at a temperature of from 50 ° C to 10 ° C, which is sieved through a sieve to remove large particles. Magnesium stearate is then added to the granules after sieving, followed by uniform mixing, and finally the granules are filled to form a powder package. 17 201036976 Preparation Method 10: Table 10 Component Weight (mg) Zalepler 5 Starch 51 Microcrystalline Cellulose 25 Pregelatinized Starch 3 Polysorbate 80 0.5 Twelfth Sodium Sulfate 1 Carboxymethyl Starch Sodium 3.5 Hard Magnesium oleate 1 Total 90 The ingredients and weights of the materials used in the preparation method are listed in Table 10. The Zaleple and sodium lauryl sulfate are premixed in a fluid processing machine, and then poured into starch, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, and mixed again in a fluid processing machine. The above six components form a powder mixture, and the polysorbate 80 is mixed with water or an alcohol to dissolve uniformly, and then water or an alcohol (such as ethanol, n-propanol or isopropanol) and polysorbate are added to the powder. The solvent of the ester 80 is sprayed to form a wet particulate mixture, and dried at a temperature of from 50 ° C to 10 ° C to obtain dry granules which are sieved to remove large particles. Magnesium stearate is then added to the granules after sieving, followed by uniform mixing, and finally the granules are filled into tablets or capsules. Preparation Method 11: Table 11 18 201036976 Ingredient Weight (mg) Zalepler 5 Starch 51 Microcrystalline Cellulose 27 Pregelatinized Starch 3.5 12% Sodium Sulfate 1 Carboxymethyl Starch Sodium 2 Magnesium Stearate 0.5 Total 90

The composition and weight of the materials used in the preparation method are shown in Table 11. Zaleple, sodium lauryl sulfate, starch, microcrystalline cellulose, pregelatinized starch, sodium carboxymethyl starch, the above six components are first sieved and premixed, and then poured into a dry granulator Granulation. Magnesium stearate is then added to the granulated granules, followed by uniform mixing, and finally the granules are filled into tablets or capsules.

It is to be understood that the Zalepl pharmaceutical composition of the present invention is formulated by the weight percentage of each component to achieve the technical features and advantages of the present invention without being limited by the preparation methods and procedures. This example is only intended to illustrate a possible preparation method of the Zleplul pharmaceutical composition of the present invention, and is not intended to limit the present invention. Example 2. Comparison of Dissolution Rate of Zaleplel's Medical Compositions This example compares the SONATA® of the original drug with the Zalpreg pharmaceutical composition (Solmin) of the present invention, and the results are listed. In Table 12 and Table 13. Experimental Design · 19 201036976 A. Number of samples: (1) Control: 6 SONATA® were tested for each solution. (2) The present invention: 6 Zlepres pharmaceutical compositions of Example 1 were tested for each of the eluents. B. Instrument: Automatic Dissolution Tester C. Rate: 50 rpm D. Type of dissolving solution: H2 〇, 〇.IN Ηα, ρΗ 4.5 Acetate Buffer, pH 6.8 Phosphate Buffer 〇 Table 12: Dissolution rate of Zalepler at different pH solutions (%) Dissolution of the control example $1 Dissolution h2o 0.1NF IC1 pH 4.5 Acetate Buffer pH6.8 Phosphate Buffer Time (min) Average (%) Average deviation (%) Average of deviations (%) Average of deviations (%) Variations 5 58.90 14.75 58.55 6.33 44.25 9.77 41.02 11.02 10 103.88 2.67 97.03 5.65 90.35 5.14 93.60 5.07 15 107.42 1,63 101.58 4.32 95.93 3.34 101.12 3.62 20 108.35 1.48 103.40 3.83 98.02 2.58 102.72 3.10 Proximity dissociation liquid of the present invention h2o 0.1NI- IC1 pH 4.5 Acetate buffer ρΗ6·8 Phosphate buffer Time (min) Average (%) Equivalent average (%) Equivalent average (%) Equivalent average (%) Crimeter 5 77.32 5.26 66.00 4.39 51.00 9.36 50.23 7.71 10 106.27 2.03 96.72 3.38 90.67 2.64 89.17 6.59 15 109.35 1.87 101.02 1.92 96.40 1.95 94.97 5.62 20 109.87 1.85 102.67 1.74 98.07 1.76 9 7.50 4.72 Note: The examples in Table 12 are the average values of the flat 20 201036976 obtained after testing with the pharmaceutical composition of the ingredients shown in Table 8. From the results of Table 12, it was found that the dissolution rate of the present invention was faster than that of the original factory at five minutes, and the standard deviation of the present invention was also smaller than that of the original one, which indicates that the pharmaceutical composition of the present invention is better than the original one, and the dissolution rate is uniform. And has the effect of rapid drug effect. Table 13: Comparison of the highest and lowest points of the dissolution rate of the present invention and the lowest point of the solution. Dissolution liquid h2o 0.1NHC1 pH 4.5 Acetate Buffer pH 6.8 Phosphate Buffer Dissolution 5 minutes Comparative Example Comparative Example of the Present Invention Comparative Example of the Present Invention Invented high point 75.8% 80.9% 63.5% 73.6% 54.9% 63.9% 56.5% 57.6% Lowest point 34.2% 67.8% 49.3% 66.0% 30.9% 38.1% 25.7% 35.2% Difference 41.6% 13.1% 14.2% 7.6% 24.0% 25.5% 30.8% 22.4% Dissolution 10 minutes Comparative Example Comparative Example of the Invention Comparative Example of the Invention Comparative Example of the Invention 107.7% of the present invention 109.6% 104.9% 102.9% 95.8% 93.1% 101.0% 99.6% Lowest point 101.4% 103.9% 88.9% 92.8 % 83.6% 87.3% 85.8% 79.5% difference 6.3% 5.7% 16.0% 10.1% 12.2% 5.8% 15.2% 20.1%

Table 13 lists the dissolution ratios of the four isolates of the comparative example and the pharmaceutical composition of the present invention, and each of the isolates tested 6 samples, and the dissolution rates of the six highest points and the lowest points were known. Whether the dissolution rate of each product is close at the same time, further know the quality of the product. The dissolution test was carried out in H20, and it was found that the highest and lowest points of the dissolution rate of the control samples of 5 and 10 minutes were 41.6% and 6.3%, while the difference of the present invention was 13.1% and 5.7%; the dissolution test was carried out at 0.1 NHC1, and 5 and 10 minutes were found. In the comparative example, the highest point of dissolution rate differs from the lowest point by 14.2% and 16.0%, while the present invention differs by 7.6% and 10.1%. The dissolution test is carried out at pH 4.5 Acetate Buffer, and the dissolution rate of the control sample of 5 and 10 minutes 21 201036976 is found to be the highest. The difference from the lowest point is 24.0%, 12.2%, and the difference between the present invention is 25.5%, 5.8%; in the ρΗ6·8 Phosphate Buffer soil, the tolerance test 'disappears the difference between the highest and lowest points of the 5 and 10 minutes. 30.8%, 15.2%, and the present invention differs by 22.4%, 20.1%. It can be seen that the comparison between the control and the present invention in four different dissolving solutions revealed that at the same time and the same eluent, the highest point of the control was The difference between the lowest points is almost twice that of the present invention, and the difference between the comparative examples is up to 41.6%, and the difference is at least 6.3%. The difference of the present invention is up to 25.5%, and the difference is at least 〇5.7%, so that the present invention can be known. Medical group The dissolution rate was superior uniformity of the original SONATA®. Preferably, the ratio of the spring number of the test pharmacokinetics of the Zale-Puller pharmaceutical composition 舆厗Jfe sonata® of the present invention is the product of the ten-preparation method of the first embodiment (the composition thereof is shown) In Tables 1 to 11), the bioequivalence test of 16 people was carried out, and the comparison results of SONATA® are shown in Table 14. ❹ The experimental test method is to allow I6 subjects to be fasted for 4 hours after taking π (4) levo to 4 fasting, and random, single-dose and two-way crossover. The following time points after each administration (Q hours, 〇 〇 -5 hours, 〇. 75 hours, 1 hour, 1.33 hours, =: things, etc. (4) are listed in 1 · 5 6 ± 54.70 Controls (average Value ± standard deviation) The present invention (mean ± standard deviation) 85.38 ± 32.88 22 201036976 AUCust-inf (ng/ml*hr) — ± 2.62 —— 1.73 ± 0.82 AUC〇.inf (ng/ml*hr) 63 ± 57.15 — 87.12 ±33.04 AUCo-iast (%) ± 1.03 97.85 ±0.85 AUMC〇.|ast(ng/ml%hr2) -^12.42 ±207.18 186.42 ±93.10 AUMCust-inf (ng/ml*hr2) —_^1.73 ±35.42 16.71 ±12.45 AUMC〇-inf (ng/ml*hr2) —.15 ±242.04 — ·— 203.13 ±98.37 MRT〇.iast (hr) —±0.43 2_12 ±0.34 MRT〇.i„f (hr) __2 .29 ±0.49 2·27 ± 0·34 Tmax (hr) ._0.89 ±0.42 0.99 ±0.37 Cmax (ng/ml) —~__41.17 ± 19.95 41.14 ±16.34 Ο Table 16 shows the equality of organisms In the test, the conventional SONATA capsules and the pharmaceutical composition of the present invention are used in the service, and the statistical analysis data of the drug concentration in the blood collection analysis of the individual 'clothing' is analyzed. The first figure is the table. 15, Table 16, with time versus average The results obtained from the concentration plots. Table 15: The original s〇nata® obtained from 16 samples in the human body, Zalepu's time-to-concentration statistical analysis data The average concentration test time (hours) of the original SONATA® Number average concentration (ng/ml) Standard deviation Standard Deviation CV (%) 0.16 16 16.5166 21.7476 131.67 0.33 16 13.9415 17.3315 124.32 0.5 16 28.5613 19.3606 67.79 0.75 16 31.0916 12.7451 40.99 1 16 28.4130 8.1590 28.72 1.33 16 27.2922 6.7665 24.79 23 201036976 1.66 16 23.6131 8.3960 35.56 2 16 23.7377 19.9322 83.97 3 16 15.1828 17.4825 115.15 4 16 8.4130 8.8386 105.06 6 16 2.5234 3.0550 121.07 8 16 1.2206 1.7119 140.25 〇 Table 16: 16 samples of the pharmaceutical composition of the invention obtained in human body, Zalep Time-to-concentration statistical analysis data The average concentration of the pharmaceutical composition of the present invention test time (hours) number average concentration (ng/ml) standard deviation Standard Deviation CV (%) 0.16 16 0.5905 0.0064 1.08 0.33 16 12.9351 13.4719 104.15 0.5 16 22.9895 16.5361 71.93 0.75 16 34.7345 18.6350 53.65 1 16 31.6862 12.2042 38.52 1.33 16 29.4891 10.2865 34.88 1.66 16 26.2629 11.5973 44.16 2 16 21.5034 9.9744 46.39 3 16 12.2282 5.8169 47.57 4 16 7.3224 3.6859 50.34 6 16 2.0596 1.2288 59.66 8 16 1.1348 0.4756 41.91

From the above Table 14, the pharmacokinetic parameters AUC (Mast, AUC丨ast_inf, AUC〇_inf, AUC〇_丨ast (%) of the pharmaceutical composition of the present invention and the original development factory 24 201036976 SONATA® can be seen. The data gaps obtained by AUMC (Mast, AUMClast_inf, AUMC〇_inf, MRT〇_iast, MRT〇_inf, Tmax, Cmax' have not been significantly different after statistics, so it is evaluated that the two have bioequivalence. Therefore, the drug efficacy is the same. In the data of Table 15 and Table 16, it can be seen that the concentration of the drug in the human body is gradually increased in the range of 0.16 to 0.75 hours, and the drug concentration in the human body is gradually decreased from 0 to 8 hours. Therefore, the data has regularity, but the original data at 0.16, 2.0 hours shows no regularity, so it can be known that the pharmaceutical composition of the present invention has better stability in drug release and absorption in the human body than the original one. The invention is good, so it can be proved that the pharmaceutical composition of the present invention has better pharmacodynamic stability than the original manufacturer. JC Example 4: The Zalepred Peony Drug Composition of the Invention The setting method of the present invention will be the embodiment of the present invention. 1 of Zalepler pharmaceutical composition is made into capsules for a long time The stability test, the content of Zaleple was measured, and the results are shown in Table 17. Table 17 Time January January February March June September December Content (%) 100.37 100.24 100.14 100.06 99.71 99.37 99.12 Today, the preparation of 'soft sap

Chengzhi Capsule's stability test after 0 months, 1 month, 2 months, 3 months, 6 months, and 12 sputum preservation results showed that Zlepule's was found after one year of preservation. The content did not decrease significantly, and the content of the product was only 2525% from March to March. Therefore, the formulation of the Zalepler medical material of the present invention is quite stable in the composition of the drug. 25 201036976 Externally dissolved ϋΞί; The pharmaceutical composition of this 2, the Leipler capsule's body is separated from the highest point and the lowest point into the difference of the dissolution rate, and the standard deviation is smaller than that of the original one. In addition, the medicinal composition of the present invention has a faster dissolution rate in five minutes than the original one, and thus has a rapid effect. In vivo tests in 16 subjects were found to have the same pharmacokinetics to bioequivalence through bioavailability tests, which can be said to be equally effective. And in the human body, the statistical analysis of the concentration of the drug found that the drug of the present invention has a regularity _ put and (four), it can be known that the release of the drug in the human body and the stability of absorption is better than the original it is good. ^ : - Year's safety test data is *, the pharmaceutical composition of the present invention has a content of Zalepler of 1 〇〇 37 to 9912% during 〇~i2 months, and differs only by 1_25%. Therefore, from the above data, it can be confirmed that the drug has a drug dissolution rate---------------------------------------------------------------------------------------------------------------- No special equipment and other embodiments are disclosed. All the features disclosed in the present invention can be combined in any manner. Features disclosed in this specification can be replaced with the same, equal or similar purpose. Thus, the features disclosed in this specification are in the form of a series of identical or similar features. In addition, in accordance with the disclosure of the present specification, those skilled in the art can easily transfer the basic features of the present invention, and do not make appropriate changes and modifications to different methods and situations without departing from the spirit and scope of the present invention. Therefore, other implementations are also included in the scope of the patent application. BRIEF DESCRIPTION OF THE DRAWINGS The first figure shows the change in concentration of Zalepler in the human body over time with the original SONATA® and the pharmaceutical composition of the present invention.

27

Claims (1)

201036976 VII. Patent Application Range: 1. A Zalepl pharmaceutical composition comprising: 5 to 15 weight percent of Zalepler; 45 to 90 weight percent filler; 0.5 to 1.5 weight percent lubricant; 1 to 10% by weight of the binder; 0.5 to 6% by weight of the surfactant; and 2 to 30% by weight of the disintegrating agent. 2. The pharmaceutical composition according to claim 1, which comprises: 5 to 15 weight percent of Zalepler; 70 to 87 weight percent filler; 0.5 to 0.8 weight percent lubricant; Up to 3 weight percent of the binder; 0.5 to 5 weight percent of the surfactant; and 2 to 8 weight percent of the disintegrating agent. 3. The pharmaceutical composition according to claim 1, wherein the filler comprises lactose, starch, pregelatinized starch, maltodextrin, mannose decyl alcohol, powdered cellulose, calcium hydrogen phosphate, sorbus Sugar alcohol or a mixture thereof. 4. The pharmaceutical composition according to claim 3, wherein the diluent is starch and/or microcrystalline cellulose. 5. The pharmaceutical composition according to claim 1, wherein the lubricant comprises stearic acid, glyceryl palmitate stearate, magnesium oxide, poloxamer, polyethylene glycol, Polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl sulfate, talc, magnesium stearate, sodium stearyl succinate, hydrogenated vegetable oil, eucalyptus oil, light mineral oil or mixture. 6. The pharmaceutical composition according to claim 5, wherein the lubricant is a magnesium stearate. 7. The pharmaceutical composition according to claim 1, wherein the binder comprises starch pulp, syrup, methyl cellulose, hydroxypropyl cellulose, pregelatinized starch, hydroxypropyl methyl cellulose, Ethylcellulose, guar gum, magnesium aluminum silicate, gelatin, polyvinyl cyanohydrin, polyvinyl alcohol, dextran or mixtures thereof. 8. The pharmaceutical composition according to claim 7, wherein the binder is a pregelatinized starch. The pharmaceutical composition according to claim 1, wherein the surfactant comprises tridecyl-di(tetradecylidene)-ammonium propane and dimethyl-bis(octadecane)ammonium. Bromine, tridecyl-hexadecyl ammonium bromine (CTAB), dimercapto-di(d-decyl) carbamide, hexadecane beta quaternary chloride, dodeca sulphate, Polysorbate 80 or a mixture thereof. 10. The pharmaceutical composition according to claim 9, wherein the surfactant is sodium lauryl sulfate and/or polysorbate 80. 11. The pharmaceutical composition according to claim 1, wherein the disintegrating agent comprises microcrystalline cellulose, sodium carboxymethyl starch, compressible starch, sodium carboxymethyl cellulose, and crosslinked polyethylene. A pyrrolidone, a low substituted hydroxypropyl cellulose, a croscarmellose sodium, a croscarmellose calcium or a mixture thereof. 12. The pharmaceutical composition according to claim 11, wherein the disintegrating agent is sodium carboxymethyl starch. 13. The pharmaceutical composition according to claim 1, which is in the form of a tablet, a capsule or a powder. 14. A method of preparing a Zalepl® pharmaceutical composition, characterized in that the resulting pharmaceutical composition comprises: 5 to 15 weight percent of Zalepler; 45 to 90 weight percent of a filler; 0.5 to 1.5 weight percent Lubricating 29 201036976 agent; 1 to 10 weight percent binder; 0.5 to 6 weight percent surfactant; and 2 to 30 weight percent disintegrating agent. 15. The method of claim 14, comprising: (a) adjusting the particle size of the Zalepule to 50 to 150 μπι; (b) preparing the Zaleple particles prepared in the step (a) Mixing with a surfactant; (c) adding a mixture of the Zalprep and the surfactant prepared in the step (b) to a pharmaceutically acceptable filler, a binder, a disintegrating agent, and pure water or an alcohol, and granulating and mixing Preparing into wet granules; (d) drying step (c) wet granules to form dry granules at a temperature of from 50 ° C to 10 ° C; and (e) adding step (d) dry granules to the lubricant and preparing The type of capsules, lozenges and powders. 30