WO2006015545A1 - Gelatin capsule of moxifloxacin and method for its prepartion - Google Patents

Abstract

The present invention discloses a kind of gelatin capsule of moxifloxacin. The content of capsule comprises moxifloxacin or its salt and/or its hydrate and additives. Said additives selected from at least one of the following materials: sodium sulfite; sodium bisulfite; oligomeric anthocyanidin; L-glutathion; sesame polyphenols; tea polyphenols; tocopherol; antiscorbic acid; araboascorbic acid; Vitamin B1; Vitamin B2; β-carotene; soybean isoflavone; L-cysteine; pyrophosphoric acid; polyphosphate and their pharmaceutical salt. Additives can be added to the content of the capsule by conventional method. Additives have an obviously inhibition effect to the decrease of dissolution during the process of storage. It makes the dissolution efficiency of capsule greatly improved.

Description

 Moxifloxacin gelatin capsule and preparation method thereof

 The present invention relates to a pharmaceutical preparation of moxifloxacin, and in particular, the present invention relates to a gelatin capsule of moxifloxacin or a salt thereof and/or a hydrate thereof, and a process for the preparation thereof. Background technique

 Moxifloxacin is a new generation of fluoroquinolone antibiotics. It is currently approved for the use of sensitive micro-organisms for upper and lower respiratory tract infections, such as acute exacerbation of chronic bronchitis, community acquired pneumonia, acute bacterial sinusitis and Treatment of uncomplicated skin and soft tissue infections.

 At present, the oral preparation of moxifloxacin only has moxifloxacin hydrochloride tablets, the Chinese patent "moxifloxacin pharmaceutical preparation", patent number 99813124. 5, discloses the oral pharmaceutical tablet, and the preparation method thereof, the drug and at least one An anhydrous binder and lactose are granulated with water, and the granules are then mixed with at least one disintegrant and at least one lubricant, and optionally tableted and coated.

 In addition, the Chinese patent application "Moxifloxacin / Sodium Chloride Preparation", application number 00811427. 7, discloses moxifloxacin hydrochloride / sodium chloride infusion, which is convenient for patients with severe illness. '

 Moxifloxacin capsules have not been reported so far. The present inventors have found that the prior art preparation of moxifloxacin is filled in a gelatin capsule shell, and the dissolution property is lowered during storage, failing to meet the medicinal requirements. .·

 The gelatin capsule shell is a capsule which is commonly used for capsules. The inventors filled the gelatin capsule shell with the preparation formula of moxifloxacin hydrochloride in the prior art, prepared a capsule, and measured the dissolution degree after performing the stability test for 60 days at 60 ° C for 10 days. It was found that the capsules were swollen and the capsules were not broken, and the contents could not be dissolved. Or even if some of the capsules were broken, they could not be completely dissolved after 45 minutes. The room temperature was observed and the dissolution began with the capsules for 15 days. The phenomenon that the placement time is extended and decreased. The inventors further used a 3.5% or 5% HPMC solution to granulate the contents of the capsule containing moxifloxacin and then filled the capsules. After 10 days of stability test, the capsules did not dissolve or the dissolution decreased. (The above dissolution method is determined according to the first method of the Chinese Pharmacopoeia 2000 edition two appendix XC dissolution measurement method, the blue method lOOrpra, the eluate is 0. lmol / L hydrochloric acid, the content of the dissolved moxifloxacin determination method Using HPLC method).

 To date, no literature has been reported on the in vitro dissolution behavior or the decrease in dissolution of Moxi's star or its salt and/or its hydrate gelatin capsules. ' '

Recognize Summary of the invention

 SUMMARY OF THE INVENTION The object of the present invention is to solve the above problems and to provide a moxifloxacin gelatin capsule which can improve the dissolution in storage and has stable dissolution properties and a preparation method thereof.

 To achieve the above object, the present invention adopts the following technical solutions:

 The present invention discloses a moxifloxacin gelatin capsule containing moxifloxacin or a salt thereof and/or a hydrate thereof, and the capsule content further comprising an additive selected from the following materials. At least one:

'Sodium sulfite, sodium bisulfite, oligocyanin, L-glutathione, sesame polyphenols, tea polyphenols, tocopherol, ascorbic acid, erythorbic acid, vitamin B1, vitamin Β2, beta-carotene, soy Flavonoids, L-cysteine, pyrophosphoric acid, polyphosphoric acid and pharmaceutically acceptable salts thereof.

 In the present invention, the additive added to the contents of the capsule may be a mixture of one or more of the above substances in order to maintain the effect of the present invention without physical form changes such as adhesion and agglomeration during the preparation process. And in the stability investigation does not affect the dissolution of the capsule and the stability of the main drug as a standard. In the present invention, the total amount of the additive added to the contents of the capsule should not exceed the normal dosage of the human body. None of the components added in the present invention were found to affect the chemical stability of the main drug.

 The weight percentage of the additive in the capsule contents is from 0.1 to 20%. · ' '

 1-16%。 When the additive is a vitamin B1, the preferred percentage of the weight percentage of the contents of the capsule is 0. 1-16%. 1-6. 5%。 The preferred range of the weight percentage of the content of the capsule is 0. 1-6. 5%. The salt of moxifloxacin includes, for example, an acid addition salt such as a hydrochloride, and/or a hydrate thereof, and for example, moxifloxacin hydrochloride is particularly preferred in the present invention.

 The pharmaceutically acceptable amount of moxifloxacin or a salt thereof and/or a hydrate thereof according to the present invention means that each capsule contains a unit dose required for clinical use. For example, each capsule of the present invention may contain 50 to 800 mg of the moxifloxacin or a salt thereof and/or a hydrate thereof, preferably 100 to 600 mg, particularly preferably 200 to 400 mg.

 The capsule content of the capsule may further comprise a pharmaceutically acceptable amount of a pharmaceutically acceptable excipient, the medicinal excipient comprising one or more of a diluent, a disintegrant, a binder, a lubricant or a glidant. Kind. Commonly used diluents, disintegrating agents such as microcrystalline cellulose, sodium carboxymethyl starch; the binder includes hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC); commonly used lubricants and help The flow agent can be selected from magnesium stearate and micronized silica gel. A pharmaceutically acceptable amount specifically refers to the amount of these excipients commonly used in the prior art. ·

The invention also discloses a preparation method of the above-mentioned moxifloxacin gelatin capsule, the method comprising the steps of: sufficiently mixing or granulating the moxifloxacin or a salt thereof and/or a hydrate thereof with the additive; Gelatin capsule shell. Further, the moxifloxacin or a salt thereof and/or a hydrate thereof is sufficiently mixed with the additive, and a pharmaceutically acceptable amount of a pharmaceutically acceptable excipient, or granulated, and filled into a gelatin capsule shell, the medicine The excipients include one or more of a diluent, a disintegrant, a binder, a lubricant or a glidant.

 The present invention also discloses another preparation method of the above-mentioned moxifloxacin gelatin capsule, which comprises the steps of: preparing the moxifloxacin or a salt thereof and/or a hydrate thereof with a coating liquid containing the additive; The granules are either powder coated, dried and filled into a gelatin capsule shell.

 Further, after the moxifloxacin or a salt thereof and/or a hydrate thereof is sufficiently mixed with a pharmaceutically acceptable amount of a pharmaceutically acceptable adjuvant, the granules are prepared or coated with a coating liquid containing the additive, After drying, it is filled into a gelatin capsule shell, and the pharmaceutical excipients include one or more of a diluent, a disintegrant, a binder, a lubricant or a glidant.

 Since the above scheme is adopted, after the additive-added moxifloxacin or a salt thereof and/or its hydrate is made into a gelatin capsule, the additive can cause the insoluble or the dissolution of the capsule to occur during storage. Obvious inhibition, after adding the additive which accounts for 0.1 to 20% of the total weight of the capsule contents, the dissolution rate of the stalk capsule is in the stability test of 10 夭 60 ° C, and the insoluble solution is not added when the additive is added. Or less than 50% increased to more than 80%, and after accelerated stability investigation (40 ° C, relative humidity 75% acceleration stability for three months), the dissolution properties are still stable, the dissolution rate is above 80%. detailed description

 The invention is further described in detail below by way of specific examples.

 The structure of moxifloxacin hydrochloride used in the present invention is as follows:

Molecular formula: C ₂₁ H ₂₄ FN ₃ 04.HC1. Molecular weight: 437. 90 The gelatin capsule used in the present invention is produced by China Suzhou Capsule Co., Ltd., the gelatin capsule meets the medicinal standard, and other accessories and additives are in compliance with medicinal or food. Additive standard.

 Test example 1

 Moxifloxacin hydrochloride 218. 4mg

Microcrystalline cellulose 68. Omg Lactose monohydrate 34. Omg

 Sodium carboxymethylcellulose sodium ** 8mg

 Magnesium stearate 2. 4mR

 Total weight 330. 8mg

 The above is the uncoated core formulation of Example 4 in the Chinese patent (Patent No. 99813124. 5, Publication No. CN1325306A), but in the publication, ** is sodium carboxymethylcellulose, which is translated by croscarmellose soldium. Come, see the second page of the original patent specification, and in fact the translation is wrong, correctly translated as cross-linked sodium carboxymethyl cellulose (disintegrant).

 Method: According to the uncoated tablet core granulation process of the moxifloxacin hydrochloride tablet reported in the patent document, the drug and the microcrystalline cellulose (the anhydrous binder in the patent literature) and the lactose are granulated with water. Then, the granules were mixed with sodium carboxymethylcellulose (disintegrant) and magnesium stearate (lubricant), half filled with gelatin capsules, and the other half pelleted.

 Stability investigation: The capsules and tablets prepared above were sealed in a composite aluminum foil bag, and the dissolution was measured after 30 days of stability at 40 ° C (according to the Chinese Pharmacopoeia 2000 edition two appendix XC dissolution method) The first method is determined by the blue method, the rotation speed is lOO rpm, the eluate is 0.1 mol/L hydrochloric acid, the sampling time is 45 minutes, and the content of the dissolved moxifloxacin is determined by HPLC method.

The conclusion is as follows:

 The results show that: according to the prescription process of the moxifloxacin hydrochloride tablet embodiment reported in the patent document (Chinese Patent Publication No. CN1325306A), it is not possible to simply prepare a gelatin hard capsule which can be placed for a long time and has the same dissolution rate as the tablet. .

 Test example 2

 Coryroxacin hydrochloride directly filled with gelatin capsules

 Composition and preparation: Take moxifloxacin hydrochloride 218. 4rag, directly filled gelatin capsules.

 Stability investigation: The method described in Test Example 1 was carried out.

 Results: The capsule shell swelled and the main drug did not dissolve.

 Test example 3

Component: Moxifloxacin hydrochloride 218. 4mg 49. Omg

 56. Omg

 4. Omg

 330. Omg

 Method: Take the above amount of raw materials, auxiliary materials, mix well, dry granulation, mix, fill gelatin capsules.

 Stability investigation: The capsules prepared above were sealed in a composite aluminum foil pouch at 40 ° C and a relative humidity of 75 ° /. After three months of accelerated stability investigation, the dissolution was measured in accordance with the method of measuring the dissolution as described in Test Example 1.

 Results: The capsule shell swelled and the main drug did not dissolve.

 Test example 4

Component _: 218. 4mg

 Microcrystalline cellulose 40. Omg

 Sodium Carboxymethyl Starch 56. Omg

 4. Omg

 Micronized silica gel 2. 6 mg

 HPMC 1. 0 mg

 330. Omg

 Method: Take the above amount of HPMC, add water to make a 1% solution as a binder; take the above amount of moxifloxacin hydrochloride, microcrystalline cellulose and sodium carboxymethyl starch, mix well, add adhesive to make wet granules, dry , whole grain, add the above amount of magnesium stearate and micro-silica gel, mix well, fill gelatin capsules.

 Stability investigation results: The capsules prepared above were sealed in a composite aluminum foil pouch, and after three months of accelerated stability at 40 ° C and 75% relative humidity, the dissolution was determined according to the method for determining the dissolution as described in Test Example 1. .

 Results: The capsule shell swelled and the main drug did not dissolve.

 Test example 5

 Component: Moxifloxacin Hydrochloride 218mg

 Carboxymethyl starch sodium 15mg

 HPMC 3. 5 mg

 236. 5mg

Method: Take the above amount of HPMC, add ice to make 3.5% solution as a binder; take the above amount of moxifloxacin hydrochloride and sodium carboxymethyl starch, mix well, add adhesive to make wet granules, dry, whole Granules, filled with gelatin capsules. Stability investigation results: The capsules prepared above were sealed in a composite aluminum foil pouch, and after three months of accelerated stability at 40 Torr and a relative humidity of 75%, the dissolution was measured in accordance with the method of measuring the dissolution as described in Test Example 1.

 Results: The capsule shell swelled and the main drug did not dissolve. Examples 1 to: 17 and Comparative Examples

 According to the amount of each component listed in Table 1 and Table 2 below, sodium sulfite, sodium hydrogen sulfite, oligocyanin, tea polyphenol, tocopherol, ascorbic acid, isoascorbic acid, L-glutathione, Sesame polyphenols, vitamin B1, vitamins Β2, β-carotene, soy isoflavones, L-cysteine, sodium pyrophosphate, calcium polyphosphate as additives, and no additives (control) to prepare hydrochloric acid Xishaxing gelatin capsules.

 Method and stability investigation: The raw materials and auxiliary materials mentioned in Table 1 and Table 2 were uniformly mixed, filled into gelatin capsule shells, and packaged in aluminum plastic blister. After 10 days of 60 Ό stability test, the dissolution rate was investigated.

 The results showed that after 10 days, the dissolution rate of the capsules added to the above-mentioned additives in an appropriate proportion of the contents of the capsules was substantially no decrease compared with the dissolution rate at the time of preparation, and was more than 95%; and the capsule shell portion without the additive was not dissolved, The average main drug dissolution was small (36%).

 The dissolution test was carried out by the method of measuring the dissolution as described in Test 1.

溶出度 （％) 98.9 99.3 98.9 99.0 98.6 98.7 36..0

Dissolution (%) 98.9 99.3 98.9 99.0 98.6 98.7 36..0

(10 days 60°C)

实施例 18〜42

Examples 18 to 42

 Composition: As shown in Table 3 to Table 8, respectively.

 Method: Take the amount of raw materials and auxiliary materials in the table and mix them well. Fill the capsules.

Stability investigation: The capsule prepared above was sealed in a composite aluminum foil bag, and after three months of investigation on the acceleration stability of 40 Ό and relative humidity of 75%, the dissolution was examined, and the dissolution was measured according to the measurement of the dissolution as described in Test Example 1. Method determination. The results show that the dissolution rate is greater than 80%.

 Table 3. (The amount of each capsule component, in mg)

表 4 (每粒胶囊组分量， 单位为 mg)

Table 4 (the amount of each capsule component, the unit is mg)

Table 5 (The amount of each capsule component, in mg)

Example 28 29 30 31 32 Components Moxifloxacin hydrochloride 218.4 218.4 218.4 218.4 218.4 Microcrystalline cellulose 48.65 47.3 29.0 16.0 16.0 Carboxymethyl starch sodium 56.0 56.0 56.0 56.0 24.0 Magnesium stearate 6.6 6.6 6.6 6.6 6.6 Tea polyphenol 0.35 1.7 20 33 65 Total 330.0 330.0 330.0 330.0 330.0 Dissolution (0 days) (%) 99 100 97 98 99 Dissolution (40 Ό, relative humidity 75% 85 99 99 96 101 Accelerated stability for three months) (%) Table 6 (each capsule component, unit Is mg)

(The amount of each capsule component, in mg)

溶出度 （0天） （％) 99 101 102 100 98 溶出度 （40°C、 相对湿度 75% 85 97 100 99 100 加速稳定性考察三个月） （％) 实施例 43〜47

Dissolution (0 days) (%) 99 101 102 100 98 Dissolution (40 ° C, relative humidity 75% 85 97 100 99 100 Accelerated stability for three months) (%) Examples 43 to 47

 Composition: as shown in Table 8

 Method: Take the amount of raw materials, excipients (except low oligomeric anthocyanins), some magnesium stearate, and some micro-silica gels, mix well, dry granulation, add oligomeric anthocyanins and residual stearic acid Magnesium, micro-silica gel, mixing, filling gelatin stability investigation: The capsule prepared above was sealed in a composite aluminum foil bag, and the dissolution rate and dissolution were investigated after three months of accelerated stability at 40 ° C and relative humidity of 75%. The measurement was carried out by the method of measuring the dissolution as described in Test Example 1. '

 The results show that the dissolution rate is greater than 80%. The specific results are shown in Table 8.

 Table 8 (quantity of each capsule component, in mg)

Moxifloxacin hydrochloride 218. 4mg

 Microcrystalline cellulose 29. Omg

 Sodium Carboxymethyl Starch 56. Omg

 6. 6mg

 10

\ 310. Orag coating solution (% w/w)

 HPMC 7. 5

 Propylene glycol 1. 5

 Sodium bisulfite 5. 0

 Tea polyphenols (80%) 3. 0

 Distilled water 83. 0

 Total 3⁄4 100. 0

 Method: Take the above amount of raw materials and auxiliary materials (take 1/2 amount of magnesium stearate) and mix them thoroughly. Dry granulation. After granules are coated with the coating liquid, add the remaining magnesium stearate and mix well to fill the gelatin capsules.

 Stability investigation: The capsule prepared above was sealed in a composite aluminum foil bag, and after three months of accelerated stability at 40 ° C and relative humidity of 75%, the dissolution was examined, and the dissolution was measured by the dissolution as described in Test Example 1. Method of determination.

 The results showed that the dissolution rate was 98%, which was not different from the freshly prepared capsule (day 0) data (99%). Example 49~70

 Composition: as shown in Table 9 to Table 10 respectively

 Method: Take the amount of raw materials and auxiliary materials in the table and mix them well. Fill the capsules.

 Stability investigation: The capsule prepared above was sealed in a composite aluminum foil bag, and after three months of investigation on the acceleration stability of 40 Ό and relative humidity of 75%, the dissolution was examined, and the dissolution was measured according to the measurement of the dissolution as described in Test Example 1. Method determination.

 The results show that the dissolution rate is more than 80%, and the specific results are shown in Table 9 to Table 10.

微晶纤维素 48.65 46.5 48.65 15.0 48.65 30.0 48.65 40.0 48.65 15.0 48.65 15.0 羧甲淀粉钠 56.0 56.0 56.0 25.0 56.0 25.0 56.0 45.0 56.0 25.0 56.0 25.0 硬脂酸镁 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 微粉硅胶 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 异抗坏血酸 0.25 1.0 0.35 65 Table 9. (The amount of each capsule component, in mg)

Microcrystalline cellulose 48.65 46.5 48.65 15.0 48.65 30.0 48.65 40.0 48.65 15.0 48.65 15.0 sodium carboxymethyl starch 56.0 56.0 56.0 25.0 56.0 25.0 56.0 45.0 56.0 25.0 56.0 25.0 Magnesium stearate 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 4.0 Micronized silica gel 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 2.6 Isoascorbic acid 0.25 1.0 0.35 65

Vitamin B1 0.05 1.0 0.35 50

Vitamin B2 0.05 0.5 0.35 20

 L-glutathione 0.35 65

Sesame polyphenol 0.35 65 Total 330.0 330.0 330.0 330.0 330.0 330.0 330.0 330.0 330.0 330.0 330.0 330.0 Dissolution ^: (0 days) 100 96 96 98 100 101 101 99 96 99 101 102 (%)'

Dissolution (40.C 99 97 100 98 99 100 98 98 98 99 87 98 relative humidity 75%,

Accelerated stability

For three months) (%: Table 10. (The amount of each capsule component, in mg)

加速稳定性考

Accelerated stability test

 3 months) (%) The above examples show that after the additive is added to the contents of the capsule, the dissolution of the gelatin capsule does not decrease significantly during storage, and the amount of the additive added It is only necessary to achieve almost the same effect of improving the dissolution stability during storage in the content range of the present invention.

Claims

Rights request  A moxifloxacin gelatin capsule, characterized in that the capsule content contains moxifloxacin or a salt thereof and/or a hydrate thereof, and an additive selected from at least one of the following: Sodium sulfite, sodium bisulfite, oligocyanin, L-glutathione, sesame polyphenols, tea polyphenols, tocopherol, ascorbic acid, erythorbic acid, vitamin B!, vitamin Β ₂ , beta-carotene, soybean Isoflavones, L-cysteine, pyrophosphoric acid, polyphosphoric acid and pharmaceutically acceptable salts thereof.  1-20%。 The weight percentage of the content of the capsule in the capsule content is 0. 1-20%.  The moxifloxacin gelatin capsule according to claim 2, wherein the weight percentage of the capsule content is 0'. 1-16% when the additive is vitamin B1.  5%。 5%. 5%. 5%。 5%. 5%. 5%.  The moxifloxacin gelatin capsule according to any one of claims 1 to 4, wherein the moxifloxacin or a salt thereof and/or a hydrate thereof means moxifloxacin hydrochloride.  6. A moxifloxacin gelatin capsule according to claim 5, wherein: the capsule content of the capsule further comprises a pharmaceutically acceptable amount of a pharmaceutical excipient, the pharmaceutical excipient comprising dilution One or more of a agent, a disintegrant, a binder, a lubricant or a glidant. .  A moxifloxacin gelatin capsule according to claim 6, wherein the diluent and the disintegrating agent comprise microcrystalline cellulose or sodium carboxymethyl starch.  A moxifloxacin gelatin capsule according to claim 6, wherein the binder comprises hydroxypropylcellulose or hydroxypropylmethylcellulose.  A moxifloxacin gelatin capsule according to claim 6, wherein: said lubricant comprises magnesium stearate. .  10. A moxifloxacin gelatin capsule according to claim 6 wherein: the glidant comprises a micronized silica gel.  11. A method of preparing a moxifloxacin gelatin capsule according to claim 1, the method comprising the steps of: thoroughly mixing or preparing the moxifloxacin or a salt thereof and/or a hydrate thereof with the additive. The granules are filled into a gelatin capsule shell. The method according to claim 11, wherein the step further comprises: the moxifloxacin or a salt thereof and/or a hydrate thereof, and the additive, and a pharmaceutically acceptable amount The medicinal excipients are thoroughly mixed or granulated and filled into a gelatin capsule shell, and the medicinal excipients include a diluent, a disintegrant, a binder, and a lubricant. Or one or more of the glidants.  13. A method of preparing a moxifloxacin gelatin capsule according to claim 1, the method comprising the steps of: applying the moxifloxacin or a salt thereof and/or a hydrate thereof to a coating containing the additive The liquid is prepared into granules or powder coated, dried and filled into gelatin capsules ^.  14. The preparation method according to claim 13, wherein the step further comprises: thoroughly mixing the moxifloxacin or a salt thereof and/or a hydrate thereof with a pharmaceutically acceptable amount of a pharmaceutical excipient. After the hooking, the granules are prepared or coated with a coating liquid containing the additive, and dried and filled into a gelatin capsule shell, the medicinal auxiliary materials including a diluent, a disintegrating agent, a binder, a lubricant or a glidant. One or several of them.