CN100384411C - Carlevodopa Orally Disintegrating Tablets - Google Patents

Abstract

The present invention discloses an oral carbidopa/levodopa disintegration tablet which uses carbidopa and levodopa as the main medicines. The oral carbidopa/levodopa disintegration tablet also comprises a disintegrating agent and a diluting agent. The oral carbidopa/levodopa disintegration tablet is characterized in that the disintegrating agent is low-substituted hydroxypropyl cellulose, and the diluting agent is prepared from microcrystalline cellulose and mannitol. The present invention also provides a production method of the oral carbidopa/levodopa disintegration tablet. The production method has the advantage of simple and stable technology, and is particularly suitable for industrial production.

Description

Carlevodopa Orally Disintegrating Tablets

technical field

The invention relates to a carbidopa orally disintegrating tablet and a production method thereof, in particular to an orally disintegrating tablet with carbidopa and levodopa as main ingredients and a production method thereof. The orally disintegrating carlevodopa tablet can be used for treating Parkinson's disease or Parkinson's syndrome and the like.

Background technique

After oral administration, levodopa enters the center and converts into dopamine to play a role. Carbidopa is a peripheral deacidase inhibitor, which is not easy to enter the center. It only inhibits the conversion of peripheral levodopa into dopamine, which increases the content of levodopa in the circulation. The amount of levodopa entering the central nervous system also increases, and levodopa is transformed into dopamine through dopamine decarboxylase in the brain to exert pharmacological effects, improve the symptoms of agitators and paralysis, and is used to treat Parkinson's disease or Parkinson's syndrome.

CN1358090A discloses a medicament for treating Parkinson's disease, the main components of which are levodopa, carbidopa and entacapone. Disclosed in CN1329487A is a dispersible composition of L-dopa ethyl ester, which contains carbidopa, disintegrating agent, filler and lubricant.

Contents of the invention

Orally disintegrating tablets are the ideal dosage form for people with moderately or severely symptomatic Parkinson's disease or Parkinsonism who have difficulty swallowing whole tablets.

On the basis of the prior art, the present invention unexpectedly finds that the orally disintegrating tablets prepared by selecting suitable disintegrants and diluents for carbidopa and levodopa have excellent tablet effect. The preparation composition of the carlevodopa orally disintegrating tablet of the present invention is different from that of the existing dispersible medicament.

The invention provides an orally disintegrating tablet, which uses carbidopa and levodopa as main ingredients, wherein the weight ratio of carbidopa and levodopa is 1: (4-10), and contains a disintegrating agent and The diluent is characterized in that the disintegrant is low-substituted hydroxypropyl cellulose (L-HPC), and the diluent is microcrystalline cellulose (CMCC) and mannitol.

Wherein said microcrystalline cellulose, can be microcrystalline cellulose pH102, microcrystalline cellulose pH301 or microcrystalline cellulose KG802, also can be microcrystalline cellulose-90 (CMCC 90) or microcrystalline cellulose-50 ( CMCC 50). Among them, the preferred microcrystalline cellulose is microcrystalline cellulose pH102, microcrystalline cellulose pH301 or microcrystalline cellulose KG802.

Wherein, the consumption of microcrystalline cellulose and mannitol, calculated by weight ratio, can be (1～2):(1～1.5), preferably 2:1.

The above-mentioned orally disintegrating tablet also contains a glidant, a lubricant or a flavoring agent. Wherein, the glidant is, for example, one or more of micropowder silica gel, talcum powder, Cab-O-sil, Arosil, sodium aluminosilicate hydrate, etc.; the lubricant is, for example, magnesium stearate, Calcium stearate, zinc stearate, glyceryl monostearate, macrogol, hydrogenated vegetable oil, sodium stearyl fumarate, polyoxyethylene monostearate, monolauric sucrose, lauryl sulfate One or more of sodium, magnesium lauryl sulfate, magnesium lauryl sulfate, and talcum powder; the flavoring agent is, for example, aspartame, banana flavor, pineapple flavor, vanillin, orange One or more of essence, orange essence, mint essence, ginseng essence, strawberry essence, citric acid, citric acid, etc.

Preferably, the orally disintegrating tablet of the present invention is: calculated by weight, 10-25 parts of carbidopa, 100 parts of levodopa, 150-200 parts of microcrystalline cellulose, 100-150 parts of mannitol, low-substituted 20-30 parts of hydroxypropyl cellulose, 2-8 parts of micropowder silica gel, 2-6 parts of magnesium stearate, 0.5-4 parts of aspartame, 0.5-2 parts of orange essence, and 0.5-2 parts of mint essence.

As one of the specific embodiments of the present invention, the orally disintegrating tablet is: calculated in parts by weight, 10 parts of carbidopa, 100 parts of levodopa, 150 parts of microcrystalline cellulose pH102, 50 parts of microcrystalline cellulose pH301 100 parts of mannitol, 25 parts of low-substituted hydroxypropyl cellulose, 5 parts of micronized silica gel, 3.6 parts of magnesium stearate, 2 parts of aspartame, 1 part of orange flavor, and 1 part of mint flavor.

As one of the specific embodiments of the present invention, the orally disintegrating tablet is: calculated in parts by weight, 10 parts of carbidopa, 100 parts of levodopa, 200 parts of microcrystalline cellulose pH102, 100 parts of mannitol, low Substitute 25 parts of hydroxypropyl cellulose, 5 parts of micronized silica gel, 3.6 parts of magnesium stearate, 2 parts of aspartame, 1 part of orange essence, and 1 part of mint essence.

The orally disintegrating tablet of the present invention has suitable hardness, preferably between 20 and 40N (Newton).

The above-mentioned orally disintegrating tablet can be used to prepare medicines for treating diseases such as Parkinson's disease or Parkinson's syndrome.

The orally disintegrating tablet of the present invention can be prepared by direct compression method. The production method of the orally disintegrating tablet of the present invention comprises the following steps: (1) uniformly mixing the raw material drug and the excipients in the prescription by a suitable method (such as incremental dilution method, etc.); (2) adjusting the tableting force to a suitable tablet hardness (for example, 20-40N), and perform tablet compression. After passing the quality inspection, the orally disintegrating tablets are packaged.

With reference to the relevant research on existing orally disintegrating tablets, and in combination with the characteristics of carbidopa and levodopa, the inventors have unexpectedly found that low-substituted hydroxypropyl cellulose (L-HPC ) as a disintegrant, using microcrystalline cellulose, especially microcrystalline cellulose pH102, microcrystalline cellulose pH301 or microcrystalline cellulose KG802 and mannitol as a diluent, the prepared orally disintegrating tablet has excellent beneficial effects . The production method of the orally disintegrating tablet of the present invention has a simple and stable process, and is particularly suitable for industrial production.

Description of drawings

Accompanying drawing 1: Carbidopa dissolution curve chart of embodiment 1 orally disintegrating tablet

Accompanying drawing 2: The levodopa dissolution curve of orally disintegrating tablet of embodiment 1

Detailed ways

The following examples will further illustrate the present invention, but should not be construed as limiting the scope of the present invention.

Embodiment 1: preparation embodiment

Carbidopa 10g, levodopa 100g, microcrystalline cellulose pH102 200g, mannitol 100g, low-substituted hydroxypropyl cellulose 25g, micronized silica gel 5g, magnesium stearate 3.6g, Aspen 2 grams of sweet potato, 1 gram of orange essence, and 1 gram of mint essence. Pass the raw material and excipients through an 80-mesh sieve, mix them uniformly according to the incremental dilution method, measure the powder content, adjust the tablet loading so that the tablet weight is the theoretical tablet weight ± 3% of the tablet weight, adjust the tablet pressing force to press the tablet, and take the tablet Test the hardness of the tablet, adjust the tablet pressing force so that the tablet hardness is 20-40 Newtons, punch with a circular shallow concave of φ12mm, and press it into 1000 tablets.

Embodiment 2: preparation embodiment

Carbidopa 10g, levodopa 100g, microcrystalline cellulose pH102 150g, microcrystalline cellulose pH30150g, mannitol 100g, low-substituted hydroxypropyl cellulose 25g, micronized silica gel 5g, stearin Magnesium acid 3.6 grams, aspartame 2 grams, orange essence 1 gram, mint essence 1 gram. According to the method described in Example 1, 1000 pieces were made.

Embodiment 3: preparation embodiment

Carbidopa 25g, levodopa 100g, microcrystalline cellulose pH102 150g, microcrystalline cellulose KG80 250g, mannitol 100g, low-substituted hydroxypropyl cellulose 30g, micronized silica gel 5g, stearin Magnesium acid 3.6 grams, aspartame 2 grams, orange essence 1 gram, mint essence 1 gram. According to the method described in Example 1, 1000 pieces were made.

Embodiment 4: comparative test

Embodiment 4a: Replace the low-substituted hydroxypropyl cellulose in embodiment 1 with 25 grams of croscarmellose sodium, and the rest are the same as in embodiment 1. According to the method described in Example 1, 1000 pieces were made.

Example 4b: 25 grams of crospovidone was used to replace the low-substituted hydroxypropyl cellulose in Example 1, and the rest were the same as in Example 1. According to the method described in Example 1, 1000 pieces were made.

Embodiment 4c: replace the mannitol in embodiment 1 with erythritol 100 grams, all the other are the same as embodiment 1. According to the method described in Example 1, 1000 pieces were made.

The basic properties of the orally disintegrating tablets of Examples 1-4 were investigated. The results are shown in Table 1.

Wherein the disintegration time limit determination method is:

Method 1: Small beaker method: Take a 5ml small beaker, add 2ml of water, put the tablet in it, and record the disintegration time of the tablet.

Method 2: Instrument test method: In order to solve the shortcoming of the disintegration instrument used in the current disintegration time determination method of the Chinese Pharmacopoeia, the frequency of disintegration is fixed, and refer to some disintegration time determinations mentioned in foreign patents for disintegration tablets Method, the present invention utilizes the existing Chinese Pharmacopoeia 2000 version II dissolution tester and the hanging basket of the lifting disintegration device. The former can adjust the speed.

Inspection: Place the beaker provided with the dissolution apparatus in a 37°C constant temperature water bath of the dissolution apparatus, inject 750 ml of water, install the hanging basket on the dissolution apparatus through the basket shaft, and immerse the hanging basket in the water to make the hanging basket The bottom is 5 cm from the bottom of the beaker. Take this product and place it in the glass tube of the hanging basket. Start the rotating shaft and time it at the same time. The rotating speed is 50 or 80 revolutions per minute. The time when all the tablet particles pass through the sieve is the disintegration time, and the disintegration time is recorded. The results are shown in Table 1

Table 1 The basic performance investigation results of carlevodopa orally disintegrating tablet formulations

The measurement results show that the orally disintegrating tablet of levodopa of the present invention uses low-substituted hydroxypropyl cellulose as the disintegrating agent, microcrystalline cellulose and mannitol as the diluent, and the orally disintegrating tablet made has an excellent preparation learning effect.

Embodiment 5: dissolution test

Assay method: take this product, according to the dissolution assay method (Chinese Pharmacopoeia 2000 edition two appendix XC first method), with 750ml 0.1N hydrochloric acid solvent, the rotating speed is 50 revolutions per minute, operate according to law, after 30 minutes, take the solution Appropriate amount, filter, take subsequent filtrate, carry out content determination, calculate dissolution rate

Carry out dissolution rate investigation to embodiment 1, take samples when 2, 5, 10, 20, 30 minutes, draw dissolution curve. Dissolution profiles are shown in Figures 1 and 2.

The orally disintegrating tablet of the present invention (taking the sample of Example 1), according to the guiding principle of the drug stability test, was respectively subjected to strong light irradiation (45001x ± 5001x), high temperature (60 degrees Celsius), high humidity (relative humidity is 90% ± 5 %) under the condition of investigating 10, investigate its stability. The test results show that the product has good stability, and the relevant substances and contents meet the requirements.

The invention has been described in terms of preferred embodiments. It should be understood that the foregoing description and examples are by way of illustration only of the invention. Without departing from the spirit and scope of the present invention, those skilled in the art can design various alternatives and improvements of the present invention, all of which should be understood as falling within the protection scope of the present invention.

Claims (10)

1. oral cavity disintegration tablet, with Carbidopa as principal agent, wherein the weight ratio of Carbidopa is 1: (4～10), comprise disintegrating agent and diluent, it is characterized in that described disintegrating agent is a low-substituted hydroxypropyl cellulose, described diluent is microcrystalline Cellulose and mannitol, and the weight ratio of microcrystalline Cellulose and mannitol is 2: 1.

2. oral cavity disintegration tablet according to claim 1, wherein said microcrystalline Cellulose are selected microcrystalline Cellulose pH102, microcrystalline Cellulose pH301 or microcrystalline Cellulose KG802 for use.

3. according to claim 1 or 2 described oral cavity disintegration tablets, wherein also comprise fluidizer, lubricant or correctives.

4. oral cavity disintegration tablet according to claim 3 is characterized in that: calculate 10 parts of carbidopas by weight, 100 parts of levodopa, microcrystalline Cellulose pH102150 part, microcrystalline Cellulose pH30150 part, 100 parts in mannitol, 25 parts of low-substituted hydroxypropyl celluloses, 5 parts of micropowder silica gels, 3.6 parts of magnesium stearate, 2 parts of aspartames, 1 part in fragrant citrus essence, 1 part in Herba Menthae essence.

5. oral cavity disintegration tablet according to claim 3, it is characterized in that: calculate 10 parts of carbidopas, 100 parts of levodopa by weight, microcrystalline Cellulose pH102200 part, 100 parts in mannitol, 25 parts of low-substituted hydroxypropyl celluloses, 5 parts of micropowder silica gels, 3.6 parts of magnesium stearate, 2 parts of aspartames, 1 part in fragrant citrus essence, 1 part in Herba Menthae essence.

6. according to claim 1 or 2 described oral cavity disintegration tablets, the hardness that it is characterized in that sheet is between 20～40 newton.

7. oral cavity disintegration tablet according to claim 3, the hardness that it is characterized in that sheet is between 20～40 newton.

8. according to claim 4 or 5 described oral cavity disintegration tablets, the hardness that it is characterized in that sheet is between 20～40 newton.

9. each described oral cavity disintegration tablet of claim 1-8 is used for the treatment of purposes in parkinson or the parkinsonism medicine in preparation.

10. the production method of each described oral cavity disintegration tablet of claim 1-8 is characterized in that comprising following steps:

(1) will write out a prescription in crude drug and adjuvant proper method mix homogeneously;

(2) adjustment compression force to 20～40 newton's sheet hardness is carried out tabletting.

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