Sublingual buccal sustained-release pharmaceutical composition

Abstract

The invention provides a sublingual buccal sustained-release pharmaceutical composition. The pharmaceutical composition consists of the following components: 0.02%-0.08% of doxercalciferol, an excipient, a disintegrating agent, a biological adhesive, a flow aid, a stabilizer, a flavoring agent and an adhesive. According to the sublingual buccal sustained-release pharmaceutical composition provided by the invention, the amount of doxercalciferol, which is a main drug, converted into previous doxercalciferol in liquid is reduced; meanwhile, during preparation, the stability of the active ingredients is enhanced due to optimization of a prescription process, and a provided quality control method is accurate and reliable.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a sublingual sustained-release pharmaceutical composition. BACKGROUND

[0002] Calcitriol is metabolized in the body, and has less effect on the skeleton and the intestinal tract. It is mainly used for the treatment of chronic diseases, especially secondary hyperparathyroidism (SHPT), which is one of the most common complications of chronic kidney disease.

[0003] Secondary hyperparathyroidism is one of the most common complications of chronic renal failure, and calcitriol is a selective vitamin D receptor agonist, which is metabolized in the liver and has less effect on the skeleton and the intestinal tract. It mainly acts on the parathyroid gland. It can effectively inhibit the secretion of intact parathyroid hormone (iPTH), and slightly increase the concentration of blood phosphorus and blood calcium. Calcitriol mainly acts on the parathyroid gland, can effectively inhibit the secretion of intact parathyroid hormone (iPTH), and is approved by FDA for reducing the iPTH level of patients with progressive chronic kidney dialysis SHPT.

[0004] Compared with traditional calcitriol, the incidence of hyperphosphatemia and hypercalcemia after the application of calcitriol is greatly reduced, and it is more effective and safe, and is an upgraded substitute for alfacalcidol, and can also effectively treat osteoporosis. Calcitriol is a 1-hydroxylate of synthetic vitamin D2, and is a vitamin D drug. Calcitriol is a safe and effective anti-parathyroid drug, has higher affinity for parathyroid VDR, has less effect on the intestinal tract and the skeleton, does not have the risk of hypercalcemia and hyperphosphatemia, and has more persistent inhibition of parathyroid hormone. It can be well used to treat hyperparathyroidism, prevent various serious complications, improve the quality of life of elderly patients, and reduce the risk. Calcitriol was approved by FDA in 2000, and is the first-line drug for the treatment of secondary hyperparathyroidism.

[0005] In 2000, Genzyme (Sanofi was acquired in 2011) launched the original research product of calcitriol (trade name: HECTOROL®). Up to now, AKORN, AMNEAL, GLAND, HIKMA, HOSPIRA, SANDOZ, SUNPHARMA, and Jianyou shares have been approved ANDA, and there are two dosage forms of capsules and injections. At present, the indications of the preparation are suitable for the treatment of secondary hyperparathyroidism in chronic kidney disease dialysis patients. However, the existing preparation has stability problems in the preparation process and storage process. SUMMARY

[0006] The present application aims to disclose a simple and stable sublingual sustained-release pharmaceutical composition, mainly solving the stability problem of the drug in the preparation process and storage process.

[0007] To achieve the above-mentioned purpose, the present application provides a sublingual sustained-release pharmaceutical composition, which is composed of the following components: calcifediol 0.02%-0.08%, excipient, disintegrant, bioadhesive, glidant, stabilizer, flavoring agent and binder.

[0008] In some embodiments, the bioadhesive is a mixture of one or more of hydroxypropyl methylcellulose, carboxymethylcellulose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose or a mixture thereof.

[0009] In some embodiments, the excipient is a mixture of one or more of mannitol, lactose, microcrystalline cellulose.

[0010] In some embodiments, the disintegrant is sodium starch glycolate, low-substituted hydroxypropyl cellulose or a mixture thereof.

[0011] In some embodiments, the stabilizer is a mixture of one or more of edetate disodium, vitamin C or its sodium salt, butylated hydroxytoluene.

[0012] In some embodiments, the glidant is colloidal silicon dioxide, magnesium stearate or a mixture thereof.

[0013] In some embodiments, the flavoring agent is a mixture of one or more of aspartame, borneol, menthol, menthol.

[0014] In some embodiments, the binder is ethanol or a mixture of ethanol and water in a certain proportion.

[0015] In another aspect, the present application also provides a preparation method of the above-mentioned pharmaceutical composition, comprising the following steps: S1, dissolving calcifediol in an appropriate amount of ethanol, adding a stabilizer and stirring to dissolve; S2, first adding excipient, disintegrant and bioadhesive into a high-speed granulator and mixing uniformly, then adding the calcifediol ethanol solution in step S1 and mixing uniformly; S3, dissolving or dispersing the flavoring agent in an appropriate concentration of ethanol water solution, adding into the high-speed granulator, starting the granulator to granulate, and then sieving the wet granules through a 24-40 mesh screen to perform wet granulation; S4, adding the wet granules prepared in step S3 into a drying device, drying at an inlet air temperature of 50-70℃ to obtain dry granules, controlling the moisture content to be ≤3.0%, and sieving the dry granules through a 30 mesh screen to perform granulation; S5, the dry granules are added into the mixer, a flow aid is added, a suitable rotation speed and time are set, and the mixture is uniformly mixed, an intermediate is sampled and detected, and the tablet weight is calculated; S6, the tablets are pressed by using a rotary tablet press, the tablet diameter is controlled to be not less than 9 mm, and the tablet hardness is controlled to be 60-100 N, and the tablets are obtained.

[0016] In some embodiments, the pharmaceutical composition is composed of the following components by weight fraction: Ecalciferol 0.01 g, mannitol 300 g, lactose 50 g, microcrystalline cellulose 100 g, L-hydroxypropyl cellulose 50 g, hydroxypropyl methyl cellulose K4M 600 g, hydroxypropyl methyl cellulose K15M 300 g, butylated hydroxytoluene 8 g, menthol 8 g, aspartame 5 g, 95% ethanol as appropriate, colloidal silicon dioxide 15 g, and magnesium stearate 10 g; or, Ecalciferol 0.025 g, mannitol 300 g, lactose 50 g, microcrystalline cellulose 100 g, L-hydroxypropyl cellulose 50 g, hydroxypropyl methyl cellulose K4M 700 g, hydroxypropyl methyl cellulose K15M 200 g, butylated hydroxytoluene 8 g, menthol 8 g, aspartame 5 g, 95% ethanol as appropriate, colloidal silicon dioxide 15 g, and magnesium stearate 10 g; or, Ecalciferol 0.02 g, mannitol 300 g, lactose 50 g, microcrystalline cellulose 100 g, L-hydroxypropyl cellulose 40 g, hydroxypropyl methyl cellulose K4M 600 g, hydroxypropyl methyl cellulose K15M 100 g, vitamin C 8 g, menthol 8 g, aspartame 5 g, menthol 2 g, 95% ethanol as appropriate, colloidal silicon dioxide 15 g, and magnesium stearate 10 g.

[0017] Compared with the prior art, the beneficial effects of the present application are: The sublingual sustained-release pharmaceutical composition provided by the present application reduces the amount of the main drug Ecalciferol converted into pre-Ecalciferol in a liquid; meanwhile, the stability of the active ingredient is enhanced due to the optimization of the prescription process during preparation, and the quality control method provided is accurate and reliable. DETAILED DESCRIPTION

[0018] The present application will be described in detail below in conjunction with the embodiments, but it should be noted that these embodiments are not a limitation on the present application, and equivalent transformations or substitutions of function, method, or structure made by those of ordinary skill in the art based on these embodiments are within the scope of the present application.

[0019] Example 1 The present embodiment provides a sublingual sustained-release pharmaceutical composition composed of the following components by weight fraction: Cholecalciferol 0.01 g, mannitol 300 g, lactose 50 g, microcrystalline cellulose 100 g, L-hydroxypropyl cellulose 50 g, hydroxypropyl methyl cellulose K4M 600 g, hydroxypropyl methyl cellulose K15M 300 g, butylated hydroxytoluene 8 g, menthol 8 g, aspartame 5 g, 95% ethanol as appropriate, colloidal silicon dioxide 15 g, magnesium stearate 10 g.

[0020] The preparation method of the above-mentioned pharmaceutical composition is: S1, dissolve cholecalciferol in appropriate 95% ethanol, add butylated hydroxytoluene, stir and dissolve, then add colloidal silicon dioxide and mix uniformly.

[0021] S2, first add mannitol, lactose, microcrystalline cellulose, L-hydroxypropyl cellulose, hydroxypropyl methyl cellulose K4M, and hydroxypropyl methyl cellulose K15M into a high-speed granulator, turn on the equipment, mix uniformly, then spray the above-mentioned cholecalciferol ethanol solution, turn on the granulator and mix uniformly.

[0022] S3, dissolve / disperse the flavoring agent menthol and aspartame in appropriate 80% concentration ethanol water, spray into the high-speed granulator, turn on the granulator, granulate, and then pass through a 24-40 mesh screen for wet granulation.

[0023] S4, add the above-mentioned wet granules into a drying equipment, set the inlet air temperature to 60°C, dry, control the moisture content to ≤3.0%, and sieve on a 30 mesh screen.

[0024] S5, add the dry granules into a mixer, add the glidant magnesium stearate, set the appropriate rotation speed and time, mix uniformly, take samples for testing intermediates, and calculate the tablet weight.

[0025] S6, use a rotary tablet press to press the tablets, control the tablet diameter to no less than 9 mm, control the tablet hardness to 60-100 N, and obtain the product.

[0026] Example 2 The present example provides a sublingual sustained-release pharmaceutical composition, which is composed of the following components in weight fractions: Cholecalciferol 0.025 g, mannitol 300 g, lactose 50 g, microcrystalline cellulose 100 g, L-hydroxypropyl cellulose 50 g, hydroxypropyl methyl cellulose K4M 700 g, hydroxypropyl methyl cellulose K15M 200 g, butylated hydroxytoluene 8 g, menthol 8 g, aspartame 5 g, 95% ethanol as appropriate, colloidal silicon dioxide 15 g, magnesium stearate 10 g.

[0027] The preparation method of the above-mentioned pharmaceutical composition is: S1, dissolve cholecalciferol in appropriate 95% ethanol, add butylated hydroxytoluene, stir and dissolve, then add colloidal silicon dioxide and mix uniformly.

[0028] S2, mannitol, lactose, microcrystalline cellulose, L-hydroxypropyl cellulose, hydroxypropyl methyl cellulose K4M, hydroxypropyl methyl cellulose K15M are first added to a high-speed granulator, the equipment is started, and mixed uniformly, then the above calcitriol ethanol solution is sprayed and added, the granulator is started, and mixed uniformly.

[0029] S3, the flavoring agent menthol, aspartame is dissolved / dispersed in an appropriate amount of 80% concentration ethanol aqueous solution, sprayed into a high-speed granulator, the granulator is started, and granulated, then sieved through a 24-40 mesh screen for wet granulation.

[0030] S4, the above wet granules are added to a drying device, the inlet air temperature is set to 60°C, drying is performed, the moisture content is controlled to be ≤3.0%, and the granules are sieved through a 30 mesh screen.

[0031] S5, the dry granules are added to a mixer, a flow aid magnesium stearate is added, the appropriate rotation speed and time are set, mixed uniformly, sample detection is performed on the intermediate product, and the tablet weight is calculated.

[0032] S6, tablets are pressed using a rotary tablet press, the tablet diameter is controlled to be not less than 9 mm, the tablet hardness is controlled to be 60-100 N, and the tablets are obtained.

[0033] Example 3 The present embodiment provides a sublingual sustained-release pharmaceutical composition, which is composed of the following components in weight fractions: Calcitriol 0.02 g, mannitol 300 g, lactose 50 g, microcrystalline cellulose 100 g, L-hydroxypropyl cellulose 40 g, hydroxypropyl methyl cellulose K4M 600 g, hydroxypropyl methyl cellulose K15M 100 g, vitamin C 8 g, menthol 8 g, aspartame 5 g, borneol 2 g, 95% ethanol, appropriate amount, colloidal silicon dioxide 15 g, magnesium stearate 10 g.

[0034] The preparation method of the above pharmaceutical composition is as follows: S1, dissolve calcitriol in an appropriate amount of 95% ethanol, add vitamin C, stir to dissolve, and then add colloidal silicon dioxide and mix uniformly.

[0035] S2, mannitol, lactose, microcrystalline cellulose, L-hydroxypropyl cellulose, hydroxypropyl methyl cellulose K4M, and hydroxypropyl methyl cellulose K15M are first added to a high-speed granulator, the equipment is started, and mixed uniformly, then the above calcitriol ethanol solution is sprayed and added, the granulator is started, and mixed uniformly.

[0036] S3, the flavoring agent menthol, aspartame is dissolved / dispersed in an appropriate amount of 80% concentration ethanol aqueous solution, sprayed into a high-speed granulator, the granulator is started, and granulated, then sieved through a 24-40 mesh screen for wet granulation.

[0037] S4, the above wet granules are added into a drying device, the inlet air temperature is set to 60℃, drying is carried out, the moisture content is controlled to be less than or equal to 3.0%, and the granules are sized on a 30-mesh screen.

[0038] S5, the dry granules are added into a mixer, a flow aid magnesium stearate is added, appropriate rotation speed and time are set, and the granules are mixed uniformly, the intermediate product is sampled and detected, and the tablet weight is calculated.

[0039] S6, the tablets are compressed by using a rotary tablet press, the tablet diameter is controlled to be not less than 9 mm, and the tablet hardness is controlled to be 60-100 N, and the tablets are obtained.

[0040] Example 4 The drug composition of the sublingual sustained-release tablets prepared in Example 1 is detected, and is compared with a commercially available product.

[0041] Chromatographic conditions for content determination: octadecylsilane-bonded silica gel is used as a filler (3 μm 150 mm x 4.6 mm), linear gradient elution is carried out according to the following table by using octadecylsilane-bonded silica gel as a filler, water as a mobile phase A, and acetonitrile as a mobile phase B; the flow rate is 1.6 ml / min; the column temperature is 30℃; the detection wavelength is 262 nm; and the injection volume is 5 μl.

[0042] Determination method: the test sample solution and the reference solution are precisely measured, are injected into a liquid chromatograph respectively, and chromatograms are recorded. The peak area is calculated according to an external standard method. The content of calcitriol (C 28 H 44 O2) should be 90.0%-110.0% of the labeled amount.

[0043] The drug composition prepared in Example 1 is compared with a commercially available product in stability test, and the detection results are shown in Table 1 (the impurity of precalcitriol is not calculated in the preparation, and the content of the main drug should be calculated according to the quality standard).

[0044] Table 1 As shown in the above table, the impurity and the content of the drug composition prepared in Example 1 are basically stable, and are obviously reduced compared with the commercially available preparation, which indicates that the calcitriol in the drug composition of the present application is more stable than that in the commercially available preparation.

[0045] The series of detailed descriptions listed above are only specific descriptions of the feasible implementation manners of the present application, and are not used to limit the protection scope of the present application, and equivalent implementation manners or changes made without departing from the spirit of the present application should be included in the protection scope of the present application.

[0046] Furthermore, it should be understood that although the specification is described in terms of embodiments, not every embodiment includes every feature or implementation described herein. The specification can include implicit combinations of explicitly mentioned features and / or implicit combinations of implicitly mentioned features. Such combinations are also expressly included within the scope of the specification and an embodiment.

Claims

1. A sublingual, buccal sustained release pharmaceutical composition, characterized in that, The pharmaceutical composition is composed of the following components: calcifediol 0.02%-0.08%, excipient, disintegrant, bioadhesive, glidant, stabilizer, flavoring agent and binder.

2. The pharmaceutical composition of claim 1, wherein, The bioadhesive is a mixture of one or more of hydroxypropyl methylcellulose, carboxymethylcellulose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose or a mixture thereof.

3. The pharmaceutical composition of claim 2, wherein, The excipient is a mixture of one or more of mannitol, lactose, microcrystalline cellulose.

4. The pharmaceutical composition of claim 3, wherein, The disintegrant is sodium starch glycolate, low-substituted hydroxypropyl cellulose or a mixture thereof.

5. The pharmaceutical composition of claim 4, wherein, The stabilizer is a mixture of one or more of edetate disodium, vitamin C or its sodium salt, butylated hydroxytoluene.

6. The pharmaceutical composition of claim 5, wherein, The glidant is colloidal silicon dioxide, magnesium stearate or a mixture thereof.

7. The pharmaceutical composition of claim 6, wherein, The flavoring agent is a mixture of one or more of aspartame, borneol, menthol, menthol.

8. The pharmaceutical composition of claim 7, wherein, The binder is ethanol or a mixture of ethanol and water in a certain proportion.

9. The pharmaceutical composition according to any one of claims 1-8, characterized in that, The preparation method of the pharmaceutical composition comprises the following steps: S1, dissolve calcifediol in an appropriate amount of ethanol, add stabilizer, stir and dissolve; S2, first add excipient, disintegrant and bioadhesive into a high-speed granulator, mix uniformly, then add the calcifediol ethanol solution in step S1, mix uniformly; S3, dissolve or disperse the flavoring agent in an appropriate concentration of ethanol water solution, add it into the high-speed granulator, start the granulator, then pass through a 24-40 mesh screen for wet granulation; S4, add the wet granules prepared in step S3 into a drying device, the inlet air temperature is 50-70℃, dry, control the moisture content ≤3.0%, 30 mesh granulation; S5, add the dry granules into a mixer, add glidant, set appropriate speed and time, mix uniformly, take sample to detect the intermediate, calculate the tablet weight; S6, use a rotary tablet press to press the tablets, control the tablet diameter not less than 9mm, control the tablet hardness 60-100N, and get the tablets.

10. The pharmaceutical composition of claim 9, wherein, The pharmaceutical composition is composed of the following components by weight: Calcifediol 0.01g, mannitol 300g, lactose 50g, microcrystalline cellulose 100g, L-hydroxypropyl cellulose 50g, hydroxypropyl methylcellulose K4M 600g, hydroxypropyl methylcellulose K15M 300g, butylated hydroxytoluene 8g, borneol 8g, aspartame 5g, 95% ethanol, colloidal silicon dioxide 15g, magnesium stearate 10g; or, Calcifediol 0.025g, mannitol 300g, lactose 50g, microcrystalline cellulose 100g, L-hydroxypropyl cellulose 50g, hydroxypropyl methylcellulose K4M 700g, hydroxypropyl methylcellulose K15M 200g, butylated hydroxytoluene 8g, menthol 8g, aspartame 5g, 95% ethanol, colloidal silicon dioxide 15g, magnesium stearate 10g; or, Calcitriol 0.02 g, mannitol 300 g, lactose 50 g, microcrystalline cellulose 100 g, L-hydroxypropyl cellulose 40 g, hydroxypropyl methyl cellulose K4M 600 g, hydroxypropyl methyl cellulose K15M 100 g, vitamin C 8 g, menthol 8 g, aspartame 5 g, borneol 2 g, 95% ethanol appropriate amount, colloidal silicon dioxide 15 g, magnesium stearate 10 g.

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