CN104623684B

CN104623684B - Preparation method of engletin mannitol composition

Info

Publication number: CN104623684B
Application number: CN201510071399.7A
Authority: CN
Inventors: 彭俊清; 余慧; 曹宇; 陈浩; 胡功允
Original assignee: Zhejiang Huahai Pharmaceutical Co Ltd
Current assignee: Zhejiang Huahai Pharmaceutical Co Ltd
Priority date: 2015-02-11
Filing date: 2015-02-11
Publication date: 2020-12-25
Anticipated expiration: 2035-02-11
Also published as: CN104623684A

Abstract

The invention provides a preparation method of an engelet mannitol composition, which is characterized in that the engelet and mannitol are mixed, then hot-melt granulated, and then mixed with other pharmaceutically acceptable carriers to prepare an oral solid preparation. The Engelliflozin mannitol composition prepared by the method has stable and controllable quality and quick dissolution.

Description

Preparation method of engletin mannitol composition

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to a preparation method of an empagliflozin mannitol composition and an oral solid preparation of empagliflozin obtained by the method.

Background

Type II diabetes becomes an increasingly prevalent disease, and its high frequency of complications (e.g., diabetic foot, blindness, renal failure, etc.) not only affect the quality of life of the patient, but also may lead to a shortened lifespan.

Empagliflozin (empagliflozin) is an oral inhibitor of sodium-glucose cotransporter-2 (SGLT-2). SGLT-2 is the transporter responsible for the reabsorption of glucose from glomerular filtrate into the systemic circulation, and by inhibiting SGLT-2, engagliflozin reduces renal reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion. The product can be used for

Glycemic control in adult patients with diabetes, developed by bliringer haghan and li, was approved by the european union 5 months 2014 and by the FDA in the united states 8 months 2014.

The chemical name of engagliflozin is: (1S) -1, 5-anhydro-1-C- [ 4-chloro-3- [ [4- [ [ (3S) -tetrahydro-3-furanyl ] oxy ] phenyl ] methyl ] phenyl ] -D-glucitol.

Engagliflozin is white to light yellow, a hygroscopic powder. Very slightly soluble in water, poorly soluble in methanol, slightly soluble in ethanol and acetonitrile, soluble in 50% acetonitrile in water, and practically insoluble in toluene. In view of the poor solubility of engagliflozin, it is often necessary to perform pulverization and micronization and then to manufacture solid oral preparations such as tablets or capsules to increase the solubility of the drug.

Patent CN102387783A discloses a method for preparing engagliflozin tablets, which achieves the effect of improving dissolution by controlling the particle size of an engagliflozin raw material, and particularly achieves good dissolution effect by achieving smaller particle size. The drug needs to be micronized when reaching the granularity, special mechanical crushing or airflow crushing equipment is needed, the production is complicated, and the production efficiency is reduced. In addition, during the micronization process of the medicine, the medicine is easy to float in the air, so that the contact area between a production worker and the medicine is greatly increased, special protective equipment is needed, otherwise, the worker is also unfavorable for the physical health of the worker, when the dust amount in the environment is increased to a certain degree, the explosion is easy to cause, and certain potential safety hazard is caused for the production.

Therefore, there is still a need to provide a method for improving solubility of empagliflozin, which avoids using jet milling equipment and is suitable for commercial production.

Disclosure of Invention

The invention provides a preparation method of an engelet mannitol composition, which is characterized in that the engelet and mannitol are subjected to hot melt granulation, the engelet mannitol composition is prepared by a hot melt extrusion technology, and after the engelet is treated, an inventor finds that a medicine has a better dissolution rate. The dissolution speed of the medicine is obviously faster than that of the medicine which is not treated by the process.

The engeletin needs to be heated and melted in the preparation method, so that the particle size of the fed engeletin is not limited too much, and the cost and the process requirement of raw material production are greatly reduced.

Mannitol is widely used in pharmaceutical formulations, mainly as a filler or diluent in tablets or capsules. It is easily soluble in water and has a melting point of 166-168 deg.C.

The invention provides a preparation method of an engelizin mannitol composition, which comprises the following steps:

a. mixing the engeletin and the mannitol to obtain a mixture;

b. heating the mixture to melt, stirring, and cooling to obtain the composition.

The specific operation is as follows:

mixing the engeletin and the mannitol, heating to melt the engeletin and the mannitol, mutually fusing the engeletin and the mannitol under the stirring condition, cooling to form a compound of the engeletin and the mannitol, selectively crushing to obtain a proper particle size according to requirements, and carrying out subsequent preparation process treatment. By adopting the process to treat the engeletin, the engeletin and the mannitol are mutually fused and dispersed, so that the specific surface area of the medicament is increased, and the mannitol has good solubility, so that the dissolution speed of the medicament can be accelerated.

The melting point of engagliflozin is 150 ℃. The melting point of mannitol is 166-168 deg.C. In the heating and melting process, a double-screw hot-melting extruder can be selected for preparation. In general, a temperature of 175 to 200 deg.C, preferably 175 to 190 deg.C, and more preferably 175 to 185 deg.C can be set.

The process is similar to a hot melt extrusion method for preparing solid dispersion, but is not completely equivalent, mainly is a high molecular carrier material used for preparing general solid dispersion, and generally has certain viscosity, such as copovidone with the tradenames of Kollidon VA64 and Plasdone S630, povidone PVP with different viscosity grades, hydroxypropyl cellulose HPC, hydroxypropyl methylcellulose HPMC and the like. In the preparation process of the melting method, the drug is melted, the polymer carrier material is formed into a molten glass state, and the drug and the polymer material are fused and cooled to form the solid dispersion.

In order to ensure that the drug and the carrier achieve a better fusion effect, the proportion of the polymer carrier material to the drug is more than 2 times, for the product, the drug specification is 25mg, so the polymer carrier material at least needs more than 50mg, the carrier usually has certain viscosity, and the high-content viscous material serves as an adhesive, so the preparation process treatment has certain difficulty. The addition of a large amount of disintegrant is mainly needed, which can cause the tablet to be easily affected with moisture to influence the stability, or ensure that the weight of the tablet is large, so as to control the high molecular carrier material in a certain small proportion and ensure the proper disintegration speed of the medicine.

The mannitol is used as a carrier material, is not a carrier material used in the common solid dispersion technology, is usually used as a filler, has no viscosity and no disintegration, is easy to dissolve in water, and has properties greatly different from high polymer materials, and the properties determine that the mannitol is more suitable for subsequent preparation process treatment without controlling larger tablet weight or adding more disintegrants in a prescription.

The solid block is formed after the empagliflozin and the mannitol are subjected to hot melt extrusion and then cooled, and is crushed by a mechanical crushing or grinding means, the proportion of 80% of the crushed material is controlled to be 40-100 meshes generally, the particle size range is used in the conventional preparation process, and the empagliflozin and the mannitol can be easily prepared by common crushing equipment.

The invention screens the ratio of empagliflozin to mannitol. It was found that as the mannitol ratio increases, the dissolution rate of the empagliflozin in the resulting composition increases. This is probably because the ratio of mannitol is increased, the dispersion degree of the empagliflozin in the formed empagliflozin mannitol compound is improved, and mannitol is an auxiliary material with better water solubility, so the dissolution speed of the medicine in the compound is improved.

Thus, according to the invention, the weight ratio of empagliflozin to mannitol is from 1:4 to 1:10, preferably from 1:6 to 1: 8. The composition is prepared according to the proportion, and then is conveniently prepared into tablets or capsules with proper weight.

Because the preparation method provided by the invention melts the medicine, the particle size of the fed empagliflozin is not strictly required, the preparation process is relatively simple, mechanical crushing or airflow crushing of the empagliflozin is not needed, and the cost and the production time are saved.

After the Empagliflozin mannitol composition is obtained, the Empagliflozin mannitol composition can be further mixed with auxiliary materials to prepare tablets or capsules and the like. Optional adjuvants include fillers, binders, disintegrants, lubricants, etc. Other active ingredients can also be optionally added to form a compound preparation.

Fillers suitable for the solid formulations of the present invention include, but are not limited to: mannitol, lactose, microcrystalline cellulose, starch, corn starch, partially pregelatinized starch, sucrose, lactose, glucose, dextrin, calcium hydrogen phosphate, calcium dihydrogen phosphate, maltitol, and the like.

Binders suitable for the solid formulations of the present invention include, but are not limited to: povidone, copovidone, hypromellose, hyprolose, etc.

Disintegrants suitable for the solid formulations of the invention include, but are not limited to: croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and the like.

Lubricants suitable for the solid formulations of the present invention include, but are not limited to: magnesium stearate, sodium stearyl fumarate, and the like.

The tablets of the invention may optionally be film coated. The coating film usually has a weight gain of 2% to 5%, and consists of: film-forming agent, plasticizer and pigment. The coating may also be carried out using commercially available coating powders.

The Engelliflozin mannitol compound prepared by the invention can obtain proper particle size by a crushing or grinding process, so that the direct tabletting process can be adopted for producing tablets, or the Engelliflozin mannitol compound is directly mixed with medicinal additives and then filled into capsules.

In addition, the preparation method can also adopt a wet granulation process for production, the engelizin mannitol composition is mixed with other auxiliary materials, ethanol, water or other wetting agents are added for granulation, drying is carried out, the lubricant or other auxiliary materials are added for mixing after screening, and the mixed materials are subjected to preparation of tablets or capsules.

In addition, the process can also be produced by adopting a dry granulation process, the engelizin mannitol composition is mixed with other auxiliary materials, the ribbon is prepared by adopting a rolling method, the ribbon is crushed and screened, then the lubricant or other auxiliary materials are added and mixed, and the mixed material is prepared into tablets or capsules.

The materials can be proportioned by the following formula.

The Engelliflozin composition provided by the invention has stable quality, the further prepared tablets and capsules have good in-vitro dissolution performance, and the prepared composition has a simple and clean method and is suitable for industrial production.

Detailed Description

The present invention will be described in further detail with reference to examples, but the present invention is not limited to the examples. To demonstrate the advantages of this technique, the engeletin charged in examples 1-4 was the starting material of comparative example 2, with a particle size of D90=149 μm. The particle diameter D90 means "the particle diameter corresponding to 90% of the total on the cumulative percentage curve" and is generally measured by laser diffraction.

Comparative example 1: the empagliflozin bulk drug is obtained after jet milling, and the particle size of the empagliflozin bulk drug is D90=24 μm.

Comparative example 2: the particle size of the raw material drug of the empagliflozin is D90=149 μm.

Example 1

Preparation of engelizin mannitol composition:

weighing 10g of empagliflozin and 40g of mannitol, mixing, adding into a hot-melt extruder, setting the temperature to 175 ℃, extruding, taking out, cooling, crushing by using a mechanical crusher, and sieving the crushed material by using a 40-mesh sieve.

Example 2

Preparation of engelizin mannitol composition:

weighing 10g of empagliflozin and 60g of mannitol, mixing, adding into a hot-melt extruder, setting the temperature at 185 ℃, taking out, cooling, crushing by using a mechanical crusher, and sieving the crushed material by using a 40-mesh sieve.

Example 3

Preparation of engelizin mannitol composition:

weighing 10g of empagliflozin and 80g of mannitol, mixing, adding into a hot-melt extruder, setting the temperature at 200 ℃, extruding, taking out, cooling, crushing by using a mechanical crusher, and sieving the crushed material by using a 40-mesh sieve.

Example 4

Preparation of engelizin mannitol composition:

weighing 10g of empagliflozin and 100g of mannitol, mixing, adding into a hot-melt extruder, setting the temperature at 200 ℃, extruding, taking out, cooling, crushing by using a mechanical crusher, and sieving the crushed material by using a 40-mesh sieve.

Dissolution results: the composition prepared in examples 1 to 4 corresponding to 25mg of the engelizin and 25mg of the engelizin bulk drug in comparative examples 1 and 2 are subjected to dissolution curve measurement in 900ml of a pH1.0 medium under the condition of 50rpm by a paddle method, and the dissolution results (unit%) are as follows:

from examples 1-4 and comparative examples 1-2, it can be seen that the dissolution rate of the drug is significantly increased after the treatment. The dissolution rate was equivalent to or faster than that of the drug (drug after jet milling) in comparative example 1.

Example 5

The preparation of the engelizin tablet comprises the following steps:

the method comprises the steps of using the engelazin mannitol composition prepared in example 1 in the prescription 1, using the engelazin mannitol composition prepared in example 2 in the prescription 2, using the engelazin mannitol composition prepared in example 3 in the prescription 3, using the engelazin mannitol composition prepared in example 4 in the prescription 4, using the engelazin in the prescription 5 with the particle size of D90=24 μm and using the engelazin in the prescription 6 with the particle size of D90=149 μm, and mixing the materials and directly tabletting.

Dissolution test of solid preparation:

taking the prescription 1-6 samples, and carrying out dissolution curve measurement on the original grinding piece of the Engelliflozin in 900ml of medium with the pH value of 1.0 by adopting a paddle method at 50rpm, wherein the results are as follows:

from the above table it can be seen that: the dissolution effects of formulas 1 to 4 containing the composition of engelan mannitol with D90=149 μm were better than those of the original engelan tablet and the coarse particle size formula 6 without the composition of engelan mannitol.

Claims

1. A preparation method of an empagliflozin mannitol composition is characterized in that: comprises the following steps:

a. mixing the engeletin and the mannitol to obtain a mixture;

b. heating the mixture to melt, stirring and cooling to obtain the Engelliflozin mannitol composition; the heating temperature is 175-200 ℃; the weight ratio of the empagliflozin to the mannitol is 1:4 to 1: 10.

2. the method of preparing the engletin mannitol composition according to claim 1, characterized in that: the weight ratio of the empagliflozin to the mannitol is 1:6 to 1: 8.

3. the method of preparing the engletin mannitol composition according to claim 1, characterized in that: and b, heating and melting by using a hot-melt extruder.

4. The method of preparing the engletin mannitol composition according to claim 1, characterized in that: the heating temperature is 175-190 ℃.

5. An oral solid preparation of engagliflozin, which is characterized in that: composition comprising the engelizin mannitol obtained according to the preparation process of one of claims 1 to 4.

6. The oral solid preparation according to claim 5, wherein: the solid preparation also contains one or more of filler, binder, disintegrant and lubricant.

7. The oral solid preparation according to claim 6, wherein: the filler is selected from one or more of the following: mannitol, lactose, microcrystalline cellulose, starch, partially pregelatinized starch, sucrose, glucose, dextrin, calcium hydrogen phosphate, calcium dihydrogen phosphate, and maltitol.

8. The oral solid preparation according to claim 6, wherein: the binder is selected from povidone, copovidone, hypromellose and hyprolose.

9. The oral solid preparation according to claim 6, wherein: the disintegrant is selected from croscarmellose sodium, crospovidone, sodium carboxymethyl starch and low substituted hydroxypropyl cellulose.

10. The oral solid preparation according to claim 6, wherein: the lubricant is selected from magnesium stearate and sodium stearyl fumarate.