KR101899773B1 - Granules comprising besifovir dipivoxil or pharmaceutical acceptable salts thereof, a pharmaceutical composition comprising the same and a method for preparing the same - Google Patents

Abstract

The present invention relates to vesifovir dipivoxil or its pharmaceutically acceptable salt-containing granules with improved gum-shielding and improved productivity, a pharmaceutical composition comprising said granules and a process for their preparation.

Description

[0001] The present invention relates to a pharmaceutical composition comprising bespovir dipivoxil or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the granules, and a process for preparing the same. same}

The present invention relates to vesifovir dipivoxil or its pharmaceutically acceptable salt-containing granules with improved gum-shielding and improved productivity, a pharmaceutical composition comprising said granules and a process for their preparation.

Bexifovir dipivoxil or its pharmaceutically acceptable salt is an antiviral drug whose main indications are nucleotide type chronic hepatitis B, and its chemical name is 3 - [({1 - [(2- 9-yl) methyl] cyclopropyl} oxy) methyl] -8,8-dimethyl-3,7-dioxo-2,4,6-trioxa-3? ^5- phosphonon-1-yl] pivalate And the structure of the maleate salt thereof is as follows.

This drug metabolizes very quickly in the body and the resulting metabolite is a phosphate nucleotide analogue of guanosine monophosphate. The metabolite is phosphorylated by phosphoric acid or triphosphate, exhibiting antiviral activity and exhibiting a maximum blood concentration of about 1.7 hours.

Bessypoviridipiperoxide or a pharmaceutically acceptable salt thereof is very strong in terms of pharmacology, has poor powder fluidity, and has a high stickiness during compression molding. In general, the wet granulation method using water or a solvent is used to improve such a disorder. However, since bissipovid epipycin or a pharmaceutically acceptable salt thereof is strongly decomposed by water and a solvent, There are many difficulties to improve using.

In addition, even if the density of the granules is increased by using a pharmaceutical additive or the wet granulation process of the main component is performed using a relatively stable solvent, the sticky physical properties are completely improved due to the main component exposed to the outside It was not. Improvement of the physical properties was not confirmed even in the improvement method using various various lubricants and even the usage amount exceeding the appropriate range. In this case, additional studies are required to secure the physical strength of the nail in order to proceed smoothly. In this case, it is necessary to further investigate the physical strength of the nail. And the cost increase due to the increase may occur.

Accordingly, there is a need to provide a composition for oral administration that can simultaneously improve the tableting sensation and brittleness of the bisphosphonidipiperide or a pharmaceutically acceptable salt thereof.

U.S. Patent No. 5,876,760 Korean Patent No. 10-1612197 International Patent Publication WO2005055986 U.S. Patent No. 5,728,403 International Patent Publication No. WO2011067667

It is an object of the present invention to provide a method, a granule or a composition capable of improving the difficulty in production due to stickiness during compression molding of bceifovir dipivicil or a pharmaceutically acceptable salt thereof and at the same time, To provide a composition.

One aspect of the present invention is directed to a granulate that is coated with a lipid-based excipient, wherein the granule is coated with vesifovir dipivoxil or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention relates to a pharmaceutical composition comprising a lipid-based excipient, wherein the lipid-based excipient is heated to a temperature above the melting point of the lipid-based excipient and melted, the melt is mixed with a solid bisphospholipidic acid or a pharmaceutically acceptable salt thereof, Or a pharmaceutically acceptable salt thereof. The present invention also relates to a process for the preparation of a bisphosphonate-blocked bisphosphonidipiperoxide or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention is a cosmetic composition comprising: a gummy-screened granule comprising betafovir dipivoxyl or a pharmaceutically acceptable salt thereof coated with a lipid-based excipient; And a pharmaceutical composition comprising a pharmaceutically acceptable additive.

Another aspect of the present invention is a method for the preparation of a pharmaceutical composition comprising mixing a gum-coated granule containing betafovir dipiperoxy or a pharmaceutically acceptable salt thereof coated with a lipid-based excipient, with a pharmaceutically acceptable additive, ≪ RTI ID = 0.0 > a < / RTI > pharmaceutical formulation.

The granule or pharmaceutical composition containing bisphovir dipivoxil or a pharmaceutically acceptable salt thereof according to an embodiment of the present invention can improve productivity by improving the stickiness characteristic of the drug, Compliance can be improved.

The manufacturing method according to an aspect of the present invention has an effect that continuous compression molding can be performed due to improvement of the tableting trouble due to the property of stickiness during compression molding.

The manufacturing method according to an embodiment of the present invention can prevent the decomposition of the drug due to the absence of water or solvent during the manufacturing process, and thus the stability can be improved.

FIG. 1 is a photograph of a granule shielded granule prepared in Example 1 of the present invention, magnified 100 times. FIG.
Fig. 2 is a photograph of the granules shielded by gummy prepared in Example 2 of the present invention, magnified 100 times. Fig.
Fig. 3 is a photograph of the coated granules prepared in Example 3 of the present invention, magnified 100 times. Fig.
FIG. 4 is a photograph of a 100-fold magnified shielded granule prepared in Example 4 of the present invention. FIG.
FIG. 5 is a photograph of the coated granules prepared in Example 5 of the present invention, magnified 100 times. FIG.
6 is a photograph of particles of Comparative Example 1 of the present invention magnified 100 times.
Fig. 7 is a photograph of the particle of Comparative Example 2 of the present invention magnified 100 times. Fig.
Fig. 8 is a photograph of the granules of Comparative Example 3 of the present invention, magnified 100 times. Fig.
Fig. 9 is a photograph of the granules of Comparative Example 4 of the present invention magnified 100 times. Fig.

In one aspect of the present invention, it is possible to provide a granulate which contains vesicovir dipivoxil or a pharmaceutically acceptable salt thereof coated with a lipid-based excipient and which has been coated with an antiseptic. The granules can be improved in flowability or fluidity.

The granules may be prepared by heating and melting the lipidic excipient above the melting point of the lipidic excipient and mixing the melt with a solid bisphospholipidic acid or a pharmaceutically acceptable salt thereof and cooling the mixture . ≪ / RTI >

Examples of pharmaceutically acceptable salts of the bisphosphonates include phosgene, hydrochloride, sulfate, phosphate, mesylate, methanesulfonate, p-toluenesulfonate, fumarate, tartarate and citrate. Preferably, the pharmaceutically acceptable salt may be maleate.

The size of the granules may be in the range of 1 μm to 2000 μm, and more specifically, the size of d (0.9) may be in the range of 50 μm to 1500 μm, and more specifically, the size of d (0.9) may be in the range of 100 μm to 1200 μm.

The granules are coated with a lipid-based excipient at a specific weight ratio, so that the bittern is blocked, and the flowability and fluidity at the time of compression molding are improved, so that the granules are useful in the manufacture of pharmaceuticals containing bisopovir dipivoxil or a pharmaceutically acceptable salt thereof Lt; / RTI >

As the lipid-based excipient, a lipid-based excipient having a melting point of 40 ° C to 90 ° C may be used, and examples thereof include waxes, fatty acids, fatty acid esters and fatty acid alcohols. But is preferably selected from the group consisting of glycerol distearate, glyceryl stearate, glyceryl oleate, glyceryl myristate, cetyl palmitate, cetyl caprate, fatty acid esters such as cetyl caprate, stearyl palmitate and stearyl stearate, and more preferred examples include glycerol distearate.

It may be melted by heating to a temperature not lower than the melting point of the lipid-based excipient, that is, in the range of more than 40 ° C to more than 90 ° C, for example, 45 ° C to 100 ° C. Thereafter, the melt may be mixed with a solid bisphoviridipiperoxide or a pharmaceutically acceptable salt thereof to disperse the solid bisphosphate dipiperoxide or a pharmaceutically acceptable salt thereof in the melt. Wherein the lipidic excipient is present in an amount of from 10 parts by weight to 70 parts by weight, such as from 10 parts by weight to 60 parts by weight, or from 10 parts by weight to 50 parts by weight, based on 100 parts by weight of bissipoviridipiperoxide or a pharmaceutically acceptable salt thereof, Weight < / RTI > Within this range, it is possible to effectively block the blemishes of beseofovir dipivoxil or a pharmaceutically acceptable salt thereof, and to improve flowability and fluidity during compression molding, thereby improving stickiness during tableting.

Thereafter, the temperature of the mixture or the dispersion can be cooled to 40 ° C or less, specifically 10 ° C to 40 ° C, more specifically, 20 ° C to 30 ° C. Upon cooling, the lipid-based excipient may be agglomerated on the particle surface of the bissipovide dipiperoxide or a pharmaceutically acceptable salt thereof to produce a surface-coated granule with a lipid-based excipient.

Optionally, the granules can be passed through a sieve of a certain size to adjust the particle size. For example, the granules can be milled or sieved to a size of 1.18 mm (USP sieve No. 16) or less.

The expression " gummy-masked " in this application means that when the formulation containing the intrinsic sweetener of the bisphosphonate dipeptide or its pharmaceutically acceptable salt itself is placed in the mouth without any additional water or beverage, It does not feel like it.

The expression " coated " herein may mean that the lipidic excipient is at least partially present on the solid surface of the bissipovide dipiperoxide or a pharmaceutically acceptable salt thereof. The coating herein may be ' melt coating '. The molten coating refers to coating by dissolving the lipid-based excipient at a temperature higher than its melting point.

In one embodiment, the coating of the bisphovir dipyficylate or pharmaceutically acceptable salt thereof can be found to be at least partially obscured by lipid-based excipients, wherein the native bed portion of the bisphosphonidipiperide or a pharmaceutically acceptable salt thereof have.

As used herein, the term 'sticky or sticky property' refers to a property in which tablets having a smooth surface are produced by attaching granules to the upper or lower surface of a punch when continuous production is continued for 10 minutes or longer using a tablet machine.

Another aspect of the present invention is a cosmetic composition comprising: a gummy-screened granule comprising betafovir dipivoxyl or a pharmaceutically acceptable salt thereof coated with a lipid-based excipient; And a pharmaceutical composition comprising a pharmaceutically acceptable additive.

The granules may be granules as described in the above embodiments. The granules may be present in the pharmaceutical composition in the range of 20% to 70% by weight, specifically in the range of 30% to 60% by weight.

Such pharmaceutically acceptable additives include pharmaceutically acceptable excipients, disintegrants, binders, lubricants, and the like.

Examples of excipients include cellulose such as microcells, microcrystalline cellulose, starch, starch, lactose, saccharin, mannitol, sorbitol, glucose, calcium monohydrogen phosphate, methylcellulose, Derivatives thereof, and the like, but the present invention is not limited thereto. In the present invention, the excipient may be contained in an amount of 5% by weight to 60% by weight based on the total weight of the pharmaceutical composition.

In one example, the pregelatinized starch may be used in an amount of 5% to 15% by weight based on the total weight of the pharmaceutical composition. In one example, the microcrystalline cellulose may be used in an amount of 10% to 30% by weight based on the total weight of the pharmaceutical composition. In one example, the microcell can be used in an amount of 10% to 30% by weight, based on the total weight of the pharmaceutical composition.

Examples of disintegrants include, but are not limited to, low-substituted hydroxypropylcellulose and pharmaceutically acceptable croscarmellose sodium, crospovidone, sodium starch glycolate, carboxymethylcellulose calcium, and the like. The disintegrant may be included in an amount of 5% to 20% by weight based on the total weight of the pharmaceutical composition.

Examples of the binder include, but are not limited to, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, methylcellulose, carboxymethylcellulose, and the like. The binder may be included in an amount of 5% to 20% by weight based on the total weight of the pharmaceutical composition.

The lubricant may be, but is not limited to, hydrogenated oils, pharmaceutically acceptable alkali metal salts, amine salts, colloidal silicon dioxide, silicates, talc, and the like. The glidant may be included in an amount of 0.2 wt% to 10 wt% based on the total weight of the pharmaceutical composition.

The pharmaceutical composition may be useful as a preventive or therapeutic agent for viral infection. Specifically, it may be for the treatment or prevention of hepatitis B, or for the treatment or prevention of human immunodeficiency virus infection. The effective amount of the betafovir dipeptide or a pharmaceutically acceptable salt thereof may vary depending on various factors such as sex, age, degree of disease, nutritional status of the patient, and the like, and can be clinically easily determined by those skilled in the art.

Another aspect of the present invention is a method for the preparation of a pharmaceutical composition comprising mixing a gum-coated granule containing betafovir dipiperoxy or a pharmaceutically acceptable salt thereof coated with a lipid-based excipient, with a pharmaceutically acceptable additive, ≪ RTI ID = 0.0 > a < / RTI > pharmaceutical formulation.

The granules and the pharmaceutically acceptable additives may be granules and pharmaceutically acceptable additives as described in the above-mentioned embodiments.

The mixing may be performed in a powdery or granular state, and the oral preparation may include formulation into tablets, granules, dry syrup or suspension syrup. Specifically, tablets may be advantageous in terms of patient convenience and compliance. Such oral formulation may include preparing tablets by tableting the mixture.

Hereinafter, the present invention will be described in detail by way of examples, but the scope of the present invention is not intended to be limited to the following examples, but is presented by way of example.

Example  1 to 5: Besifovir Diptype With maleate  Glycerol Distearate  Manufacture of coated granules

The glycerol distearate was melted in a high speed mixer set at 80 DEG C according to the mixing ratio by weight of the bisphosphobiphenylmethyl maleate and glycerol distearate shown in Table 1 below and then bisphosphor dipic butyl malate was added to the mixture And then cooled at room temperature. Thereafter, the granules of Examples 1 to 5 were prepared by using a 1.18 mm (USP sieve No. 16) sieve.

Comparative Example  1 to 2: Besifovir Diptype Maleate  Or glycerol Distearate  particle

A powder containing only bisforbid diplymate maleate particles as Comparative Example 1 and a powder containing only glycerol distearate (Fresh Roll ATO5 ^® (manufactured by Gattefossse, France)) was used as Comparative Example 2.

Comparative Example  3 and 4: Besifovir Diptype With maleate  Glycerol Distearate  Manufacture of granules

In Examples 1 to 5, Comparative Example 3 and Comparative Example 3 were carried out in the same manner as in Examples 1 to 5 except that the mixing ratio by weight of bisphosphobiphenylmethyl malate and glycerol distearate was varied according to the ratio shown in Table 1 below. 4 < / RTI >

Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Bexifovir dipiviris
Maleate 100 100 100 100 100 100 0 100 100 Glycerol
Distearate 10 15 20 30 50 0 100 2 5

Example  6 to 10: Besifovir Diptype With maleate  Glycerol Distearate  Preparation of Tablets Containing Coated Granules

Each of the granules prepared in Examples 1 to 5 was mixed according to the composition ratios shown in Table 2 below. The mixture was compressed into a circular tablet using a rotary tablet machine (trade name: PKT-30, manufactured by Pharmatech Korea) To prepare tablets of Examples 6 to 10.

Comparative Example  5 to 7: Besifovir Diptype Maleate  Particles or granules containing glycerol distearate particles

The granules of Comparative Example 1 or the granules of Comparative Examples 3 and 4 were mixed at the composition ratios shown in Table 2 below, and the mixture was compressed with a circular tablet using a rotary tablet machine (trade name: PKT-30, manufactured by Pharmatech Korea) And tablets were molded into tablets of Comparative Examples 5 to 7, respectively.

Example 6 Example 7 Example 8 Example 9 Example 10 Comparative Example 5 Comparative Example 6 Comparative Example 7 Example 1 50.3 - - - - - - - Example 2 - 51.4 - - - - - - Example 3 - 52.5 - - - - - Example 4 - - - 54.5 - - - - Example 5 - - - - 58.0 - - - Comparative Example 1 - 47.9 - - Comparative Example 3 - - 48.4 - Comparative Example 4 - - - - - - 49.2 Pregelatinized starch 6.8 6.6 6.5 6.2 5.7 7.1 7.0 6.9 Microcrystalline cellulose 13.4 13.1 12.8 12.3 11.4 14.1 13.9 13.7 Microcell 100 20.0 19.6 19.1 18.3 16.9 21.0 20.8 20.5 Low-substituted hydroxy
Propyl cellulose 9.0 8.8 8.6 8.2 7.6 9.4 9.4 9.2 Hydrogenated oil 0.5 0.5 0.5 0.5 0.4 0.5 0.5 0.5 Sum 100 100 100 100 100 100 100 100

* Unit: Weight%

Experimental Example  One

The granules or particles of Examples 1 to 5 and Comparative Examples 1 to 4 were observed under a microscope (trade name: Eclipse te2000-u, Nikon), and the changes in particle appearance were shown in Figs. 1 to 9, respectively.

It can be confirmed that the surface of the crystalline particles is gradually coated as the weight ratio of glycerol distearate is increased on the basis of the particles of Comparative Example 1. [

Particularly, a change in apparent shape was observed from Example 1 in which the weight ratio was 10, and it was found that when the weight ratio of glycerol distearate was 10 or more based on the weight 100 of the bissipovide dipylacrylate, It can be visually observed that the surface of the diphenylmaleic acid salt particle is coated.

The granules of Comparative Examples 3 and 4 had a weight ratio of glycerol distearate of 2 or 5, based on 100 weight of bissipovide dipylacyl malate, compared to the particles of Comparative Example 1, And that this is done only partially.

Experimental Example  2

The mixture of the compositions of Examples 6 to 10 and the compositions of Comparative Examples 5 to 7 (see Table 2) was compression molded using a rotary tablet machine (trade name: PKT-30, manufactured by Pharmatech Korea) Respectively. When an abnormality was found on the production tablet surface during the continuous production, the tablet machine was stopped and it was confirmed whether or not the granules stick to the upper and lower surfaces of the punches. The results are shown in Table 3 below.

Example
6 Example
7 Example
8 Example
9 Example
10 Comparative Example
5 Comparative Example
6 Comparative Example
7 Improvement - - - - - +++ +++ ++ +++: Within 10 minutes of the start of the tablet, the surface is not smooth, granular stenosis occurs on the surface of the punch, and continuous production itself is difficult
++: Within 10 minutes of initiation of the tablet, some poor quality tablets with smooth surface are formed, granular stenosis occurs partially on the punch surface, and continuous production itself is difficult
≪ + >: Some poor refinement was observed after 10 minutes from the start of the punching, but there was no granular punching on the surface of the punch after completion of the punching
-: no poor refinement was observed even after 10 minutes of onset of punching, and there was no stenosis of granules on punch surface after punching

It can be confirmed that the compositions of Examples 6 to 10 are improved in the property that the granules become very sticky in the compression molding process, thereby enabling efficient production of tablets continuously. From the above results, it can be confirmed that the continuous production can be efficiently performed by purification as the weight ratio of glycerol distearate is increased to 10 or more based on 100 parts by weight of bissipovide dipipermyl malate.

Experimental Example  3

remind The tablets of Examples 6 to 10 and the tablets of Comparative Examples 5 to 7 were evaluated for their degree of blocking.

Regarding gummy, it is recommended that a tablet containing 183 mg of bissipovid dipylymic acid malate is placed in the mouth without any water or beverage in a healthy adult applicant. If the gummy is not felt after 10 seconds, ++, and +++ when feeling grit at 5 seconds or less and less than 10 seconds. The experimental results are summarized in Table 4 below.

Example
6 Example
7 Example
8 Example
9 Example
10 Comparative Example
5 Comparative Example
6 Comparative Example
7 Roughness degree + + + + + +++ +++ ++

From the results shown in Table 4, it can be confirmed that the tablets of Examples 6 to 10 were blocked with bissipofivir dipylyl malate. As a result, the weight of glycerol distearate is increased to 10 or more based on 100 parts by weight of bispovidipic acid malate, and thus it can be seen that the sweetness of bissipovide dipipermyl malate can be remarkably improved.

Claims (14)

The present invention relates to a granule which is coated with a lipid-based excipient and which contains betafovir dipivoxil or a pharmaceutically acceptable salt thereof,
The lipid-based excipient may be selected from the group consisting of glycerol distearate, glyceryl stearate, glyceryl oleate, glyceryl myristate, cetyl palmitate, Wherein the fatty acid ester is at least one selected from the group consisting of cetyl caprate, stearyl palmitate, and stearyl stearate. The coated granules of claim 1, wherein the lipid-based excipient is 10 parts by weight to 70 parts by weight based on 100 parts by weight of the bissipovide dipiperoxide or a pharmaceutically acceptable salt thereof. The coated granules of claim 1, wherein the lipid excipient has a melting point of from 40 캜 to 90 캜. The composition of claim 1, wherein the lipidic excipient is one or more of glycerol distearate, glyceryl stearate, glyceryl oleate, and glyceryl myristate. The selected granulate, which has been shielded. 3. The composition of claim 1, wherein the shampoo is not felt for a period of time after 10 seconds when the formulation containing the intrinsic sweetness of beseifovir dipivoxil or its salt itself is placed in the mouth without water or a drink, Gummy-coated granules. Coating with a lipid-based excipient, comprising heating and melting the lipidic excipient above its melting point, mixing the melt with bissipovir dipivoxil in solid form or a pharmaceutically acceptable salt thereof, and cooling the mixture, A process for the production of gummy-screened granules comprising the bissifovir dipivoxil or its pharmaceutically acceptable salt,
The lipid-based excipient may be selected from the group consisting of glycerol distearate, glyceryl stearate, glyceryl oleate, glyceryl myristate, cetyl palmitate, Wherein the fatty acid ester is at least one selected from the group consisting of cetyl caprate, stearyl palmitate, and stearyl stearate. 7. The process according to claim 6, wherein the lipid excipient has a melting point in the range of 40 캜 to 90 캜. 7. The method according to claim 6, wherein the cooling is cooling to a temperature in the range of 10 占 폚 to 40 占 폚. 7. The method of claim 6, further comprising sieving after cooling. 6. A pharmaceutical composition comprising an antiseptic-shielded granule according to any one of claims 1 to 5 and a pharmaceutically acceptable additive. 11. The pharmaceutical composition according to claim 10, wherein the bitter-screened granules are in the range of 20% to 70% by weight, based on the weight of the pharmaceutical composition. 11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is a tablet, which is a tablet prepared by directly kneading a mixture of an antiseptic granule of a bissipovide dipylacyl maleate coated with a lipid-based excipient and a pharmaceutically acceptable additive Gt; Coated corpuscles containing vesicovir dipivoxil or a pharmaceutically acceptable salt thereof coated with a lipid-based excipient are mixed with a pharmaceutically acceptable additive,
≪ / RTI > or a pharmaceutically acceptable salt thereof, and orally formulating said mixture. 14. The method of claim 13, wherein the formulation is prepared by direct tabletting of the mixture.

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