CN110582272A

CN110582272A - Granules containing Besifovir dipivoxil or a pharmaceutically acceptable salt thereof, pharmaceutical composition comprising the granules, and method for preparing the same

Info

Publication number: CN110582272A
Application number: CN201880016228.6A
Authority: CN
Inventors: 李尚宁; 郑奎镐; 金泰光; 康在勋
Original assignee: IL Dong Pharmaceutical Co Ltd
Current assignee: IL Dong Pharmaceutical Co Ltd
Priority date: 2017-03-07
Filing date: 2018-03-06
Publication date: 2019-12-17
Also published as: KR101899773B1; KR20180102375A; PH12019501967A1; SG11201907826YA; TW201832759A; WO2018164458A1; MY195264A; TWI786092B

Abstract

The present invention relates to granules containing benciclovir dipivoxil or pharmaceutically acceptable salts thereof with improved bitterness screening and productivity, pharmaceutical compositions comprising the granules, and a method for preparing the same.

Description

Granules containing Besifovir dipivoxil or a pharmaceutically acceptable salt thereof, pharmaceutical composition comprising the granules, and method for preparing the same

Technical Field

The present invention relates to granules containing benciclovir dipivoxil or a pharmaceutically acceptable salt thereof, which have improved bitterness screening and productivity, pharmaceutical compositions comprising the granules, and a method for preparing the pharmaceutical compositions.

Background

Besifovir dipivoxil or a pharmaceutically acceptable salt thereof is an antiviral drug mainly indicated for chronic hepatitis B having a nucleotide sequence, and the chemical name of the Besifovir dipivoxil is 3- [ ({1- [ (2-amino-9H-purin-9-yl) methyl ] cyclopropyl } oxy) methyl ] -8, 8-dimethyl ] -3, 7-dioxo-2, 4, 6-trioxa-3 lambda 5-phosphanon-1-yl ] pivalate, and the structure of the maleate salt thereof is as follows.

The above drugs are metabolized in the body very rapidly, and the metabolite produced therefrom is a nucleotide phosphate analog of guanosine monophosphate. The above metabolites are phosphorylated into diphosphate or triphosphate to exhibit antiviral activity, and the maximum blood concentration is exhibited in about 1.7 hours.

Pharmaceutically acceptable Besifovir dipivoxil or a pharmaceutically acceptable salt thereof has a very strong bitter taste, and is poor in powder flowability, and thus, the tablet-making trouble frequently occurs due to the sticky nature during compression molding. In general, such obstacles are improved by a wet granulation method using water or a solvent, but benciclovir dipivoxil or a pharmaceutically acceptable salt thereof is difficult to improve by such a preparation method due to strong decomposition properties by water and a solvent.

Also, even when a method of increasing the particle density using a pharmaceutical additive or a wet granulation process of the main component using a relatively stable solvent is performed, the sticky physical properties are not completely improved due to exposure to the main component from the outside. In the improvement methods using various lubricants, even if the amount of the lubricant used is not less than the appropriate range, the improvement in physical properties cannot be confirmed. In addition, although a drug having a strong bitter taste is usually coated with an appropriate coating agent to try to block the bitter taste, in such a case, it is necessary to separately perform a study for securing the physical strength of the tablet in order to smoothly perform the process, and there is a problem that the cost increases due to an increase in the process.

Therefore, it is desirable to provide a composition for oral administration which can improve both the tableting trouble and the bitter taste of besiflower or a pharmaceutically acceptable salt thereof.

Disclosure of Invention

Technical problem

An object of the present invention is to provide a method, granules or composition for improving the difficulty in production due to stickiness upon compression molding of besiflower or a pharmaceutically acceptable salt thereof and for increasing the convenience of administration by blocking the bitterness.

Technical solution

One embodiment of the present invention relates to a granule containing besiflower or a pharmaceutically acceptable salt thereof coated with a lipid excipient, wherein the granule has a masked bitter taste.

Another embodiment of the present invention relates to a method for preparing granules containing besiflower ester or its pharmaceutically acceptable salt with masked bitter taste, which comprises the following steps: heating a lipid excipient to a temperature not lower than the melting point of the lipid excipient to melt the lipid excipient; mixing the above melt with solid state Besifovir dipivoxil or pharmaceutically acceptable salt thereof; and cooling the mixture.

In another embodiment, the present invention relates to a pharmaceutical composition comprising granules having a bitter taste masked effect, which are besiflower ester or a pharmaceutically acceptable salt thereof coated with a lipid excipient, and a pharmaceutically acceptable additive.

Another embodiment of the present invention relates to a method for preparing a pharmaceutical preparation, comprising the steps of: mixing granules which contain benciclovir dipivoxil coated by lipid excipient or bitter taste of pharmaceutically acceptable salt thereof and are shielded with pharmaceutically acceptable additives; and making the above mixture into oral preparation.

Advantageous effects

The granules or pharmaceutical compositions containing Bexifuwei ester or a pharmaceutically acceptable salt thereof according to an embodiment of the present invention can improve the sticky property peculiar to the above-mentioned drugs to increase the productivity and effectively block the bitter taste, thereby improving the administration compliance.

The preparation method of one embodiment of the present invention has the following effects: improves the ingot-making obstacle caused by the sticky property when compression molding is carried out, and can realize continuous compression molding.

the preparation method according to an embodiment of the present invention does not use moisture or a solvent during the preparation process, and thus can prevent the decomposition of the drug to improve the stability.

Drawings

fig. 1 is a photograph taken at 100 x magnification of a bitter taste masked particle prepared in example 1 of the present invention.

Fig. 2 is a photograph taken at 100 x magnification of a bitter taste masked particle prepared in example 2 of the present invention.

Fig. 3 is a photograph taken at 100 x magnification of a bitter taste masked particle prepared in example 3 of the present invention.

Fig. 4 is a photograph taken at 100 x magnification of a bitter taste masked particle prepared in example 4 of the present invention.

Fig. 5 is a photograph taken at 100 x magnification of a bitter taste masked particle prepared in example 5 of the present invention.

Fig. 6 is a photograph taken at 100 x magnification of the particles of comparative example 1 of the present invention.

Fig. 7 is a photograph taken at 100 times magnification of the particles of comparative example 2 of the present invention.

Fig. 8 is a photograph taken at a magnification of 100 times of the particles of comparative example 3 of the present invention.

Fig. 9 is a photograph taken at a magnification of 100 times of the particles of comparative example 4 of the present invention.

Detailed Description

In one embodiment of the present invention, there is provided granules which contain besiflower ester or a pharmaceutically acceptable salt thereof coated with a lipid excipient and have a masked bitter taste. The flowability or flowability of the above particles can be improved.

The above particles can be prepared by: heating a lipid excipient to a temperature not lower than the melting point of the lipid excipient to melt the lipid excipient, mixing the molten product with solid Bevacizumab or a pharmaceutically acceptable salt thereof, and cooling the mixture.

Examples of the pharmaceutically acceptable salt of besiflower ester include maleate, hydrochloride, sulfate, phosphate, methanesulfonate, methanesulfonic acid, p-toluenesulfonic acid, fumaric acid, tartaric acid, citric acid, and the like, and the pharmaceutically acceptable salt is preferably maleate.

The above particles may have a size of 1 μm to 2000 μm, specifically, a size of d (0.9) is 50 μm to 1500 μm, more specifically, a size of d (0.9) is in a range of 100 μm to 1200 μm.

The granules are coated with a lipid excipient in a specific weight ratio, whereby bitterness can be blocked and flowability or flowability during compression molding can be improved, and the granules can be effectively used for preparing a formulation comprising besiflower or a pharmaceutically acceptable salt thereof.

As the lipid excipient, a lipid excipient having a melting point of 40 to 90 ℃ can be used, and examples thereof include waxes, fatty acids, fatty acid esters, and fatty acid alcohols. Preferred examples thereof include fatty acid esters such as glycerol distearate (glycerol distearate), glycerol stearate (glycerol stearate), glycerol oleate (glycerol oleate), glycerol myristate (glycerol myristate), cetyl palmitate (cetyl palmitate), cetyl decanoate (cetyl palmitate), stearyl palmitate (stearyl stearate), and glyceryl stearate (glyceryl stearate), and more preferred examples thereof include glycerol distearate (glycerol distearate).

The lipid excipient may be melted by heating to a temperature not lower than the melting point of the lipid excipient, i.e., in the range of from more than 40 ℃ to more than 90 ℃, for example, from 45 ℃ to 100 ℃. Thereafter, the melt may be mixed with the solid state of besiflower ester or a pharmaceutically acceptable salt thereof to disperse the solid state of besiflower ester or a pharmaceutically acceptable salt thereof in the melt. In this case, the lipid excipient may be in a range of 10 to 70 parts by weight, for example, 10 to 60 parts by weight or 10 to 50 parts by weight, based on 100 parts by weight of the besiflower or the pharmaceutically acceptable salt thereof. Within the above range, the bitterness of the besiflower ester or a pharmaceutically acceptable salt thereof can be effectively blocked, and the flowability or fluidity during compression molding can be improved and the sticky feeling during pastillation can be improved.

Thereafter, the temperature of the above mixture or dispersion may be cooled to 40 ℃ or less, specifically, to a range of 10 ℃ to 40 ℃, more specifically, to a range of 20 ℃ to 30 ℃. Upon cooling, the lipid excipient coagulates on the surface of the particles of Besifovir dipivoxil or a pharmaceutically acceptable salt thereof, thereby producing granules coated with the lipid excipient on the surface.

Optionally, the prepared granules are passed through a sieve of a specific size to adjust the particle size. For example, the prepared granules described above may be crushed or passed through a sieve having a size of 1.18mm or less (USP sieve No. 16).

In the present application, the expression 'bitterness masked' means that when a formulation containing besiflower ester or a pharmaceutically acceptable salt thereof is put into the mouth without taking water or a beverage, the bitterness inherent to the besiflower ester or the pharmaceutically acceptable salt thereof is not perceived within a period of 10 seconds.

In the present application, the expression 'coating' may mean that the lipid-based excipient is at least locally present on the solid surface of the besiflower ester or a pharmaceutically acceptable salt thereof. In the present application, coating may be referred to as "melt coating". Melt coating means coating by heating the lipid-based excipient to a temperature above its melting point to melt.

in one example, the coating of the besiflower ester or the pharmaceutically acceptable salt thereof is such that the needle-like site of the besiflower ester or the pharmaceutically acceptable salt thereof itself is at least partially covered with the lipid-based excipient.

In the present application, the expression 'sticky feeling or nature' refers to the physical properties of a tablet having a non-smooth surface, which is prepared by attaching particles to the upper surface or the lower surface of a punch in continuous production using a pastillator for 10 minutes or more.

In another embodiment, the present invention relates to a pharmaceutical composition comprising a granule containing besiflower ester or a pharmaceutically acceptable salt thereof coated with a lipid excipient, wherein the granule has a masked bitter taste; and pharmaceutically acceptable additives.

The above particles can be used for the particles described in the above embodiments. In the pharmaceutical composition, the above particles can be included in a range of 20 to 70 wt%, specifically 30 to 60 wt%.

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

Examples of the excipient include, but are not limited to, shellac, microcrystalline cellulose, pregelatinized starch, lactose, white sugar, mannitol, sorbitol, glucose, calcium hydrogen phosphate, methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, cellulose derivatives of sodium carboxymethyl cellulose, and starches. In the present invention, the above excipient may be included in an amount of 5 to 60% by weight, based on the total weight of the pharmaceutical composition.

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

examples of the disintegrant include, but are not limited to, pharmaceutically acceptable croscarmellose sodium including low-substituted hydroxypropylcellulose, crospovidone, sodium starch glycolate, and calcium carboxymethylcellulose. The above-mentioned disintegrant can 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, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, methyl cellulose, and carboxymethyl cellulose. The above-mentioned binder can 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, pharmaceutically acceptable alkali metal salts including hydrogenated oils, amine salts, colloidal silica, silicates, talc, or the like. The above lubricant may be included in an amount of 0.2 to 10% by weight, based on the total weight of the pharmaceutical composition.

The above pharmaceutical composition is useful as a prophylactic or therapeutic agent for viral infection. Specifically, the therapeutic or prophylactic agent can be used for treating or preventing hepatitis B or HIV infection. The effective dose of the besiflower or its pharmaceutically acceptable salt may vary depending on various factors such as sex, age, disease degree, nutritional status, etc. of the patient, and can be easily determined clinically by the practitioner.

The above-described granules and pharmaceutically acceptable additives can be used for the granules and pharmaceutically acceptable additives described in the above-described embodiments.

The mixing may be in the form of powder or granule, and the oral preparation may be in the form of lozenge, granule, dry syrup or suspension syrup. In particular, lozenges may be advantageous in terms of patient convenience and compliance. Thus, the above oral formulation may comprise tableting the above mixture to prepare a lozenge.

The present invention will be described more specifically with reference to the following examples, which are provided by way of illustration only and do not limit the scope of the present invention.

Example 1 to example 5: preparation of coated granules of besiflower maleate and glyceryl distearate

The following table 1 shows the mixing weight ratio of besiflower maleate to glyceryl distearate, and the following table was followed by melting glyceryl distearate in a high-speed mixer set at 80 ℃, adding besiflower maleate thereto, mixing, and cooling at room temperature. Thereafter, the granules of examples 1 to 5 were prepared by conditioning with a sieve of 1.18mm (USP sieve No. 16).

comparative examples 1 to 2: besifovir dipivoxil maleate or glyceryl distearate particles A powder comprising only Besifovir dipivoxil maleate particles was used as comparative example 1, and glyceryl distearate (Pecilol @) alone was used(product of Gattefosse, france)) as comparative example 2.

Comparative examples 3 and 4: preparation of granules of besiflower maleate and glyceryl distearate

The same procedures as in examples 1 to 5 were carried out to prepare granules of comparative examples 3 and 4, except that the mixing weight ratio of besiflower maleate to glyceryl distearate was adjusted differently from those of table 1 below.

[ Table 1]

Example 6 to example 10: preparation of lozenges comprising coated granules of besiflower maleate and glyceryl distearate

Tablets of examples 6 to 10 were prepared by mixing the granules prepared in examples 1 to 5 in the composition ratio shown in table 2 below, and compressing the mixture into round tablets using a rotary tablet machine (trade name: PKT-30, korean pharmaceutical science) to form tablets.

Comparative example 5 to comparative example 7: lozenge containing besiflower maleate or glyceryl distearate particles

Tablets of comparative examples 5 to 7 were prepared by mixing the granules of comparative example 1 or the granules of comparative examples 3 and 4 at the composition ratios shown in table 2, and compressing the mixture into round tablets using a rotary tablet machine (trade name: PKT-30, korean pharmaceutical science) to form tablets.

[ Table 2]

Unit: by weight%

Experimental example 1

The pellets or particles of examples 1 to 5 and comparative examples 1 to 4 were observed under a microscope (trade name: Eclipse te2000-u, Nikon) to show changes in the shape of the pellets in FIGS. 1 to 9, respectively.

It was confirmed that the surface of the crystalline particles was gradually coated as the mixing weight ratio of glyceryl distearate based on the particles of comparative example 1 was increased.

In particular, the change in appearance was clearly observed in example 1 in which the weight ratio was 10, whereby the coating of the surface of the crystalline besiflower maleate particles was observed by naked eyes when the ratio of the parts by weight of glyceryl distearate was 10 or more based on 100 parts by weight of besiflower maleate.

The granules of comparative examples 3 and 4 were based on 100 parts by weight of besiflower maleate and 2 or 5 parts by weight of glyceryl distearate, and it was confirmed that the coating was extremely locally achieved due to the needle-like structure as compared with the granules of comparative example 1.

Experimental example 2

Tablets were continuously produced for 10 minutes or more by compression molding a mixture of the compositions of examples 6 to 10 and comparative examples 5 to 7 (see table 2 above) using a rotary tablet machine (trade name: PKT-30, korean pharmaceutical science and technology). In the continuous production, when an abnormality was found in the surface of the produced tablet, the tablet machine was stopped, and whether or not the pellets were adhered to the upper and lower surfaces of the punch was confirmed, and the results are shown in table 3 below.

[ Table 3]

It was confirmed that the compositions of examples 6 to 10 had improved very sticky properties of the granules in the compression molding process and became efficient for continuous production of tablets. From the above results, the following can be confirmed: continuous production of troches can be efficiently achieved as the weight part of glyceryl distearate is increased to 10 or more based on 100 parts by weight of besiflower maleate.

Experimental example 3

The troches of examples 6 to 10 above and the troches of comparative examples 5 to 7 above were evaluated for the degree of bitterness blocking.

Bitterness was evaluated as follows: when 1 tablet containing 183mg of besiflower maleate was placed in the mouth without separately taking water or a beverage, the tablet was evaluated as + if no bitterness was perceived within 10 seconds, as + +, if bitterness was perceived within a range of more than 5 seconds and 10 seconds or less, and as + + +, if bitterness was perceived within 5 seconds, as a subject for healthy adult volunteers. The results are summarized in Table 4 below.

[ Table 4]

From the results of table 4 above, it was confirmed that the troches of examples 6 to 10 had blocked the bitter taste of besiflower maleate. Accordingly, it is found that the bitterness of besiflower maleate is remarkably improved by increasing the weight of glyceryl distearate to 10 or more based on 100 parts by weight of besiflower maleate.

Claims

1. A granule containing Besifovir dipivoxil or a pharmaceutically acceptable salt thereof, wherein the Besifovir dipivoxil or the pharmaceutically acceptable salt thereof is coated with a lipid excipient and has a bitter taste-masking effect.

2. The granule containing benciclovir dipivoxil or a pharmaceutically acceptable salt thereof according to claim 1, wherein 10 to 70 parts by weight of the lipid-based excipient is used based on 100 parts by weight of the benciclovir dipivoxil or the pharmaceutically acceptable salt thereof.

3. the granules containing Besifovir dipivoxil or a pharmaceutically acceptable salt thereof according to claim 1, wherein the lipid-based excipient is a wax, a fatty acid ester, or a fatty acid alcohol having a melting point of 40 ℃ to 90 ℃.

4. The granule containing besiflower ester or its pharmaceutically acceptable salt according to claim 3, wherein said lipid excipient is one or more fatty acid esters selected from glyceryl distearate (glycerol distearate), glyceryl stearate (glycerol stearate), glyceryl oleate (glycerol oleate), glyceryl myristate (glycerol myristate), cetyl palmitate (cetyl palmitate), cetyl decanoate (cetyl caprate), stearyl palmitate (stearyl palmitate) and stearyl stearate (stearyl stearate).

5. The granule containing benciclovir dipivoxil or a pharmaceutically acceptable salt thereof according to claim 1, wherein the bitterness-masking effect is such that the bitterness inherent in the preparation containing benciclovir dipivoxil or a salt thereof is not felt within a period of 10 seconds after the preparation is put into the mouth without taking water or a beverage.

6. A process for preparing granules containing Besifovir dipivoxil or a pharmaceutically acceptable salt thereof, having a bitter taste masking effect, comprising:

Melting a lipid-based excipient by heating above its melting point to form a melt;

Mixing the melt with the Bevacizumab in solid form, or a pharmaceutically acceptable salt thereof, to form a mixture; and

The mixture is cooled down and the mixture is cooled down,

Wherein the Besifovir dipivoxil or the pharmaceutically acceptable salt thereof is coated with the lipid excipient.

7. The method for producing granules containing besiflower ester or a pharmaceutically acceptable salt thereof according to claim 6, wherein said lipid excipient is a wax, a fatty acid ester or a fatty acid alcohol having a melting point in the range of 40 ℃ to 90 ℃.

8. The process for preparing granules containing besiflower ester or its pharmaceutically acceptable salt according to claim 6, wherein cooling is to a temperature in the range of 10 ℃ to 40 ℃.

9. The method of claim 6 further comprising the step of sieving the cooled mixture.

10. A pharmaceutical composition comprising the granules containing besiflower ester or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 and a pharmaceutically acceptable additive.

11. The pharmaceutical composition of claim 10, wherein the content of the granules containing besiflower ester or a pharmaceutically acceptable salt thereof is 20 to 70% by weight based on the weight of the pharmaceutical composition.

12. The pharmaceutical composition of claim 10, which is a tablet prepared by directly tableting a mixture of granules of besiflower maleate coated with a lipid excipient and the pharmaceutically acceptable additive, and has a bitter taste-masking effect.

13. A method of preparing a pharmaceutical formulation comprising:

Mixing granules containing besiflower ester or its pharmaceutically acceptable salt coated with lipid excipient with pharmaceutically acceptable additives to form mixture, wherein bitter taste of the granules is shielded; and

The mixture is formulated orally.

14. A method of preparing a pharmaceutical formulation according to claim 13, wherein the mixture is directly pastilled to prepare a lozenge.