KR20150002014A - Pediatric granule formulation comprising valacyclovir - Google Patents

Abstract

The present invention relates to a pediatric granule formulation comprising valacyclovir. The pediatric granule formulation comprising the valacyclovir according to the present invention uses a sweetening agent and a fragrance ingredient, thereby shielding bitterness of valacyclovir and improving stability of valacyclovir. Therefore, the pediatric granule formulation can be useful for treating pediatric herpes simplex (HSV) type I and II, herpes zoster, varicella-zoster virus (VZV), and the likes.

Description

A pediatric granule formulation comprising valacyclovir,

The present invention relates to a granule formulation for children comprising valacyclovir, and more particularly to a granule formulation with a sweetener and a flavoring agent, which is shielded and has excellent stability.

(S) -2 - [(2-amino-6-oxo-6,9-dihydro-3H-purin-9-yl) methoxy] ethyl Amino-3-methylbutanoic acid) is an antiviral agent and is used as a therapeutic agent for herpes simplex virus (HSV) type I, type II, herpes zoster, and chicken pox (VZV).

≪ Formula 1 >

The most commonly used valacyclovir hydrochloride is hydrolyzed and converted into acyclovir, which is passed through the body at the time of administration into the body. The acyclovir is converted to monophophate form (thymidine kinase) by the virus thymidine kinase And then phosphorylated with acyclo-GTP in triphosphate form by intracellular kinase to inhibit DNA polymerase to inhibit DNA synthesis and viral replication.

The formulation containing valacyclovir is currently marketed as a tablet called Valtrex ( ^R ), but has a problem in that it is difficult to swallow due to the difficulty in swallowing because of the large amount of tablets used by children. In order to solve these problems, a granule including Chinese granule (75mg, granule as Balaci clover) has been developed, but it is disadvantageous in that it is strong enough to be taken by children.

Therefore, it is required to develop a formulation that can block the scent of valacyclovir to facilitate the taking of children and at the same time, exhibit excellent stability.

It is an object of the present invention to provide a formulation comprising valacyclovir which can shield the bittern of the valacyclovir and exhibit excellent stability at the same time.

In order to achieve the above object, the present invention provides a pharmaceutical composition comprising valacyclovir or a pharmaceutically acceptable salt thereof; Sweetener; And a flavoring agent.

The granule formulation for children according to the present invention can improve the stability of valaciclober as well as shield the sweetness of valaciclover by using sweeteners and flavoring agents and thus can be used for the treatment of herpes simplex virus (HSV) , Chicken pox (VZV), and the like.

FIG. 1 is a graph showing the increase (%) of the amount of the suppositories stored in the granular formulations of Comparative Examples 7 to 15 under the harsh conditions, initial, week, week, and four weeks.
Fig. 2 is a graph showing the increase (%) of the suppository in the granular formulations of Comparative Examples 7 to 15 at the initial stage, one month, three months and six months under the accelerated condition.
FIG. 3 is a graph showing the increase (%) of the suppository in the granular formulations of Comparative Examples 16 to 21 when stored for 1 week, 2 weeks, and 4 weeks under harsh conditions.
FIG. 4 is a graph showing the increase (%) of the suppository in the granular formulations of Examples 1 to 5 at the initial stage, one month, three months and six months under accelerated conditions.

The present invention relates to valacyclovir or a pharmaceutically acceptable salt thereof; Sweetener; And a flavoring agent.

Balaciclovir is an antiviral agent used as a therapeutic agent for herpes simplex virus (HSV) type I, type II, herpes zoster, varicella zoster virus (VZV) and the like. The most effective way to mask these stains is to coat the drug particles so that they are not disintegrated in the mouth and disintegrated by the digestive tract in the digestive tract. However, this method is disadvantageous in that it is difficult to adjust the disintegration rate and the absorption rate, to complicate the manufacturing process, and to increase the manufacturing cost. On the other hand, it is possible to consider the use of various excipients in order to shield the coriander, but the stability of the preparation is deteriorated depending on the kind and content of the excipients used.

The technical feature of the present invention is that a sweetener and a flavoring agent are used to remove the stickiness of valacyclovir and ensure stability.

Hereinafter, the components used in the present invention will be described in detail.

(1) valacyclovir or a pharmaceutically acceptable salt thereof

The valacyclovir or a pharmaceutically acceptable salt thereof used as the active ingredient in the granule formulation of the present invention may be contained in an amount of 5 to 60% by weight, preferably 10 to 30% by weight, based on the total amount of the formulation, But is not limited thereto. The pharmaceutically acceptable salt of valaciclovir may be in the form of a pharmaceutically acceptable salt to which an inorganic or organic acid has been added. Preferred examples of the salt include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, Examples of the acid addition salts include lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, Salicylic acid, methanesulfonic acid, benzenesulfonic acid, or toluenesulfonic acid.

(2) sweeteners

The sweetening agent, which is included as an essential ingredient in the granule formulation of the present invention, combines with the flavoring agent described below to shield the taste. The sweetener may be selected from the group consisting of acesulfame K, aspartame, steviol glycosides, thaumatin, sucralose, and mixtures thereof. In one embodiment of the invention, the sweetener may be selected from the group consisting of acesulfame K, thaumatin, sucralose, and mixtures thereof. In another embodiment of the present invention, the sweetener may be sucralose.

The sweetener may be used in an amount of 0.2 to 5 wt%, preferably 1 to 3 wt%, based on the total amount of the formulation. If the amount of the sweetener is at least 0.2% by weight, it is possible to effectively block the bittern of the active ingredient, valacyclover, and if the amount of the sweetener is less than 5% by weight, excellent stability of the product can be assured without remaining taste of the taste. .

(3) Flavoring agents

The flavoring agent, which is included as an essential ingredient in the granule formulation of the present invention, combines with the above-mentioned sweetening agent to enhance the gummy shielding effect and improve the stability of valacyclovir. The flavoring agent may be selected from the group consisting of strawberry, orange, grape, apple, iced sugar, peppermint, lemon, cherry, and mixtures thereof. The flavoring agent may be used in an amount of 0.1 to 5% by weight, preferably 0.5 to 3% by weight, based on the total amount of the formulation. The flavoring agent may be used in the form of a liquid or solid phase powder.

(4) Pharmaceutically acceptable additives

The valacyclovir granule formulation of the present invention may further comprise a pharmaceutically acceptable additive. Examples of the above-mentioned pharmaceutically acceptable additives include water-soluble diluents, binders and the like.

The water-soluble diluent that can be used in the present invention is a substance which imparts a disintegrating power of the granules and dilutes the concentration of the main ingredient, and which is capable of providing a sweetening effect, such as sucrose, saccharides such as lactose, glucose, maltose, xylose, mannitol, sorbitol, Xylitol, and the like, and mixtures thereof, but the present invention is not limited thereto. The water-soluble diluent may be used in an amount of 30 to 90% by weight, preferably 50 to 80% by weight, based on the total amount of the formulation.

Binders that can be used in the present invention have the function of forming granules through binding between the main ingredient and other excipients, and may include hydroxypropylmethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, methylcellulose or carboxymethylcellulose sodium, povidone, gelatin, But are not limited to, alginic acid, sodium alginate, starch and pregelatinized starch, and mixtures thereof. The binder may be used in an amount of 1 to 10% by weight, preferably 2 to 5% by weight, based on the total amount of the formulation.

The granule formulation according to the present invention can be prepared based on conventional processes. As one embodiment according to the present invention, the granulation process may comprise the following steps.

(a) blending valacyclovir with a sweetener, a flavoring agent and other pharmaceutically acceptable additives, wherein the pharmaceutically acceptable additive is selected from the group consisting of substances necessary for stability, processing or formation of a water-soluble diluent, binder or other unit dosage form / RTI > (b) adding a granulating solvent to the mixture obtained in the step (a), wherein the preferred granulating solvent includes a solvent which does not affect the stability of the product in water, ethanol, isopropyl alcohol and combinations thereof . Binding agents, buffers, etc. may also be added to the granulation solvent);

(c) drying the combined material obtained in the step (b) through fluid bed drying, air drying or oven drying (drying temperature is not limited to, for example, 40 or 60, drying time is 30 minutes to 2 Time); And

(d) sieving or pulverizing the material obtained in the step (c), wherein the pulverization can be carried out using a pit mill and an oscillator, and the sieving is carried out, for example, at 14 to 40 mesh, preferably 20 to 30 mesh Can be used.

Although the present invention has been described with respect to the granoclone granule formulation, it can be applied not only to granule formulations, but also to fine granules, syrups or suspension syrup formulations.

Hereinafter, the present invention will be described in detail with reference to Examples. However, the present invention is not limited to the Examples.

Comparative Examples 1 to 6: Preparation of Granule Formulation Using Sweetener Only

The granular formulations of Comparative Example 1 and Comparative Examples 2 to 6 using only the sweetener were prepared according to the composition of Table 1 below. Specifically, valacyclovir, an active ingredient, mannitol as a water-soluble diluent, and hydroxypropylcellulose as a binder were mixed, and 5 mg of each sweetener was added to the granules of Comparative Examples 2 to 6 except for Comparative Example 1, followed by addition of a solvent Granules were prepared. The granules thus prepared were dried, sieved in a sieve of 20 to 30 mesh, and then subdivided into single-dose portions.

Then, 50 adult men (20 to 50 years old) were allowed to take the granule formulation (420 mg) in the form of the granules described above, and then the granules of the valacyclovir granules were evaluated according to the following criteria.

1: I can not feel the bitterness.

2: It feels a little bitter, but does not make you feel uncomfortable.

3: Bitter taste.

4: The bitter taste is strong and it is difficult to take.

ingredient Comparative Example
One Comparative Example
2 Comparative Example
3 Comparative Example
4 Comparative Example
5 Comparative Example
6 Valacyclovir hydrochloride 75 75 75 75 75 75 Mannitol 320 320 320 320 320 320 Hydroxypropyl
cellulose 20 20 20 20 20 20 Steviol glycoside - 5 - - - - Aspartame - - 5 - - - Tom Martin - - - 5 - - Acesulfame potassium - - - - 5 - Sucralose - - - - - 5 Average rating 4 3.6 ± 0.18 3.8 ± 0.36 2.4 ± 0.41 3.1 ± 0.57 2.6 ± 0.50

As shown in Table 1, the granular formulations of Comparative Example 1 which did not contain sweeteners showed very bitter taste, but the granular formulations of Comparative Examples 2 to 6 containing sweeteners showed bitter taste weakness. However, in the case of a formulation using only sweeteners, the target of the present invention did not reach the target of an averaging of less than 2.0 points.

Comparative Example  7 to 15: Sweetener  Preparation of Granule Formulations with Different Dosages

The granular formulations of Comparative Examples 7 to 15 were prepared in the same manner as in the following Table 2 except that the dosage of the three kinds of sweeteners (sucralose, tartin and acesulfam potassium) , And the stain was evaluated as described above.

ingredient Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 10 Comparative Example 11 Comparative Example 12 Comparative Example 13 Comparative Example 14 Comparative Example 15 Valacyclovir hydrochloride 75 75 75 75 75 75 75 75 75 Mannitol 320 320 320 320 320 320 320 320 320 Hydroxypropylcellulose 20 20 20 20 20 20 20 20 20 Sucralose One 5 25 - - - - - - Tom Martin - - - One 5 25 - - - Acesulfame potassium - - - - - - One 5 25 Average rating 3.5 ± 0.27 2.6 ± 0.50 2.1 ± 0.37 3.4 ± 0.64 2.4 ± 0.41 1.8 ± 0.55 3.7 ± 0.21 3.1 ± 0.57 2.6 ± 0.44

As shown in the above Table 2, the use of sweeteners did not achieve the aim of the present invention.

In addition, if the amount of the sweetener used is increased, the bitter taste of the sweetener itself may appear and the stability of the product may also be a problem. Therefore, in the following test example, the amount of the produced substance of valacyclovir was measured.

Test Example 1: Determination of the amount of a substance produced in valacyclovir

Storage stability of the granular formulations prepared in Comparative Examples 7 to 15 was measured. The stability test was evaluated under severe (60 ° C) and accelerated conditions (40 ° C and 75% RH) with reference to the Balaci Clover term in the Chinese Pharmacopoeia (CP).

Specifically, the granular formulations were individually packed in an aluminum bag and stored under a severe condition of 60 DEG C and acceleration conditions of 40 DEG C and 75% RH. The asclover with the largest change in the degradation products of valaciclovir was determined by HPLC under the following conditions: 1 week, 2 weeks and 4 weeks in the severe condition, and 1 month, 3 months and 6 months in the acceleration condition.

- Detector: ultraviolet absorption spectrophotometer (measuring wavelength: 251 nm)

Column: column packed with octadecylsilylated silica gel

- Flow rate: 1.0 mL / min

- mobile phase: phosphoric acid buffer solution: methanol = 85: 15 (phosphoric acid buffer: solution of potassium dihydrogenphosphate at a concentration of 0.01 mol / L and adjusted to pH 3.0 with phosphoric acid)

The results are shown in Tables 3 and 4 and FIGS.

Increased asclover (severe condition: 60 ℃) Early(%) 1 week (%) 2 weeks(%) 4 weeks (%) Comparative Example 7 0.18 0.3 0.5 0.68 Comparative Example 8 0.2 0.4 0.61 0.75 Comparative Example 9 0.22 0.61 1.03 1.25 Comparative Example 10 0.2 0.51 1.02 1.31 Comparative Example 11 0.22 0.84 1.41 2.01 Comparative Example 12 0.23 1.01 1.78 3.52 Comparative Example 13 0.18 0.32 0.71 1.02 Comparative Example 14 0.19 0.45 0.81 1.51 Comparative Example 15 0.19 0.65 1.15 1.74

Increased amount of ascyler (Acceleration condition: 40 ℃ and 75% RH) Early 1 month 3 months 6 months Comparative Example 7 0.18 0.28 0.45 0.61 Comparative Example 8 0.2 0.34 0.56 0.65 Comparative Example 9 0.22 0.54 0.89 1.12 Comparative Example 10 0.2 0.45 0.9 1.51 Comparative Example 11 0.22 0.95 1.46 2.54 Comparative Example 12 0.23 1.21 1.95 3.86 Comparative Example 13 0.18 0.29 0.64 0.98 Comparative Example 14 0.19 0.46 0.83 1.54 Comparative Example 15 0.19 0.65 1.24 1.77

As shown in Tables 3 and 4 and FIGS. 1 and 2, as the amount of the sweetener used increases, the amount of the asclover, which is a representative softener of valacyclovir, is increased and the stability is not good.

Test Example 2: Measurement of the amount of valacyclovir suppository produced by using sucralose

Based on the results of Test Example 1, the sucralose having the best sweetening effect and the best stability as a sweetener was used, and granulometric formulations were prepared by varying the amount of sucralose, and the increment (%) of the ascroller with time was measured.

First, granule formulations were prepared by varying the sucralose content according to the composition shown in Table 5 below.

ingredient Comparative Example 16 Comparative Example 17 Comparative Example 18 Comparative Example 19 Comparative Example 20 Comparative Example 21 Valacyclovir hydrochloride 75 75 75 75 75 75 Mannitol 320 320 320 320 320 320 Hydroxypropylcellulose 20 20 20 20 20 20 Sucralose 0.5 One 5 15 25 35 Sweetener content (%) 0.1 0.2 One 3 5 7

 Then, the increase amounts of the asclover were measured under the accelerated conditions for the granular formulations of Comparative Examples 16 to 21. The measurement results are shown in Table 6 and FIG.

Early 1 month 3 months 6 months Comparative Example 16 0.12 0.20 0.39 0.52 Comparative Example 17 0.18 0.28 0.45 0.75 Comparative Example 18 0.20 0.34 0.68 0.92 Comparative Example 19 0.20 0.45 0.85 1.03 Comparative Example 20 0.22 0.61 1.03 1.25 Comparative Example 21 0.23 1.18 1.89 3.81

As shown in Table 6 and FIG. 3, it was confirmed that as the amount of sucralose used increased, the amount of asclever, a representative softener of valacyclovir, was increased. The above results show that it is difficult to secure the stability of the product only by using sucralose alone.

Example  1 to 5: Sweetener  And The flavoring agent  Preparation of used granule formulations

In order to improve the gummy shielding effect and stability, granules were prepared by adding various flavoring agents to the granular formulation of Comparative Example 8 according to the composition of the following Table 7, and the gelatin was evaluated as described above.

ingredient Example 1 Example 2 Example 3 Example 4 Example 5 Valacyclovir hydrochloride 75 75 75 75 75 Mannitol 320 320 320 320 320 Hydroxypropylcellulose 20 20 20 20 20 Sucralose 5 5 5 5 5 Park Hahn 5 - - - - Ice Sugar Flavor - 5 - - - Lemon incense - - 5 - - Cherry incense - - - 5 - Strawberry incense - - - - 5 Average rating 2.2 ± 0.51 1.6 ± 0.42 1.4 ± 0.32 1.6 ± 0.87 1.4 ± 0.67

As shown in Table 7, the formulation using the sweetener and the flavoring agent was superior to the formulation using the sweetener only in comparison with the comparative example. In the case of the present invention, It was confirmed that it could be reached.

Test Example  3: Sweetener  And The flavoring agent  Of the granular formulation used Balaci clover Flexible material  Production amount measurement

The increment of the asclover was measured under accelerated conditions on the granular formulations using the sweeteners and flavorings prepared in Examples 1 to 5 at the same time. The measurement results are shown in Table 8 and FIG.

Early 1 month 3 months 6 months Example 1 0.19 0.31 0.65 0.89 Example 2 0.19 0.33 0.66 0.91 Example 3 0.20 0.34 0.68 0.92 Example 4 0.20 0.33 0.61 0.88 Example 5 0.22 0.35 1.71 0.98

As shown in Table 8 and FIG. 4, the granule formulation using the sweetener and the flavoring agent at the same time showed significantly less asclover increase than the granule formulation using only the sweetener.

The above results show that the use of the sweetener and the flavoring agent simultaneously ensures not only shielding but also stability.

Claims (12)

Valaciclovir or a pharmaceutically acceptable salt thereof; Sweetener; And a flavoring agent.
The granule formulation of claim 1, wherein the valacyclovir or pharmaceutically acceptable salt thereof is present in an amount of 5 to 60% by weight based on the total amount of the formulation.
2. The granule formulation for children according to claim 1, wherein the sweetener is selected from the group consisting of sucralose, acesulfame potassium, aspartame, toastatin, steviol glycosides and mixtures thereof.
The granule formulation of claim 1, wherein the sweetener is present in an amount of 0.2 to 5% by weight based on the total weight of the granular formulation.
The granule formulation for children according to claim 1, wherein the flavoring agent is selected from the group consisting of strawberry flavor, orange flavor, grape flavor, apple flavor, mint flavor, lemon flavor, ice sugar flavor, cherry flavor and mixtures thereof.
The granule formulation for children according to claim 1, wherein the flavoring agent is present in an amount of 0.1 to 5% by weight, based on the total weight of the granular formulation.
The granule formulation of claim 1, wherein the granular formulation further comprises a pharmaceutically acceptable additive.
The granule formulation for children according to claim 7, wherein the pharmaceutically acceptable additive is a water-soluble diluent or binder.
The granule formulation for children according to claim 8, wherein the aqueous diluent is selected from the group consisting of sucrose, lactose, glucose, maltose, xylose, mannitol, sorbitol, xylitol and mixtures thereof.
The granule formulation of claim 8, wherein the aqueous diluent is present in an amount of 30 to 90% by weight based on the total weight of the granule formulation.
The composition according to claim 8, wherein the binding agent is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, microcrystalline cellulose, methylcellulose or carboxymethylcellulose sodium, povidone, gelatin, alginic acid, sodium alginate, starch, pregelatinized starch, ≪ RTI ID = 0.0 > 1, < / RTI >
The granule formulation for children according to claim 8, wherein the binder is present in an amount of 1 to 10% by weight based on the total amount of the granule formulation.

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