JP6638947B1 - Levocetirizine pharmaceutical composition with excellent storage stability - Google Patents

Abstract

An object of the present invention is to provide a levocetirizine pharmaceutical preparation having excellent storage stability. The present invention is characterized by containing levocetirizine or a pharmaceutically acceptable salt thereof and an inorganic phosphate anhydride. [Selection diagram] None

Description

  The present invention relates to a pharmaceutical preparation having excellent storage stability and containing levocetirizine or a pharmaceutically acceptable salt thereof as an active ingredient.

  Levocetirizine hydrochloride (chemical name: 2- [2- [4-[(R)-(4-chlorophenyl) phenylmethyl] piperazin-1-yl] ethoxy] acetic acid dihydrochloride) is a histamine H1 receptor antagonist It is useful for treating allergic diseases.

As a preparation containing levocetirizine hydrochloride, “Zysal tablet 5 mg” (Zyzar is a registered trademark) has been released (Non-patent Document 1).
Levocetirizine hydrochloride is known to be unstable to low molecular weight polyols and heat and humidity due to its chemical properties.
In view of this, formulations using lactose having good blending qualities among polyols (Patent Documents 1 to 4) and formulations containing a pH adjuster for stabilization even when a polyol is used have been developed (Patent Document 5). , 6).
However, even if lactose having good blending stability is used, it cannot be said that sufficient stability can be maintained, and a more stable formulation without packaging is desired in order to obtain a formulation that can be packaged.

Japanese Patent No. 4724367 Japanese Patent No. 5476785 Japanese Patent No. 5623447 JP 2018-184436 A JP 2006-526554 A JP-A-2006-094364

Interview form of Zaisal Tablets 5 mg, Zaisal Syrup 0.05% (Revised April 2018 (10th edition))

  An object of the present invention is to provide a levocetirizine pharmaceutical preparation having excellent storage stability.

The pharmaceutical composition according to the present invention contains levocetirizine or a pharmaceutically acceptable salt thereof and an inorganic phosphate anhydride.
Here, the inorganic phosphate anhydride may be any of anhydrous calcium hydrogen phosphate and anhydrous calcium dihydrogen phosphate.

The pharmaceutical composition according to the present invention may further contain crystalline cellulose.
Note that Patent Documents 1 and 2 disclose formulations containing microcrystalline cellulose, but do not combine them with inorganic phosphate anhydride.

The pharmaceutical composition according to the invention is substantially free of polyols having a molecular weight of less than 950 g / mol.
Here, “substantially not contained” means that the active ingredient in the present invention, levocetirizine or a pharmaceutically acceptable salt thereof may be contained within a range that does not affect the storage stability.
For example, when the pharmaceutical composition according to the present invention is used to form a film-coated tablet, if the uncoated tablet does not substantially contain a polyol having a molecular weight of less than 950 g / mol, the film substrate used for coating includes: A polyol may be included as a component.
Here, the term "substantially free of a polyol (solid polyol)" means that a polyol having a molecular weight of less than 300 is defined as a very reactive polyol in, for example, Patent Documents 1 and 2, If polyols having a molecular weight between 950 are defined as reactive polyols, unless the amount of these polyols exceeds a molar ratio to the active ingredient levocetirizine of 10, no unacceptable amounts of undesired reaction products are produced.
Desirably, as described in the statement that the molar ratio should not exceed 5, the present invention permits the inclusion of such an amount of the polyol.

  By adding an inorganic phosphate anhydride to levocetirizine or a pharmaceutically acceptable salt thereof, a pharmaceutical composition having excellent stability can be obtained.

The active ingredient of the pharmaceutical composition according to the present invention is levocetirizine or a pharmaceutically acceptable salt thereof, and has a chemical name of 2- [2- [4-[(R)-(4-chlorophenyl) phenylmethyl] piperazine- 1-yl] ethoxy] acetic acid or a pharmaceutically acceptable salt thereof.
The content in the pharmaceutical composition according to the present invention is not particularly limited, can be appropriately set depending on the purpose, and is preferably in the range of 0.50% by mass to 25.00% by mass.

The anhydrous inorganic phosphate contained in the pharmaceutical composition according to the present invention is preferably any of anhydrous calcium hydrogen phosphate and anhydrous calcium dihydrogen phosphate.
The content of the inorganic phosphate anhydride in the pharmaceutical composition according to the present invention is not particularly limited, can be appropriately set according to the purpose, and is preferably in the range of 30 to 90% by mass.

  The presence or absence and content of crystalline cellulose in the pharmaceutical composition of the present invention are not particularly limited and can be appropriately set according to the purpose.

  The solid polyol having a molecular weight of less than 950 g / mol is, for example, xylitol, mannitol, sorbitol, dextrose, sucralose, lactose (lactose), polyethylene glycol, polyvinyl alcohol, polyvinyl alcohol / polyethylene glycol graft copolymer, polyvinyl alcohol / acrylic acid -A methyl methacrylate copolymer is mentioned as an example.

Other components are not particularly limited as long as the effects of the present invention are not impaired, and additives that are generally used in the field of pharmaceutical preparations can be appropriately selected depending on the purpose.
For example, disintegrating agents, lubricants, flow agents, coating agents and the like can be mentioned.

As the disintegrant, for example, croscarmellose sodium, carmellose, carmellose calcium, low-substituted hydroxypropylcellulose, crospovidone, partially pregelatinized starch and the like can be used.
As the lubricant, for example, magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid and the like can be used.
As the fluidizing agent, for example, light anhydrous silicic acid, hydrous silicon dioxide, calcium silicate, magnesium metasilicate, and the like can be used.
As the coating agent, for example, hypromellose, hydroxypropylcellulose, titanium oxide, talc and the like can be used.

  The levocetirizine-containing pharmaceutical composition of the present invention is not particularly limited, and examples thereof include tablets such as ordinary tablets, orally disintegrating tablets, and chewable tablets. Among these, ordinary tablets, particularly film-coated tablets, are preferred.

  The shape, structure, and size of the tablet are not particularly limited, and can be appropriately selected depending on the purpose.

The method for producing the pharmaceutical composition according to the present invention is not particularly limited, and it can be produced by a known production method according to the dosage form.
For example, when the dosage form is a tablet, it can be produced by compression molding by a conventional method through the steps of mixing, granulating, sizing and the like, if necessary, of the components of the oral pharmaceutical composition.

  The tableting machine used for tableting is not particularly limited, and for example, a known tableting machine such as a rotary tableting machine or a single-shot tableting machine can be appropriately selected and used.

  Hereinafter, the present invention will be specifically described based on examples, but the present invention is not limited to these test examples.

Each additive of levocetirizine hydrochloride, anhydrous calcium hydrogen phosphate, crystalline cellulose, light anhydrous silicic acid, carmellose, and calcium stearate is mixed so that each tablet has a core tablet component ratio as shown in Table 1 so that the mass becomes 100 mg. Tableting was performed with a rotary tableting machine to obtain core tablets of Examples 1 to 4.
Next, hypromellose, hydroxypropylcellulose, titanium oxide, and talc were dissolved and dispersed in purified water so that the film coating component ratio per tablet was as shown in Table 1, to prepare a coating solution.
A coating solution was sprayed on the core tablets so that the film weight per tablet was 3 mg using a pan-type coating machine to obtain coated tablets.

In the same manner as in the Examples, each additive of levocetirizine hydrochloride, anhydrous calcium hydrogen phosphate, crystalline cellulose, lactose hydrate, light anhydrous silicic acid, carmellose, calcium stearate, or magnesium stearate is used as a core tablet in Table 1 per tablet. The components were mixed so as to have the component ratio, and the mixture was tableted with a rotary tableting machine so as to have a mass of 100 mg to obtain core tablets of Comparative Examples 1 to 3.
Next, hypromellose, hydroxypropylcellulose, titanium oxide, and talc are dissolved or dispersed in purified water or opadry (hypromellose, titanium oxide, macrogol 400) so that the film coating component ratio per tablet becomes the film coating component ratio shown in Table 1. ) Was dissolved and dispersed in purified water to prepare a coating solution, and the core tablet was sprayed with a coating solution using a pan-type coating machine so that the film weight per tablet was 3 mg, to obtain a coated tablet.

A stability test was performed on tablets containing 5 mg of levocetirizine hydrochloride (Example 1 and Comparative Example 1).
The stability test was performed as described below.

At the start, individual maximum analogous substance amount, total analogous substance amount of tablets obtained after storage for 2 weeks in AL pillow package (PTP + AL pillow) and unpackaged respectively under severe conditions of temperature and humidity (60 ° C./75% RH) Was measured.
The total amount of related substances is the sum of the amounts of a plurality of related substances measured and quantified by an automatic analysis method using high-performance liquid chromatography.The numerical value of the amount of related substances described is the value of each related substance with respect to the peak area of levocetirizine. The percentage of the sum of the peak areas of the substances is shown as a percentage.
The test conditions for high performance liquid chromatography are as follows.

Table 3 shows that the formulation based on anhydrous calcium hydrogen phosphate and crystalline cellulose (Example 1) has a clearly higher storage stability than the formulation based on lactose hydrate and crystalline cellulose (Comparative Example 1). Is improving.

  Generally, it is said that a low-content preparation tends to have poorer stability. However, there is no difference in stability when compared with Example 1 and, for example, Example 4, and the formulation according to the present invention has a lower content. However, stability was maintained.

As a result of Table 4, in the formulation based on lactose hydrate and crystalline cellulose, an increase in related substances was confirmed without packaging under severe conditions (60 ° C., 75% RH for 2 weeks) (Comparative Example 2).
Similarly, even with a formulation based on lactose hydrate and anhydrous calcium hydrogen phosphate, an increase in related substances was confirmed without packaging under severe conditions (60 ° C., 75% RH for 2 weeks) (Comparative Example 3). ).
On the other hand, anhydrous calcium hydrogen phosphate containing no lactose hydrate (Example 2) or a formulation containing anhydrous calcium hydrogen phosphate and microcrystalline cellulose (Examples 3 and 4) contained a formulation containing lactose hydrate (comparative). Related substances hardly increased as compared with Examples 2 and 3).
Example 2 does not contain crystalline cellulose, and the stability is improved only by the addition of anhydrous calcium hydrogen phosphate.
Examples 3 and 4 are examples in which the amount of anhydrous calcium hydrogen phosphate was reduced and crystalline cellulose was added. The stability was further improved by the combination of anhydrous calcium phosphate and crystalline cellulose.

  From the above results, the storage stability of a pharmaceutical composition containing levocetirizine compared to conventional lactose hydrate (lactose monohydrate) was improved by combining inorganic phosphate anhydride or inorganic phosphate anhydride with crystalline cellulose. It has become clear that the performance can be improved.

Claims (3)

Levocetirizine or a pharmaceutically acceptable salt thereof, and 30 to 90% by mass of inorganic phosphate anhydride,
A pharmaceutical composition substantially free of a polyol having a molecular weight of less than 950 g / mol , wherein the inorganic phosphate anhydride is anhydrous calcium hydrogen phosphate or anhydrous calcium dihydrogen phosphate . Levocetirizine or a pharmaceutically acceptable salt thereof, 30 to 60% by weight of inorganic phosphate anhydride, and 34 to 64% by weight of crystalline cellulose,
A pharmaceutical composition substantially free of a polyol having a molecular weight of less than 950 g / mol , wherein the inorganic phosphate anhydride is anhydrous calcium hydrogen phosphate or anhydrous calcium dihydrogen phosphate . A coated tablet obtained by film-coating a plain tablet comprising the pharmaceutical composition according to claim 1 or 2 .