JP5042447B2 - Mixed preparation - Google Patents

Description

  The present invention relates to a granular preparation which does not solidify even under wet heat conditions and can mask the unpleasant taste of levofloxacin.

Various dosage forms such as tablets and capsules are known in medicine, but the role played by granular preparations such as granules or fine granules is great. That is, in addition to being able to freely change the dosage at the time of medication, it is extremely important for improving the dosage and compliance of children and the elderly. In recent years, the demand is increasing as the patient ages rapidly.
On the other hand, even in the case of a granular preparation, in the case where a drug having an unpleasant taste is included, it cannot necessarily be a preparation that is easy to take. Various pharmaceutical approaches have been made to solve these problems. In general, there is a method of coating the surface of a granular material with a coating agent that does not dissolve in the mouth, such as wax and a water-insoluble polymer, as the most commonly used preparation technique. In this case, conventionally, a method of spray coating by dissolving a coating agent in an organic solvent has been used. However, the use of an organic solvent has many problems such as sanitary adverse effects on workers, environmental pollution, and residual in the preparation. For this reason, recently, a method of coating by dispersing a coating agent in water together with a plasticizer has been found and widely used. However, this method is also unsuitable for substances that are unstable to water, and when applied to a readily water-soluble drug, the drug easily dissolves in the coating solution. And defects such as film formation failure. In the case of spray coating, there are many factors that cause fluctuations in manufacturing conditions such as coating speed and temperature, so it is necessary to always manage the conditions with high accuracy in order to obtain a preparation with a constant quality.

Separately, for the purpose of masking bitterness, glyceryl monostearate, an oily substance, is used as a low-melting substance, and this is obtained by melt granulation with a pulverized drug or a pulverized excipient and drug. There is a method in which the obtained granular material is melt-coated using only talc as a coating agent, but it has been found that the granular material obtained by the production method tends to solidify over time when exposed to wet heat conditions.
In general, it is known that a granulated product containing an oily substance consolidates when stored at a temperature below the melting point of the oily substance (Non-patent Document 1), and granulation affects the consolidation of such a granular material. As the physical properties of the product, the particle size of the granulated product, the content of oily substances, etc. are reported. Although a small amount of fine powder additive has been reported as a method for suppressing aggregation and preventing caking of such granular preparations [Non-Patent Documents 2 to 4], conversely, in the system of granulated products containing oily substances It has been reported that the addition of a small amount of the fine powder additive reduces fluidity and increases caking (Non-Patent Document 1).

Naoki Wakiyama, Pharm Tech Japan. (1994), vol.10. P819) P. York, Journal of Pharmaceutical Sciences (P. York. J. Pharm. Sci.), (1975), 64, 1216-1221 S. Dawood Bai and C.I. T.A. Rhodes, Drug Development and Industrial Pharmacy (S. Dawoodbhai and C. T. Rhodes, Drug Dev. Ind. Pham.), (1990), 16, 2409-2429 G. Gold et al. J. Pharm. Sci., (1968), 57, 667-671

  An object of the present invention is to provide a granular preparation that does not solidify even under wet heat conditions and can effectively mask the bitterness of levofloxacin.

  TECHNICAL FIELD The present invention relates to a granular preparation obtained by coating finely divided oily low-melting substance, levofloxacin, and optionally an excipient by melt granulation with finely divided ethylcellulose by melt coating, and a method for producing the same.

The granular preparation of the present invention has not only excellent caking prevention effects, but also excellent properties in terms of taste masking in the mouth, elution of levofloxacin, appearance, strength, stability and the like. In addition, it has the following extremely useful points.
(1) Compared with the production of general masking particulates, it is not necessary to prepare a binding solution or a coating solution, and the production time can be greatly reduced. Quality products can be produced with good yield.
(2) Since no solvent is used, there is no danger of safety, hygiene, pollution, residue in the product, etc., and the stability of levofloxacin is not impaired.
(3) The particle size of the product can be easily controlled by changing the particle size of the oily low melting point substance. For example, when glyceryl monostearate having a particle size of 150 to 250 μm is used during granulation, a fine granule having a particle size of 250 to 500 μm is obtained, and when glyceryl monostearate having a particle size of 300 to 850 μm is used, a granule having a particle size of 500 to 1400 μm is obtained. Can do.
(4) Masking property and elution property of levofloxacin can be freely controlled by adjusting the amount of the oily low-melting substance and the hydrophobic and oil-absorbing polymer compound or the kind and amount of the excipient.

  The oily low melting point substance used in the present invention may be an oily substance having a melting point of 30 to 100 ° C., more preferably 50 to 80 ° C. Examples thereof include monostearic glycerin ester and acetylated glycerin mono. Stearate, sorbitan monostearate, esters such as hexadecyl palmitate and octadecyl stearate, waxes such as carnauba wax and beeswax, hydrocarbons such as paraffin and microcrystalline wax, oils and fats such as hardened oil, wood wax and cocoa butter Examples thereof include preferably monostearic acid glycerin ester.

As the particle size of the oily low-melting-point substance, those having a particle size of 850 to 100 μm are usually preferably used, but the particle size varies depending on the purpose of granulation, that is, the type of granular preparation obtained. For example, a particle having a particle size of 850 to 360 μm, preferably 700 to 350 μm may be used for the purpose of granules, and a particle having a particle size of 250 to 100 μm, preferably 200 to 110 μm for fine particles. Use it.
In addition, in description of this specification other than a reference example and an Example, the term "particle diameter" means an average particle diameter.
The amount of such an oily low-melting substance used is usually 0.01 to 0.5 parts by weight, preferably 0.05 to 0.3 parts by weight, based on 1 part by weight of the finally obtained granular preparation.

The drug used in the present invention is not particularly limited, but generally a drug having a bitter taste for the purpose and purpose of the present invention is preferably used, and specific examples thereof include nefiracetam, levofloxacin, ecabapid and the like. Can be mentioned.
The particle size of such a drug is usually 50 μm or less, preferably 10 to several μm, and the amount used is usually 0.01 to 0.5 in 1 part by weight of the finally obtained granular preparation. Used by weight. In the process of granulating the drug by melt granulation with the oily low-melting substance, if desired, the drug may be granulated using excipients such as corn starch, lactose, talc, etc., and particles of these excipients The diameter is usually 50 μm or less, and the amount used is an appropriate amount, generally about 0.02 to 0.3 parts by weight per 1 part by weight of the obtained granular preparation.

The melt granulation in the present invention is a fluid that uses the adhesiveness generated when the low melting point substance is melted by the heat of the low melting point substance around the oily low melting point substance as described above. This refers to a method for producing a mononuclear granular material by uniformly adhering to the bottom (“Particle Design and Formulation Technology”, pages 130-132, published on October 30, 1993 by Yakuho Hokpo Co., Ltd.). The melt granulation is performed as follows. That is, a fine powdery oily low-melting substance as described above is mixed with levofloxacin housing and, if desired, the excipient as described above, and the resulting mixture is heated and stirred at a temperature higher than the melting point of the oily low-melting substance. Then, by cooling, levofloxacin and excipients are uniformly attached around the oily low-melting substance, and then the mononuclear granular material can be produced by cooling below the melting point.
The heating temperature in the melt granulation as described above is generally about 5 to 45 ° C. higher than the melting point of the oily low melting point substance, and the granulation time varies depending on the raw materials used and the production scale. In the production scale of about 1 to 10 kg, it is usually 10 to 30 minutes.

By selecting ethylcellulose as the fine powdery hydrophobic and oil-absorbing polymer compound, and then coating the fine powder of excipients such as talc by melt coating on the granular material thus obtained. It can be a granular preparation.
Here, the hydrophobicity of the polymer compound specifically means a property that is more compatible with oil than water, and a substance having such a property is hardly soluble in water, but is not suitable for oil or nonpolar solvents. Becomes easy to melt. On the other hand, the oil absorbing property specifically means the property of selectively absorbing and swelling oil.
The particle size of the above-mentioned ethyl cellulose is usually 10 μm or less, and the amount used is about 0.0001 to 0.5 parts by weight, preferably 0.001 in 1 part by weight of the finally obtained granular preparation. -0.1 parts by weight.
In the above melt coating, the particle diameter of the excipient added as desired is usually 50 μm or less, and the amount used is an appropriate amount, generally 0.1 to 0. About 5 parts by weight.

The melt coating in the present invention is a mixture of a granular material produced by melt granulation and a fine powder coating agent, and this is heated to a temperature higher than the melting point of the oily low melting point material under flow to melt the oily low melting point material, granular This refers to elution on the surface of a product, and a coating layer is formed by attaching a coating agent around the granular material using its adhesive force (“Particle Design and Formulation Technology”, pages 132-134, October 1993). May 30 (published by Yakuho Hokpo).
In the present invention, the melt coating may be performed as follows. That is, an oily low-melting-point substance used by mixing granular material produced by melt granulation as described above, finely divided ethyl cellulose and, if desired, finely granular excipient, under flow, rolling or stirring. By heating and granulating at a temperature equal to or higher than the melting point, ethyl cellulose can be adhered around the granular material, and finally a coating layer comprising an oily low melting point substance and ethyl cellulose, and optionally an excipient is formed. Can do.
The heating conditions and granulation time in the melt coating are the same as those of melt granulation, and a sufficient effect can be expected.
After completion of melt coating, the desired granular preparation can be obtained by cooling.

In addition, in order to produce various powders used in the present invention, the powder may be pulverized according to a normal pulverization method such as a ball mill or a jet mill, and this may be sieved using a sieve having a target pore size. .
The granular preparation thus obtained can be sieved using a sieve having an appropriate pore size to obtain a granular preparation having a more uniform particle size.
If the granular preparation thus obtained is mixed with an appropriate fluidizing agent and / or coating agent, a more preferable anti-caking effect can be expected. Examples of the fluidizing agent include talc, light anhydrous silicic acid, magnesium aluminate metasilicate, and a mixture thereof. Examples of the coating agent include titanium oxide, magnesium oxide, and a mixture thereof. These fluidizing agents and / or coating agents are usually used in an amount of about 1% to 5% in the total amount of the final granular preparation obtained by mixing as described above. As for the particle size of the fluidizing agent or coating agent, it is sufficient to use a commercially available particle size, but usually it may be appropriately selected from the range of about 0.001 to 75 μm.

Next, the present invention will be specifically described with reference to examples.
Reference example 1
In a fluid bed granulator (Glat WSG-5 type), 1.2 kg of nefiracetam (average particle size: 50 μm or less), talc (particle size: 100 μm or less) 1.08 kg, lactose (particle size: 250 μm or less) 0.534 kg, Corn starch (particle size: 125 μm or less) 0.27 kg, glyceryl monostearate (average particle size 100-200 μm) 0.846 kg, granulated while heating and flowing at an intake air temperature of 90 ° C., cooled, and passed through a 500 μm sieve And sieved to obtain a granular material (fine granule). 3.275 kg of this granular material is again put into a fluidized bed granulator together with 1.650 kg of talc (particle size: the same as above), and fluidized while heating at an intake air temperature of 90 ° C., and all the powder adheres to the coated granular material ( That is, after melt coating) (about 20 minutes), hot air was changed to room air by a damper operation to obtain a granular material (fine granule) in which the sample temperature was cooled to 40 ° C.

Reference example 2
What was prepared by changing the amount of ethyl cellulose of the coating agent obtained by replacing part of talc with ethyl cellulose (average particle size: 10 μm or less) to 2 to 50% by weight in the granular material before melt coating obtained in Reference Example 1 Was prepared and melt coated in the same manner as in Reference Example 1 to obtain a granular material (fine granule).
The granular material was subjected to a caking test, a mouth masking test, and a dissolution test (T75%). The consolidation test was evaluated by the naked eye (Table 1).
In Table 1, + indicates consolidation, ± indicates partial consolidation, and-indicates no consolidation.

As apparent from Table 1, when ethyl cellulose was added, the blocking effect of the granular preparation was recognized regardless of the increase in the amount added.
In the mouth masking test, 0.75 g of sample was included in the mouth and the time until bitterness was felt was measured (N = 6), and the average value was shown (the values in parentheses indicate the lowest and highest values). The dissolution test is carried out according to the Japanese Pharmacopoeia General Test Method Dissolution Test Method No. 2. After starting the test using water, sample the test solution up to 2, 5, 10, 15, 20, 30, 40, 60 minutes, The absorbance of nefiracetam was measured, and the time to reach 75% elution rate (T75%) was determined by calculation (Table 2).

  As shown in Table 2, the masking time gradually increases as the amount of ethyl cellulose added is increased. On the other hand, the elution time (T75%) was not significantly different from the non-added sample up to an addition amount of 10%, but tended to increase when the addition amount exceeded 10%.

Reference example 3
988 g of the granular preparation obtained in Reference Example 2A was mixed well with 12 g of a mixture of talc and light silicic anhydride (mixing ratio 9: 1 w / w) to obtain a fluidizing agent mixed preparation.

Reference example 4
In a fluidized bed granulator (FLO-5 type), levofloxacin (average particle size: 20 μm or less) 0.6 kg, talc 1.5 kg, lactose 1.176 kg, glyceryl monostearate (average particle size 100 to 200 μm) 0.924 kg And granulated while heating and flowing at an intake air temperature of 90 ° C., cooled, and sieved with a 500 μm sieve to obtain a granular material (fine granule). After 3.5 kg of this granular material is again put into a fluidized bed granulator together with 1.5 kg of talc, it is fluidized while heating at an intake air temperature of 90 ° C., and after all the powder adheres to the coated granular material (melt coating) (about 15 Minute), the granular material (fine granule agent) which changed hot air into room air by damper operation, and cooled the sample temperature to 40 degreeC was obtained. The particle diameters of talc and lactose used were the same as in Reference Example 1.

Example 1
Prepare the granular material before melt coating obtained in Reference Example 4 with a coating agent obtained by replacing part of talc with ethyl cellulose (particle diameter: 10 μm or less) in which the amount of ethyl cellulose is 11.7% by weight. A granular material (fine granule) was obtained by melt coating in the same manner as in Example 4.
The resulting granular product was subjected to a mouth masking test and dissolution test (T75%), showing the minimum and maximum time until bitterness was felt (Table 3), and the time to reach a dissolution rate of 75%. (Table 3).

Example 2
967 g of the granular preparation obtained in Example 1 is mixed with 33 g of a light caustic anhydride and talc mixture (mixing ratio: 10: 1 w / w, average particle diameter of the mixture: 50 μm or less) to obtain a fluidizing agent mixed preparation. , Bottled.
The following caking test was performed on the obtained bottled preparation. The results are shown in Table 4.
Consolidation test method Place 20 g of a sample into a No. 5 standard bottle to make a bottled preparation, and store it in an arbitrary environment. The bottled preparation after storage is naturally cooled to room temperature (room temperature for 1 hour or more), and then the bottle is gently rotated to invert the bottle. At this time, when the sample remains in the bottle + (consolidated), when there is no sample remaining but aggregates are observed in the discharged sample ± (partially consolidated), no residue and aggregates are recognized The case was defined as one (no consolidation).

Example 3
959.5 g of the granular preparation obtained in Example 1 was mixed with 40.5 g of titanium oxide and light anhydrous silicic acid (mixing ratio; 20.5: 20 w / w, average particle diameter of the mixture: 50 μm or less), and flowed An agent and coating agent mixed preparation was obtained, bottled, and subjected to a caking test. The results are shown in Table 5.

Reference Example 5
Fluidized bed granulator (FLO-5 type) with nefilacetam (average particle size: 50 μm or less) 1.2 kg, talc 0.87 kg, lactose 0.534 kg, corn starch (particle size: 125 μm or less) 0.27 kg, monostearin Add 0.846 kg of glycerin acid (average particle size 100-200 μm) and 0.12 kg of croscarmellose sodium (particle size: 250 μm or less), granulate while heating and flowing at an intake air temperature of 90 ° C., cool, and put on a 500 μm sieve And sieved to obtain a granular material (fine granule). 3.2 kg of this granular material was put into a fluidized bed granulator together with 1.35 kg of talc and 0.035 kg of ethyl cellulose (average particle size: 10 μm or less) and fluidized while heating at an intake air temperature of 90 ° C., and all the powder was coated. After adhering to the granular material (that is, melt coating) (about 20 minutes), a hot air was changed to room air by a damper operation to obtain a granular material (fine particle agent) cooled to 40 ° C. 980 g of these particles are mixed with a mixture of titanium oxide and light anhydrous silicic acid (mixing ratio: 15: 5 w / w, average particle diameter of the mixture: 50 μm or less) to obtain a fluidizing agent and coating agent mixed preparation, 20 g was put into a No. 5 standard bottle to make a bottled preparation. The particle diameters of talc and lactose used were the same as in Reference Example 1.
The caking preparation obtained was subjected to a consolidation test. The results are shown in Table 6.

Claims (6)

Add talc and pulverized ethylcellulose to granulated material by mixing excipients with olefloxacin, an oily low-melting substance with a fine powder melting point of 30-100 ° C, and coating by melt coating The oily low-melting substance is an ester selected from glyceryl monostearate, acetylated glyceryl monostearate, sorbitan monostearate, hexadecyl palmitate, and octadecyl stearate, The excipient is a granular preparation that is an excipient containing at least one of corn starch and lactose and talc, and
A fluidizing agent selected from talc, light anhydrous silicic acid, magnesium aluminate metasilicate and mixtures thereof, and / or
Coating agent selected from titanium oxide, magnesium oxide and mixtures thereof
A mixed preparation consisting of The mixed preparation according to claim 1, wherein the excipient comprises lactose and talc. The mixed preparation according to claim 1, wherein the excipient comprises corn starch, lactose and talc. The mixed preparation according to any one of claims 1 to 3, wherein the oily low melting point substance is glyceryl monostearate. The mixed preparation according to any one of claims 1 to 4, wherein the oily low-melting-point substance has a particle size of 100 to 850 µm. Ethyl cellulose is 0.001-0.1 weight part in 1 weight part of granular preparations, The mixed preparation of any one of Claims 1-5.