JPH10226644A - Medicinal composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a small bulk which is easy to be digested in patients by preparing the composition which comprises a mixture of at least two disintegrants containing a pharmacologically active agent and sodium starch glycolate and carboxymethyl cellulose calcium. SOLUTION: This composition for pharmaceutical manufacturing neither affording the bulkiness nor changing the color to yellow is obtained by mixing (A) a pharmaceutically active ingredient, for example, a HMG-CoA reductase inhibitor, e.g. fluvastatin sodium, (B) sodium starch glycolate which possesses the average degree of polymerization of about 100-400, the degree of substitution of 0.1-0.5, the specific gravity of 1.2-1.7g/cm<3> and the grain size of 5-100μm and is obtained in the weight ratio of 1:1-2:1 based on the component A, (C) carboxymethyl cellulose calcium which possesses the average degree of polymerization of 200-400, the degree of etherification of 0.5-0.8, the specific gravity of 450-550g/L and the granularity of 200 mesh pass 95% and is contained in the weight ratio of 1:2-2: 1 based on the component B and (D) a water-soluble base for keeping the required basicity, e.g. sodium hydrogencarbonate and the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a pharmaceutical composition, especially in unit dosage form, containing a pharmacologically active substance.

[0002]

BACKGROUND OF THE INVENTION Pharmaceutical compositions generally contain, in addition to the pharmacologically active agent, fillers (diluents), binders, glidants, lubricants and anti-adhesives. It contains various excipients that impart good workability from the bulk to the unit dosage form and that enhance the properties of the pharmaceutical composition, such as stabilizers, such as buffers and disintegrants.

[0003] Certain pharmacologically active agents may require a possible bulk of additional excipients to produce a commercially acceptable composition. Such a bulk leads to the disadvantage that the composition has an undesirably large size and is therefore not easily digested by the patient.

For example, fluvastatin, a known HMG-CoA reductase cholesterol biosynthesis inhibitor useful in the treatment of hyperlipoproteinemia and atherosclerosis, is disclosed in USP, the contents of which are incorporated herein by reference.
It is used in the form of a sodium salt (hereinafter referred to as Compound A) in a pharmaceutical composition in a hard gelatin capsule as described in 5,356,896.

Compound A capsules have a p-value of at least 8
H is sold by Novartis under the trade name LESCOL, which includes a pharmaceutical composition of Compound A in an alkaline stabilizing medium capable of providing an aqueous solution or dispersant of the composition. More specifically, the composition comprises precipitated calcium carbonate and sodium bicarbonate as alkaline stabilizing media, microcrystalline cellulose and pregelatinized starch as filler, talc as glidants and magnesium stearate as lubricant. Including. USP5,
The 20 mg Compound A capsule described in Example 1 of 356,896 is: Component Weight (mg) Compound A 21.06 (equivalent to 20 mg fluvastatin) Calcium Carbonate 62.84 Sodium Bicarbonate 2.00 Microcrystalline Cellulose 57. 23 Pregelatinized starch 41.90 Talc 9.43 Magnesium stearate 1.05 Contains 195.5 total. Hereinafter, it is referred to as composition I.

[0006] Thus, as can be seen, 89% by weight of the unit dose containing excipients and 56% by weight of the unit dose containing excipients other than the particular alkaline stabilizing medium are required. The form of the unit dose formulation of the high dose form of Compound A is
It's bulky.

[0007]

SUMMARY OF THE INVENTION After exhaustive testing, Applicants have discovered that pharmaceutical compositions have particular pharmacological properties of interest and can be obtained in small bulks.

In one embodiment, the present invention provides a pharmaceutical composition comprising a pharmacologically active agent and a mixture of at least two disintegrants including sodium starch glycolate and calcium carboxymethylcellulose.

Although the present invention is described herein with reference to Compound A, it includes contraceptives, sedatives, steroids, sulfonamides, vaccines, vitamins, antimigraines, enzymes, bronchodilators, It is inherently applicable to a wide variety of pharmacologically active agents, such as vascular drugs, analgesics, antibiotics, anticonvulsants, anti-inflammatory drugs, antiparkinson drugs, prolactin secretion inhibitors, antiasthmatics and antimalarials.

Activators include a wide range of chemical compounds, for example,
It may be selected from lipophilic and / or hydrophilic actives, including statins. This suggestion is of particular interest with active agents that are degradable in gastric juice, such as Compound A or paravastatin.
Disintegrants are present in about 5 to 40% by weight of the total composition.

[0011] Sodium starch glycolate (also known as starch carboxymethyl ether) is, for example,
It can be manufactured as described in SP3034911. this is
It is described in National Formulary XVI. Preferably, it has an average degree of polymerization of about 100 to 400. The degree of substitution can be, for example, from 0.1 to 0.5 (ie, 10% to 50%). Specific gravity is from 1.2 to 1.7
g / cm ³ . The particle size is, for example, from 5 to 100
Can be microns.

The sodium starch glycolate preferably has a degree of substitution of 0.25 (25%) and a specific gravity of 1.5 g / g.
has cm ^3, particularly preferably, WA Scholtens Chemisch
e Brand Primogel available from Fabrieken NV, Foxhol, Holland [hereinafter component B].

[0013] The sodium starch glycolate is preferably present in an amount of about 10 to about 25% of the total composition. Preferably, the weight ratio of sodium starch glycolate to activator is from 1: 1 to 2: 1.

Carboxymethylcellulose calcium
(Also known as calcium carmellose and calcium salt of cellulose carboxymethyl ether)
nal Formulary XVI. Preferably, 20
It has an average degree of polymerization of 0 to 400. Preferably, 0.
It has a degree of etherification of 5 to 0.8 (ie, 50 to 80%). The specific gravity can be between 450 and 550 g / l. Preferably, 95% pass through a 200 mesh sieve.

The calcium carboxymethylcellulose preferably has a degree of polymerization of 300 ± 100, 0.6 ± 0.3.
Specific brand ECG505 with a degree of etherification of 1
[Hereinafter, component C].

[0016] The calcium carboxymethylcellulose is preferably present in an amount of 1 to 10% by weight of the total composition. Preferably, the weight ratio of calcium carboxymethylcellulose to activator is from 1: 2 to 2: 1. Preferred weight ratios of sodium starch glycolate to calcium carboxymethylcellulose are from 5: 1 to 2:
It is one.

The composition has a long shelf life, even in moisture. The active agent stability of the composition of the present invention is 18
98% to 99% at 25 ° C, even for months or longer
%.

The composition preferably comprises an activator and an "alkaline medium", which is provided by imparting a pH of at least 7, for example 8, to an aqueous solution or dispersant of the composition. The composition can be stabilized.
Preferably, the active agent and the alkaline medium are in intimate contact within the composition to achieve optimal pharmaceutical stability.

As used herein, the term "alkaline medium" refers to an aqueous solution or dispersant of a composition of the present invention that has a pH of at least 7, preferably at least 8, more preferably at least 9 and up to about pH 10. 1 that can be given
Means one or more pharmacologically acceptable substances. More specifically, the alkaline medium forms a "micro-pH" of at least 8 around the particles of the composition when water is adsorbed therein or when a small amount of water is added to the composition. The alkaline medium is inert to the activator unless otherwise specified. pH is determined by taking the unit dosage form of the composition,
The composition can be measured by dispersing or dissolving the composition in 0 to 100 ml of water.

The pharmacologically acceptable alkaline substances forming the alkaline medium can range from water-soluble to slightly water-soluble to essentially water-insoluble.

Examples of water-soluble alkaline substances which can impart the required basicity include certain pharmacologically acceptable inorganic carbonates such as sodium or potassium carbonate, sodium or potassium hydrogen carbonate; Phosphates selected from anhydrous sodium phosphate, potassium dibasic phosphate or calcium dibasic phosphate or trisodium phosphate; and alkali metal hydroxides such as sodium hydroxide, potassium hydroxide or lithium hydroxide;
It contains the aforementioned mixtures and especially sodium bicarbonate.

Examples of water-soluble or slightly water-soluble alkaline substances which may also be useful for forming a stabilized alkaline medium in the composition are those which are also commonly used in acid-resistant formulations (eg,
Magnesium oxide, magnesium hydroxide or magnesium carbonate; magnesium hydrogen carbonate; aluminum or calcium hydroxide or aluminum or calcium carbonate; complex aluminum-magnesium compounds such as magnesium aluminum hydroxide); and phosphoric acid such as tribasic calcium phosphate Pharmacologically acceptable salts; and mixtures thereof, especially calcium carbonate.

Among the above alkaline substances, pharmacologically acceptable inorganic carbonates and bicarbonates, such as sodium carbonate, sodium bicarbonate, calcium carbonate and mixtures thereof, are referred to as "pharmacologically. "Acceptable carbonates" have been found to be particularly effective for forming the alkaline medium.

Compositions that also have attractive storage stability include both water-soluble alkaline excipients and water-insoluble or slightly water-soluble alkaline excipients. For example, a substantial improvement in stability and other benefits is achieved by using an alkaline medium comprising a water-soluble carbonate and a water-insoluble carbonate, especially a combination of sodium bicarbonate and calcium carbonate.

The sodium bicarbonate advantageously acts to neutralize acidic groups in the composition in moisture which can be adsorbed on the particles of the composition during pharmaceutical storage. Calcium carbonate has a buffering effect in the storage composition. The carbonate stabilizes the drug substance sufficiently so that conventional water-based preparation methods, for example tritylation by water or wet granulation, can be used in the preparation of the stabilized composition of the present invention. The calcium carbonate is a precipitate or a powdered substance, but is preferably a precipitate.

The alkaline medium may be, for example, at least 8,
And preferably a pH as high as 9 and pH 10
The composition may be present in the composition in an amount sufficient to impart to an aqueous solution or dispersant of the composition. Generally, the compositions of the present invention comprise from about 0.1 to 60% (typically 3 to 15%) by weight of an active agent and from about 50 to 90%, preferably 50 to 70% by weight of an alkaline medium. Including.

The amount of the particular stabilizer used depends to some extent on the intended preparation. For example, in a tableting composition, the calcium carbonate should not exceed an amount that can be conveniently subjected to compression, and is generally used in combination with more easily compressible alkaline substances, such as sodium bicarbonate. You. On the other hand, capsule dosage forms may contain higher levels of less compressible excipients,
However, all compositions leave sufficient free-flow and workability.

The solid unit dosage composition may have a weight ratio of water soluble carbonate to insoluble carbonate of 1:40 to 2: 1. A capsule composition may include these excipients, for example, in a ratio of 25: 1 to 35: 1 by weight. Preferably, the weight ratio of sodium starch glycolate to alkali stable medium is from 1: 2 to 1: 5.

In addition to the drug substance and the alkaline medium, fillers are also used to impart workability to the composition.
Suitable suitable fillers are known in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed.
(1990), Mack Publishing Co., Easton, PA, pp.1635-16
36), lactose and other carbohydrates,
Pregelatinized starch such as Starch 1500® (C
olorcon Corp.), corn starch, dicalcium phosphate, cellulose, microcrystalline cellulose (Avicel®, FMC Corp), sugar, sodium chloride and mixtures thereof, among which microcrystalline cellulose , Pregelatinized starch and mixtures thereof are preferred. The total amount of filler is preferably from about 1 to 10% by weight of the composition, based on the weight of the total composition.

Other ingredients that may be included in the composition to facilitate workability and / or enhance the properties of the product dosage form include known tablet binders such as gelatin, sugar, carboxymethylcellulose, methylcellulose, Polyvinylpyrrolidone, hydroxypropylmethylcellulose,
Microcrystalline cellulose and mixtures thereof, such as microcrystalline cellulose and mixtures thereof, natural and synthetic gums); lubricants (e.g., magnesium stearate,
Hydrogenated vegetable oils, carnauba wax, etc.); glidants (eg, silicon dioxide), anti-adhesives or glidants (eg,
Talc) as well as sweeteners, dye media (eg, iron oxide, aluminum lake), flavor media, and antioxidants. The selection of a particular ingredient or ingredients and the amounts to use can be readily determined by those skilled in the art with reference to standard methods and practices of preparing tablets or encapsulation or other unit dosage forms. Generally, an effective amount of tablet binder is about 1 to 10%, and preferably 1 to 5% by weight, based on the total weight of the composition; about 0.1 to 10% by weight of the anti-adhesive or glidants; And the lubricant comprises about 0.1 to 2% by weight.

Preferably, however, the other excipients comprise no more than 30% by weight of the total composition, for example no more than 10%. Such compositions comprise a standard homogeneous orally active agent,
For example, 10 mg, 15 mg, 20 mg, 30 mg, 4 mg
An active mass of Compound A, such as 0 mg, can be formulated in known manner to provide capsules, tablets, pellets, and the like.

The compositions of the present invention can be manufactured by various methods and manufacturing methods common in the art. In the manufacture of the composition, it is important that the activator and the alkaline medium be in intimate contact. Dry mixing of these components achieves a substantially homogeneous mixture (preferably prior to the addition of fillers and remaining excipients), followed by a compression step to achieve the desired intimate contact.

It is a further advantage that the stabilized compositions of the present invention can be readily prepared by aqueous or other solvent-based techniques, such as humidification granulation.

The aqueous or other solvent-based preparation process preferably involves mixing the activator, alkaline medium, sodium starch glycolate and calcium carboxymethylcellulose with one another in the presence of a small amount, eg, water, Used to provide particles that contain the substance in an intimate mixture.

In one embodiment of such a method, the activator, alkaline medium, sodium starch glycolate and calcium carboxymethylcellulose are tritylated with water and the resulting particles are subsequently dried. The filler and the remaining excipients set aside to form the "external phase" of the particles are then mixed with the dry particles to provide a composition suitable for encapsulation, tableting, and the like.

In another embodiment of a solvent-based process that can assist in subsequent drying in a fluidized bed, the active agent and sodium starch glycolate, calcium carboxymethylcellulose and an alkaline medium are prepared by known techniques, ie, in a wet state, Wet granulation by mixing with a certain amount of the filling material. The granules thus formed, after drying, are then combined with the remaining fillers and other reserves, such as binders, lubricants, and can thus be tableted, encapsulated or so. If not,
It can be formed into unit dose form.

In order to achieve an extended shelf life of the composition, the particles produced by tritylated or other wet granulation or other aqueous-based methods are substantially completely
That is, drying is performed until the weight loss (LOD) upon drying is no more than 3%, preferably no more than 2%.

Drying is conveniently effected in tray drying or a fluidized bed, preferably in the latter. Drying is typically performed at an injection temperature of about 50 ° C., at 50% RH or less.

In preparing the compositions, the active component and the remaining components (other than lubricants) in unit dosage form are preferably passed through a 30 to 40 mesh screen prior to tritylation or wet granulation, and the active agent is , Generally sieved first and then mixed with the sieved excipients. In addition, the dry particles or granules may be mixed with a 1
Pass through an 8 to 20 mesh sieve.

The compositions of the present invention obtained by the above techniques are formed into dosage forms by techniques known in the art, for example, tableting, encapsulation, pelletizing, molding and the like.

The tableting or capsule unit dosage forms obtained should be protected from temperature or light-induced oxidation and humidity contamination during storage.

Capsules and tablets made from the compositions of the present invention have been found to have attractive storage stability.

The tablets or capsules of the present invention may have a disintegration time of greater than 75% within about 10 to 30 minutes, preferably 8 minutes.

Certain pharmaceutical compositions, such as HMG-CoA
A problem that occurs with reductase inhibitor compositions is the bleaching of a white appearance to yellow or brown. The applicant has
It has been found that the compositions of the present invention undergo negligible bleaching. Thus, negligible yellowing of the composition occurs.

In another embodiment, the present invention relates to a salt of starch glycolic acid, such as a sodium salt and a salt of carboxymethyl cellulose, typically used as a disintegrant.
Provided is a method for preventing decolorization of a pharmaceutical composition, for example, by adding at least two components including a calcium salt. In a specific embodiment, the present invention provides a method for preparing HMG-CoA, comprising adding sodium starch glycolate and calcium carboxymethylcellulose to a composition.
Methods for preventing decolorization, eg, yellowing, of a reductase inhibitor composition, eg, a fluvastatin composition, are provided.

In another embodiment, the present invention relates to at least two components, including salts of starch glycolic acid, such as sodium salts and salts of carboxymethylcellulose, such as calcium salts, typically used as disintegrants in pharmaceutical compositions. Provides use of. In a specific embodiment,
The present invention provides an HMG-CoA reductase inhibitor composition,
For example, there is provided the use of sodium starch glycolate and calcium carboxymethylcellulose in preventing decolorization, eg, yellowing, of a fluvastatin composition.

The amounts and weight ratios of each of the disintegrants, for example, sodium starch glycolate and calcium carboxymethylcellulose, can be as described above.

The compositions of the present invention are useful in the known formulation of the particular active agent contained therein. The activator is HMG-
When a CoA reductase inhibitor, ie, a cholesterol biosynthesis inhibitor, the pharmaceutical composition is useful for treating hyperlipoproteinemia and atherosclerosis.

The precise amount of active agent and composition to be administered depends on many factors, for example, the condition to be treated, the duration of the desired treatment and the rate of release of the active agent. For example, the amount of active agent required and its release rate may be based on known in vitro or in vivo techniques, for how long the concentration of a particular active substance in plasma remains at a fictitious level for a therapeutic effect. Can be measured to determine

The preferred regimen is 10, 1 once a day.
Contains 5, 20 or 30 mg of active agent. Alternatively, for example, if 20 mg should be administered, this would be 10 times twice daily.
It can be provided in mg administration. Doses up to 60 mg / day can be tolerated.

An example of a cholesterol lowering dosage with Compound A is the compound of Example 1A described herein,
It can be administered once a day.

For details of the composition, see HP Fiedler, 3rd Edi
tion, 1989, Editor Cantor Aulendorg, German, “Lexikon fur Pharmazie, Kosmetik and Angrenzende
Gebiete ”;, American Pharmaceutical Association, W
ashington, USA and The Pharmaceutical Society of
“Handbo” co-published by Great Britain, London, England
ok of Pharmaceutical Excipients "1st Edition 1986
As well as described in various NationalFormularies or obtained from the respective manufacturers.

The total weight of the compositions described herein, when adapted to a capsule-containing unit dosage form, is essentially the contents of the capsule,
That is, it means that there is no capsule shell.

In the following, only the compositions according to the invention are described by way of example. The following examples are intended to illustrate the invention without limiting it in any way.

[0055]

【Example】

Example 1: 30 and 20 mg third size (A and B)
Or 15 or 10 mg # 4 size (C and D) oral fluvastatin capsules were prepared containing the following formulations:

[0056]

[Table 1] Amount of component (mg) ABCD Compound A 31.59 21.06 15.795 10.53 Calcium carbonate, USP ³ 170 113.33 85 56.67 Sodium hydrogen carbonate, USP 6432 Microcrystalline cellulose, NF ^b 3.41 2.27 1.705 1.14 Selatinized starch, NF ^c 5 3.33 2.5 1.67 Sodium starch glycolate ^d 45 30 22.5 15 Carboxymethylcellulose-calcium 14 9.33 7 4.67 Purified water, USP qs * qs * qs * qs * Reserved: talc USP 5 3.33 2.5 1.67 Magnesium stearate, NF 1 0.67 0.5 0.33 Total 281.00 187.32 140.50 93.68 a Heavy, precipitated b Avicel, PH102, FMC Corp. c Starch 1500, Colorcon Corp. d Component B e Component C f Removed during the process

(A) Compound A, calcium carbonate, sodium bicarbonate, microcrystalline cellulose, sodium starch glycolate and carboxymethylcellulose and pregelatinized starch are mixed for 5 minutes, and the mixture is passed through a 40 mesh sieve and further mixed for 3 minutes. Mix for a minute. (b) Add water to the mixture with stirring for about 4 minutes to form wet granules. (c) The wet granules are poured in a fluidized bed dryer at an injection temperature of 50
Dry at ℃. (d) Pass the dried granules through a 20-mesh sieve and mix with the saved microcrystalline cellulose for about 10 minutes. Talc and magnesium stearate (each pre-screened with a 60 mesh sieve) are added with mixing for about 5 minutes. (e) Fill the composition into blue opaque capsules and polish by hand with salt.

The active ingredient (Compound A) was found to be 99% intact for 18 months at 30 ° C. in a light-protected, protected environment.

Example 1 Dissolution rate of capsules after the following time 10 min 8 min> 95%> 70% in water> 95%> 80% in bile solution (pH 12) Phosphate buffer pH 6.5 100%> 80% pH 7.2 100%> 90% Bioavailability characteristics of Example 1A in 10 healthy adult male subjects

AUC Cmax Tmax T1 / 2 ng.h / ml ng / ml h Time 287.9 278.7 0.7 0.9

Continued on the front page (72) Inventor Hideaki Uchiyama 2-4-6 Pastoral Sengen 403, Tsukuba City, Ibaraki Pref.

Claims (6)

[Claims] 1. A pharmaceutical composition, optionally in granular or powder form, comprising a pharmacologically active ingredient, preferably a mixture of fluvastatin sodium and at least two disintegrants comprising sodium starch glycolate and calcium carboxymethylcellulose. 2. The composition according to claim 1, further comprising sodium bicarbonate and / or calcium carbonate. 3. The composition according to claim 1, wherein the composition is in a unit dose form containing less than 10% by weight of aggregates of other excipients. 4. The composition according to claim 1, which is for oral administration. 5. A medicament by mixing the composition with at least two components typically used as disintegrants, including a starch glycolate, such as a sodium salt and a carboxymethylcellulose salt, such as a calcium salt. A method of preventing decolorization, eg, yellowing, of a composition, eg, an HMG-CoA reductase inhibitor composition, preferably a fluvastatin composition. 6. A pharmaceutical composition, eg, HMG, of at least two components typically used as disintegrants, including a starch glycolate, eg, a sodium salt and a carboxymethylcellulose salt, eg, a calcium salt.
The use of a CoA reductase inhibitor composition, in particular a fluvastatin composition, in the prevention of bleaching, for example yellowing.