阅读说明：本技术 用于压片的羟烷基烷基纤维素和包含所述羟烷基烷基纤维素的固体制剂 (Hydroxyalkyl alkylcellulose for tableting and solid formulation comprising the same ) 是由 横泽拓也 丸山直亮 于 2015-02-12 设计创作，主要内容包括：本发明提供一种少量添加时可成形性优异且不导致崩解显著延迟的羟烷基烷基纤维素；一种含所述羟烷基烷基纤维素的固体制剂；一种制备所述固体制剂的方法；一种用于压片的羟烷基烷基纤维素,该羟烷基烷基纤维素具有通过BET方法测量的0.5至5.0m～(2)/g的比表面积；一种含所述羟烷基烷基纤维素的固体制剂；一种制备所述用于压片的羟烷基烷基纤维素的方法,该方法包括以下步骤：使浆粕与碱金属氢氧化物溶液接触以获得碱性纤维素,使该碱性纤维素与醚化剂反应以获得第一羟烷基烷基纤维素,研磨所述第一羟烷基烷基纤维素,并使经研磨的所述第一羟烷基烷基纤维素经受在酸催化剂存在下水解或在氧化剂存在下氧化降解以获得第二羟烷基烷基纤维素。(The present invention provides a hydroxyalkyl alkylcellulose which is excellent in formability when added in a small amount and does not cause significant delay in disintegration; a solid preparation containing the hydroxyalkyl alkylcellulose; a method for preparing the solid preparation; a hydroxyalkyl alkylcellulose for tableting, the hydroxyalkyl alkylcellulose having a BET method of 0.5 to 5.0m 2 Specific surface area per gram; a solid preparation containing the hydroxyalkyl alkylcellulose; a method for preparing the hydroxyalkyl alkylcellulose for tablettingThe method comprises the following steps: contacting a pulp with an alkali metal hydroxide solution to obtain an alkali cellulose, reacting the alkali cellulose with an etherifying agent to obtain a first hydroxyalkyl alkylcellulose, grinding the first hydroxyalkyl alkylcellulose, and subjecting the ground first hydroxyalkyl alkylcellulose to hydrolysis in the presence of an acid catalyst or oxidative degradation in the presence of an oxidizing agent to obtain a second hydroxyalkyl alkylcellulose.)

1. A hydroxyalkyl alkylcellulose for tableting having 0.5 to 3.0m as measured by the BET method²A specific surface area per g, and has an average particle size of 10 to 50 μm, wherein a 2 wt% aqueous solution thereof has a viscosity of 1 to 15 mPa-s at 20 ℃, and wherein the hydroxyalkyl alkylcellulose is a hydroxypropylmethylcellulose having a degree of substitution of methoxyl group of 19.0% to 30.0% by weight and a degree of substitution of hydroxypropoxyl group of 3.0% to 12.0% by weight.

2. A hydroxyalkyl alkylcellulose for tabletting according to claim 1 having a bulk volume density of 0.05 to 0.5 g/mL.

3. A solid preparation comprising the hydroxyalkyl alkylcellulose for tableting as claimed in claim 1 or 2.

Technical Field

The present invention relates to (in the field of medicines and foods) a hydroxyalkyl alkylcellulose exhibiting high formability even when added in a small amount and a solid preparation comprising the hydroxyalkyl alkylcellulose.

Background

In the pharmaceutical and food fields, the method for producing solid preparations, particularly tablets, includes a dry direct compression method comprising a step of compressing a mixture of a drug and an additive as it is; and a wet granulation tableting process comprising the steps of: the mixture of drug and additives is granulated, dried and tabletted in the presence of a binder solution or a suitable solvent such as water. In the dry direct compression method, when the drug or additive has poor flowability or formability, the mixture may be subjected to rolling (dry granulation), crushing, and then compression (dry granulation compression). In the wet granulation tableting method, a stirring granulator or a fluidized bed granulator may be used.

The dry direct compression method has been frequently employed in recent years because it can be used even when the drug is sensitive to water, or its simple steps contribute to process control. However, dry direct compression methods generally require larger amounts of additives to ensure formability than wet granulation compression methods. Examples of the additive having high formability include crystalline cellulose having high formability (JP 06-316535a), hydroxyalkyl cellulose fine particles (WO/2011/065350), and low-substituted hydroxypropyl cellulose having high formability and high fluidity (JP 2010-254756A).

On the other hand, there is a recent trend toward: tablets are reduced in size to make them easier to swallow, and therefore certain amounts of additives such as binders are inhibited. Therefore, a binder capable of enhancing the hardness of the tablet even when added in a small amount is required.

Disclosure of Invention

However, the crystalline cellulose disclosed in JP 06-316535a should be added in a large amount to ensure formability, so it is not suitable for use in a solid preparation or a small tablet having a high drug content. The fine particles disclosed in WO/2011/065350 are inferior in disintegration property, but have excellent formability. On the other hand, the low-substituted hydroxypropylcellulose disclosed in JP 2010-254756A is excellent in disintegratability but does not have satisfactory formability. Therefore, in the conventional art, when such an additive is added in a small amount, it is difficult to ensure high formability without sacrificing disintegratability.

The present invention has been made in view of the above problems. An object of the present invention is to provide a hydroxyalkyl alkylcellulose which exhibits excellent formability even when added in a small amount and does not cause significant delay in disintegration; a solid preparation comprising the hydroxyalkyl alkylcellulose; and a method for preparing the solid preparation.

The present inventors have conducted intensive studies in order to achieve the above object. As a result, it has been found that the object can be achieved by using a hydroxyalkyl alkylcellulose having a specific surface area, leading to the completion of the present invention.

In one aspect of the present invention, there is provided a hydroxyalkyl alkylcellulose for tableting, the hydroxyalkyl alkylcellulose having a value of 0.5 to 5.0m as measured by the BET method²Specific surface area per gram; and a solid preparation comprising hydroxyalkyl alkylcellulose for tableting. In another aspect of the present invention, there is also provided a method for preparing hydroxyalkyl alkylcelluloses for tableting, the hydroxyalkyl alkylcelluloses having a value of 0.5 to 5.0m as measured by the BET method²Specific surface area per gram; the method comprises the following steps: contacting a pulp with an alkali metal hydroxide solution to obtain an alkali cellulose, reacting the alkali cellulose with an etherifying agent to obtainObtaining a first hydroxyalkyl alkylcellulose, grinding the first hydroxyalkyl alkylcellulose, and subjecting the ground first hydroxyalkyl alkylcellulose to hydrolysis in the presence of an acid catalyst or oxidative degradation in the presence of an oxidizing agent for depolymerization to obtain a second hydroxyalkyl alkylcellulose. In another aspect of the present invention, there is also provided a method for preparing a solid formulation, the method comprising: the steps for the process for preparing hydroxyalkyl alkylcellulose for tableting and the step of tableting the hydroxyalkyl alkylcellulose by dry direct tableting or dry granulation tableting.

According to the present invention, since the hydroxyalkyl alkylcellulose exhibits high formability, it can enhance tablet hardness when a tablet is prepared by dry direct compression or dry granulation compression. In particular, it can be effectively used for a formulation in which the amount of additives is limited, for example, a formulation in which the content of a drug should be increased, a formulation for a mini tablet, or a formulation for a granule-containing tablet that requires compression at low pressure. In addition, according to the present invention, since hydroxyalkyl alkylcellulose exhibits high formability, flakes can be obtained in high yield in a dry granulation process, and when the flakes are reground into granules or fine particles, the amount of fine powder produced is small and the obtained tablets have high tablet hardness.

Detailed Description

The present invention will be described more specifically below.

The hydroxyalkyl alkylcelluloses have a molar mass of from 0.5 to 5.0m, as measured by the BET (BET multipoint) method²A/g, preferably from 0.5 to 4.0m²In g, more preferably from 0.6 to 3.0m²G, still more preferably from 1.0 to 3.0m²Specific surface area in g. When the specific surface area is less than 0.5m²At/g, the desired formability may not be obtained. When the specific surface area is more than 5.0m²At/g, when the hydroxyalkyl alkylcellulose is contained by a tablet, miscibility or fluidity with a drug is reduced.

The specific surface area can be analyzed using the BET (BET multipoint) method, which is based on low-temperature low-humidity physical adsorption of inert gas, which allows molecules having a known adsorption area to be adsorbed onto the surface of powder particles of a sample at a liquid nitrogen temperature and determines the specific surface area of the sample from the adsorbed amount. It can be measured according to "method 2 in Specific Surface Area by Gas absorption method" in the usual test (General Tests) of the japanese pharmacopoeia (16 th edition): the volume Method (Method 2: The volume Method) "and is measured, for example, using an automated surface area and porosimetry analyzer" TriStar II 3020 "(trade name; product of Micromeritics Instrument Corporation).

The viscosity of a 2% by weight aqueous solution of hydroxyalkyl alkylcellulose at 20 ℃ is preferably from 1 to 15 mPa-s, more preferably from 2 to 6 mPa-s, still more preferably from 2.5 to 4.5 mPa-s. When the viscosity is less than 1mPa · s, the disintegratability may deteriorate. When the viscosity is more than 15mPa · s, not only disintegration but also formability may deteriorate, resulting in failure to increase tablet hardness. Polymers with a lower degree of polymerization (i.e. low viscosity) are known to generally have lower formability, as described in JP 06-316535a or WO 2011/065350. However, surprisingly, the present inventors have found that hydroxyalkyl alkylcelluloses with a lower degree of polymerization are excellent in formability. It is presumed that hydroxyalkyl alkylcelluloses having a lower viscosity (i.e., a lower degree of polymerization) may undergo rearrangement of molecular chains and easily cause plastic deformation during compression to improve formability and increase tablet hardness.

With respect to the above viscosity, a viscosity of 600 mPas or more can be measured using a type B viscometer according to JIS Z8803, and a viscosity of less than 600 mPas can be measured using an Ubbelohde viscometer (Ubbelohde viscometer) according to JIS K2283-1993.

The hydroxyalkyl alkylcelluloses preferably have an average particle size of from 5 to 70 μm, more preferably from 10 to 50 μm, still more preferably from 10 to 30 μm. When the average particle size is more than 70 μm, a sufficient specific surface area may not be ensured, so that desired formability may not be obtained. When the average particle size is less than 5 μm, miscibility or flowability with a drug may be reduced when the hydroxyalkyl alkylcellulose is contained by a tablet.

Average particle size means The average particle size on a volume basis and is as described, for example, in "revised and expanded version of Powder characteristics example" (revision and supplement) edited by The Society of Powder Engineering (The Society of Powder Technology) and The japan Powder Industry Technology Association (The Association of Powder industrial and Engineering), published in 1985, by The book of technical japan (Nikkei Gijutsu Tosho co. ltd.), which uses The formula [ sigma (nD) (nD d) (n.d.) in page 88 of Physical Properties of powders with inset (Powder Properties of with ingredients) ]³)/Σn}^1/3A calculation is performed, where D is the particle diameter, n is the number of particles each having a particle diameter D, and Σ n is the total number of particles. The term "D₅₀"means the particle size (average particle size) when the cumulative particle size distribution is 50%. The average particle size can be measured using a dry laser diffraction method. For example, the volume average particle size may be determined from the diffraction intensity obtained by irradiating a laser to a powder sample ejected by compressed air, as in a method using "Mastersizer 3000" (trade name; product of Malvern instruments ltd (Malvern) in england) or "HELOS" (trade name; product of nepadtex ltd (Sympatec) in germany).

The hydroxyalkyl alkylcelluloses preferably have a bulk density of from 0.05 to 0.5g/mL, more preferably from 0.1 to 0.4g/mL, still more preferably from 0.1 to 0.3 g/mL. When the bulk density is less than 0.05g/mL, miscibility or fluidity with a drug may be reduced when the hydroxyalkyl alkylcellulose is contained by a tablet. When the bulk density is more than 0.5g/mL, formability may deteriorate.

The term "bulk density" means the bulk density in a loose-packed state and is determined by: a cylindrical container made of stainless steel and having a diameter of 5.03cm and a height of 5.03cm (capacity: 100ml) was uniformly filled, wherein the sample was passed through a JIS22 mesh sieve having an opening of 710 μm at 23cm above the container, thereby flattening the top surface of the sample, and then weighed.

Hydroxyalkyl alkylcelluloses are nonionic polymers obtained by etherification of some of the hydroxyl groups on the glucose ring of cellulose. Examples of hydroxyalkyl alkylcelluloses include hydroxypropyl methylcellulose and hydroxyethyl methylcellulose. Among them, hydroxypropylmethylcellulose is particularly preferable from the viewpoint of formability and disintegratability.

The degree of substitution of the hydroxyalkyl alkylcellulose is not particularly limited. For example, hydroxypropylmethylcellulose has a degree of substitution with methoxy groups of preferably 16.5% to 30.0% by weight, more preferably 19.0% to 30.0% by weight; and has a degree of substitution of hydroxypropoxy groups of preferably 3.0% to 32.0% by weight, more preferably 3.0% to 12.0% by weight. These degrees of substitution can be measured using a method based on the determination of the degree of substitution of hydroxypropylmethylcellulose (hypromellose) in the japanese pharmacopoeia (16 th edition).

Next, a solid preparation containing hydroxyalkyl alkylcellulose will be described.

Since the hydroxyalkyl alkylcellulose has high formability, the hardness of the tablet can be enhanced even with a small amount of addition of the hydroxyalkyl alkylcellulose when the tablet is prepared by dry direct compression or dry granulation compression. Although the meaning of the term "small" in the "small amount" differs depending on the weight or shape of the tablet or the type of drug contained in the tablet, the content of the hydroxyalkyl alkylcellulose in the solid preparation is preferably 20% by weight or less, more preferably 10% by weight or less, still more preferably 5% by weight or less. When the content is more than 20% by weight, the disintegration time may be deteriorated, but the tablet hardness is increased. Although the lower limit of the hydroxyalkyl alkylcellulose content differs depending on the weight or shape of the tablet or the type of the drug contained in the tablet, the hydroxyalkyl alkylcellulose content is preferably 0.1% by weight or more, more preferably 1% by weight or more. When the content is less than 0.1% by weight, the desired formability may not be obtained.

Next, a method for preparing hydroxyalkyl alkylcellulose will be described.

The alkali metal hydroxide solution and the pulp are brought into contact with each other by a conventional method to obtain alkali cellulose. The pulp may be in the form of flakes or chips, preferably in the form of powder obtained by grinding in a grinder. The step of contacting the pulp with the alkali metal hydroxide solution may be preferably performed in a reactor having an internal stirring structure.

The thus obtained alkali cellulose is reacted with an etherifying agent by a conventional method to obtain a first (high polymerization degree, before depolymerization) hydroxyalkyl alkylcellulose.

Etherifying agents suitable for producing the first hydroxyalkyl alkylcellulose are known and not particularly limited. Examples of etherifying agents include alkylating agents such as methyl chloride and hydroxyalkylating agents such as propylene oxide or ethylene oxide.

The first hydroxyalkyl alkylcellulose obtained by the etherification reaction may optionally be purified and/or dried by conventional methods.

The purification method or the apparatus to be used for purification is not particularly limited. The purification process or apparatus is preferably a washing process or a washing apparatus using hot water, preferably water, more preferably 85 ℃ to 100 ℃.

The drying method or the apparatus to be used for drying is not particularly limited. The drying method or apparatus is preferably a method or apparatus capable of setting the temperature of the first hydroxyalkyl alkylcellulose at 40 ℃ to 80 ℃ during drying.

The viscosity of a 2% by weight aqueous solution of the first hydroxyalkyl alkylcellulose at 20 ℃ (optionally after purification and/or drying) is preferably greater than 20 mPa-s, more preferably from 50 to 200,000 mPa-s, still more preferably from 100 to 10,000 mPa-s, particularly preferably from 100 to 3000 mPa-s. With respect to the viscosity of an aqueous solution of the first hydroxyalkyl alkylcellulose at 20 ℃ at 2% by weight, the viscosity of 600mPa · s or more can be measured using a type B viscometer according to JIS Z8803, and the viscosity of less than 600mPa · s can be measured using an Ubbelohde viscometer according to JIS K2283-1993. The first hydroxyalkyl alkylcellulose is optionally ground after purification and/or drying to particles having an average particle size of preferably 5 to 200 μm, more preferably 10 to 100 μm, in order to have the hydroxyalkyl alkylcellulose with the above-mentioned specific surface area as the final product. After milling, the resulting particles may optionally be classified by a sieve having a predetermined opening size to control the specific surface area.

The grinding method or the apparatus to be used for grinding is not particularly limited. The apparatus is preferably an impact (impact) grinder such as "Turbo Mill" (trade name; product of Freund-Turbo Corporation), "PPSR" (trade name: product of Pallmann Industries), "virtory Mill" (trade name; product of Hosokawa Micron Corporation), and "Jet Mill" (trade name; product of Nippon Pneumatic Mfg co., Ltd.); or a pressure mill (compaction mill) such as a vibration mill, a ball mill, a roll mill, and a bead mill, in order to obtain a high specific surface area.

Next, the first hydroxyalkyl alkylcellulose is depolymerized to a second (low degree of polymerization, after depolymerization) hydroxyalkyl alkylcellulose. Further improvements in formability can be expected from depolymerization which reduces the degree of polymerization. Depolymerization is carried out by hydrolysis in the presence of an acid catalyst or oxidative degradation in the presence of an oxidizing agent. The depolymerization is preferably carried out by hydrolysis in the presence of an acid catalyst.

Examples of the acid to be used for depolymerization by hydrolysis in the presence of an acid catalyst preferably include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid. The acids may be used alone or in a combination of two or more acids.

The acid to be added to the system is in gaseous form or in solution. The acid is preferably added as a solution. The amount of acid to be added is preferably 0.1 to 3.0% by weight, more preferably 0.15 to 1.5% by weight, relative to the weight of the hydroxyalkyl alkylcellulose.

The internal temperature during depolymerization is not particularly limited, and is preferably 50 ℃ to 130 ℃, more preferably 60 ℃ to 110 ℃, still more preferably 60 ℃ to 90 ℃. The depolymerization time is preferably set based on the respective viscosities of 2% by weight aqueous solutions of the first (pre-depolymerization) hydroxyalkyl alkylcellulose and the second (post-depolymerization) hydroxyalkyl alkylcellulose at 20 ℃ and the depolymerization conditions.

The viscosity of a 2% by weight aqueous solution of the second hydroxyalkyl alkylcellulose obtained after depolymerization is preferably from 1 to 15 mPa-s.

When the thus obtained second hydroxyalkyl alkylcellulose has a specific surface area outside the scope of the present invention, the second hydroxyalkyl alkylcellulose may be further ground to obtain a hydroxyalkyl alkylcellulose having the specific surface area of the present invention. The specific surface area can be controlled by classifying the milled hydroxyalkyl alkylcellulose through a sieve or the like having a predetermined opening size. The grinding method or the device to be used for grinding is not particularly limited, and the above-mentioned device or the like can be used. The sieve to be used for classification is not particularly limited, and preferably includes sieves such as JIS 200 mesh sieve having 75 μm openings, JIS 235 mesh sieve having 63 μm openings, JIS 330 mesh sieve having 45 μm openings, JIS 390 mesh sieve having 38 μm openings.

Next, a method for producing a solid preparation comprising the resulting hydroxyalkyl alkylcellulose for tableting will be described.

The solid formulation can be obtained by: the hydroxyalkyl alkylcellulose for tableting is tableted or granulated together with the drug and various types of additives commonly used in the art, such as excipients, disintegrants, binders, anti-aggregation agents or solubilizers for pharmaceutical compounds. Examples of the solid preparation include tablets, granules, powders and capsules.

Among the above, the tablet can be prepared by any one of dry direct compression, dry granulation compression, wet agitation granulation compression and fluidized bed granulation compression. Dry direct compression and dry granulation compression are particularly preferred because they do not require dissolution of the hydroxyalkyl alkylcellulose.

Dry direct compression is a process comprising the following steps: the hydroxyalkyl alkylcellulose for tableting, the drug, the optional excipient, the optional disintegrant, the optional lubricant, and the like are dry-blended to obtain a mixture and the mixture is tableted. Since the dry direct compression does not include a granulation step, the preparation process can be simplified. Therefore, dry direct compression is a high throughput process.

The dry granulation tabletting is a method comprising the following steps: the hydroxyalkyl alkylcellulose for tableting, the drug, an optional excipient, an optional disintegrant, an optional lubricant, and the like are compression-granulated to obtain granules and the granules are tabletted. Dry granulation tableting is a method effective for water or solvent sensitive drugs. The granules may be obtained, for example, by compacting by rollers using a compaction granulator such as a roller compactor. The roller pressure differs depending on the physical properties of the powder, and is preferably 1 to 30MPa, more preferably 2 to 12 MPa. The rotational speed of the rollers is preferably 1 to 50rpm, more preferably 2 to 20 rpm. The rotation speed of the screw is preferably 1 to 100rpm, more preferably 2 to 50 rpm. The flakes obtained by the roll compression are ground and sized into a tableting powder by using a grinder or a pulverizer such as a driven mill (comil), a rapid-grinding pulverizer, or an electric grinding pulverizer.

Hydroxyalkyl alkylcelluloses for tableting can also be used for orally disintegrating tablets which have been actively studied in recent years.

The drug to be contained in the solid preparation containing the hydroxyalkyl alkylcellulose of the present invention is not particularly limited as long as it can be orally administered. Examples of such drugs include drugs for the central nervous system; drugs for the cardiovascular system; medicaments for the respiratory system; drugs for the digestive system; (ii) an antibiotic; antitussives and expectorants; an antihistamine; analgesic, antipyretic and anti-inflammatory agents; a diuretic; a botanical nerve agent; an antimalarial drug; an antidiarrheal agent; (ii) a psychotropic drug; and vitamins and their derivatives.

Examples of the drugs used in the central nervous system include diazepam (diazepam), idebenone (idebenone), aspirin, ibuprofen (ibuprofen), paracetamol (paracetamol), naproxen (naproxen), piroxicam (piroxicam), diclofenac (dichlofenac), indomethacin (indomethacin), sulindac (sulindac), lorazepam (lorazepam), nitrazepam (nitrazepam), phenytoin (phenoytoin), acetaminophen (acetaminophen), ethenzamide (ethenzamide), ibuprofen (ketoprofen), and chlordiazepoxide (chlordiazepoxide).

Examples of drugs for the cardiovascular system include molsidomine (molsidomine), vinpocetine (vinpocetine), propranolol (propranolol), methyldopa, dipyridamole (dipyridamol), furosemide (furosemide), triamterene (triamterene), nifedipine (nifedipine), atenolol (atenolol), spironolactone (spironolactone), metoprolol (metoprolol), pindolol (pindolol), captopril (captopril), isosorbide dinitrate (isosorbide nitrate), delapril hydrochloride (delapril hydrochloride), meclofenoxate hydrochloride (meclofenoxate hydrochloride), diltiazem hydrochloride (delapride hydrochloride), eforelin hydrochloride (etilefrilodone hydrochloride), dihydroxanthosine (dihydrochlorid), and prozolirtiol hydrochloride (hydrochloride).

Examples of drugs for the respiratory system include amlexanox, dextromethorphan, theophylline, pseudoephedrine, salbutamol, and guaifenesin.

Examples of the drugs used in the digestive system include benzimidazole-based drugs having an antiulcer effect such as 2- [ (3-methyl-4- (2,2, 2-trifluoroethoxy) -2-pyridyl) methylsulfinyl ] benzimidazole and 5-methoxy-2- [ (4-methoxy-3, 5-dimethyl-2-pyridyl) methylsulfinyl ] benzimidazole (benzimidazole), cimetidine (cimetidine), ranitidine (ranitidine), pirenzepine hydrochloride (pirenzepine hydrochloride), pancreatin (pancreatin), bisacodyl (bisacodyl), and 5-aminosalicylic acid.

Examples of antibiotics include phthalazinone hydrochloride (talampicilin hydrochloride), bacampicillin hydrochloride (bacampicilin hydrochloride), cefaclor (cephaclor), and erythromycin.

Examples of antitussives and expectorants include noscapine hydrochloride (noscapine hydrochloride), pentoxyverine citrate (carbendamide citrate), dextromethorphan hydrobromide (dextromethorphan hydrobromide), isornike citrate (isoaminile citrate), and dimemorfan phosphate (dimemorfan phosphate).

Examples of antihistamines include chlorpheniramine maleate, diphenhydramine hydrochloride, and promethazine hydrochloride.

Examples of analgesic, antipyretic and anti-inflammatory drugs include ibuprofen, diclofenac sodium, flufenamic acid, dipyrone (sulpyrine), aspirin and ketoprofen.

Examples of diuretics include caffeine.

Examples of the autonomic nerve drugs include dihydrocodeine phosphate (dihydrocodeine phosphate), racemic methylephedrine hydrochloride (dl-methamphrine hydrochloride), atropine sulfate (atropine sulfate), acetylcholine chloride (acetylcholine), and neostigmine (neostigmine).

Examples of antimalarial drugs include quinine hydrochloride (quinine hydrochloride).

Examples of antidiarrheals include loperamide hydrochloride (loperamide hydrochloride).

Examples of psychotropic drugs include chlorpromazine.

Examples of vitamins and derivatives thereof include vitamin a, vitamin B1, fursultiamine (fursultiamine), vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, calcium pantothenate, and tranexamic acid.

Examples of the excipient include sugars such as sucrose, lactose and glucose; sugar alcohols such as mannitol, sorbitol, and erythritol; starch; crystalline cellulose; calcium phosphate; and calcium sulfate.

Examples of the binder include polyvinyl alcohol, polyacrylic acid, polymethacrylic acid, polyvinylpyrrolidone, glucose, sucrose, lactose, maltose, dextrin, sorbitol, mannitol, polyethylene glycol (macrogols), acacia, gelatin, agar and starch, crystalline cellulose, and low-substituted hydroxypropylcellulose.

Examples of disintegrants include low substituted hydroxypropyl cellulose, carboxymethylcellulose and its salts, croscarmellose sodium, sodium carboxymethyl starch, crospovidone, crystalline cellulose, and crystalline cellulose sodium carboxymethyl cellulose.

Examples of lubricants and anti-agglomeration agents include talc, magnesium stearate, calcium stearate, colloidal silicon dioxide, stearic acid, waxes, hydrogenated oils, polyethylene glycol, and sodium benzoate.

Examples of solubilizers for pharmaceutical compounds include organic acids such as fumaric acid, succinic acid, malic acid, and adipic acid.

Examples

The present invention will be described more specifically below by way of examples. And should not be construed as limiting the invention to or by such embodiments. Those skilled in the art can make various modifications within the technical concept of the present invention.

< example 1>

A powdery pulp having a cellulose content of 6.0kg was placed in an internal stirring type pressure reactor. After the vacuum treatment, 15.4kg of an aqueous solution of 49% by weight of sodium hydroxide was added thereto, and stirred to obtain alkali cellulose. Then, 12.4kg of methyl chloride and 2.8kg of propylene oxide were added thereto, reacted with alkali cellulose, washed, dried, and ground to obtain a first (high polymerization degree, before depolymerization) hydroxypropylmethyl cellulose. The obtained first hydroxypropylmethylcellulose had a degree of substitution with methoxy groups of 29% by weight, a degree of substitution with hydroxypropoxy groups of 10% by weight and a specific surface area of 0.24m²(ii)/g, and a 2% by weight aqueous solution thereof has a viscosity of 1510 mPas at 20 ℃.

The first hydroxypropylmethylcellulose was added with a 12% by weight aqueous hydrochloric acid solution in an amount such as to have a concentration of 0.3% by weight based on the first hydroxypropylmethylcellulose. The internal temperature was controlled to 81 ℃ and depolymerization was performed for 200 minutes to obtain a second (low polymerization degree, after depolymerization) hydroxypropylmethylcellulose. The second hydroxypropyl methylcellulose thus obtained is ground using a high speed rotary impact Mill "victoriy Mill" equipped with a 0.3-mm open mesh (screen) to obtain the second hydroxypropyl methylcellulose intended. The resulting powder had a specific surface area, an average particle size, a bulk density and a viscosity in a 2% by weight aqueous solution at 20 ℃ as shown in table 1.

Next, the components of the following tablet composition (except magnesium stearate) were mixed in a plastic bag for 3 minutes, and then magnesium stearate was added and then mixed for 30 seconds. The resulting mixture was dried under the following tabletting conditions and directly compressed to obtain tablets. The tablet hardness and disintegration time of the thus obtained tablets were evaluated. The results are shown in table 1.

Composition of tablets

Fine acetaminophen powder (product of Yamamoto corporation): 50.0 parts by weight

Lactose hydrate (trade name "lactose S", product of Freund corporation): 44.5 parts by weight

Hydroxypropyl methylcellulose: 5.0 parts by weight

Light silicic anhydride: 0.5 part by weight

Magnesium stearate: 0.5 part by weight

Tabletting conditions

A tablet press: rotary tablet press (trade name "VIRGO"; product of Kikusui Seisakusho)

Tablet size: 200 mg/tablet, diameter (D)8mm and radius of curvature (R)12mm

Tabletting pressure: 10kN

Tabletting speed: 20rpm

< measurement conditions >

According to "method 2 in the Specific Surface Area by Gas absorption method" in the usual test (General Tests) of the Japanese pharmacopoeia (16 th edition): volume method "the specific surface area is measured by the BET (BET multipoint) method. It was measured by a gas adsorption method using an autoamtic specific surface area and porosimetry analyzer "TriStar II 3020" (trade name; product of Mimmeritick Co., Ltd.), at a relative pressure (P/P) of 0.05 to 0.30_o) In the context of refrigerants using nitrogen as the adsorbing gas and liquid nitrogen, where P_oRepresents the saturated vapor pressure and P represents the measured equilibrium pressure. The sample was absolutely dried before the measurement, since the sample had been held at 105 ℃ for two hours. The amount of sample used for measurement varies in the range of 0.5 to 2g depending on the type of sample.

The viscosity of a 2% by weight aqueous solution at 20 ℃ was measured as follows. When the viscosity was 600 mPas or more, the viscosity was measured using a type B viscometer according to JIS Z8803. When the viscosity is less than 600 mPas, the viscosity is measured using an Ubbelohde viscometer in accordance with JIS K2283-1993.

The average particle size was measured by laser diffraction with a fraunhofer approximation at a dispersion pressure of 2 to 3 bar and at a scattering intensity of 2 to 10% using a "Mastersizer 3000" (trade name; product of marvin instruments ltd, uk).

The bulk density was measured using a powder tester "PT-S" (product of Mikroo K.K.K.). The sample was uniformly supplied from 23cm above the container through a JIS22 mesh sieve having a 710 μm opening into a cylindrical container made of stainless steel and having a diameter of 5.03cm and a height of 5.03cm (capacity: 100ml), and weighed after flattening the top surface of the sample.

Tablet hardness was measured using a tablet hardness tester (trade name "TBH-125"; product of ERWEKA GmbH, Germany). A load was applied to the diameter direction of the tablet at a speed of 1 mm/sec and the maximum breaking strength at which the tablet was broken was measured.

According to the japanese pharmacopoeia (16 th edition), the disintegration time was measured by using pure water as a test liquid.

< example 2>

The milled second hydroxypropyl methylcellulose obtained in example 1 was sieved through a sieve having 38 μm-openings to obtain the desired hydroxypropyl methylcellulose powder. Physical properties of the powder and those of tablets obtained by dry direct compression in the same manner as in example 1 are shown in table 1.

< example 3>

A first (high polymerization degree, before depolymerization) hydroxypropylmethylcellulose was obtained in the same manner as in example 1, except that 8.2kg of an aqueous 49% by weight sodium hydroxide solution, 7.1kg of methyl chloride, and 1.6kg of propylene oxide were used. The obtained first hydroxypropylmethylcellulose had a degree of substitution with methoxy groups of 22% by weight and a degree of substitution with hydroxypropoxy groups of 9% by weight.

To the first hydroxypropylmethylcellulose was added a 12% by weight aqueous hydrochloric acid solution in an amount such as to have a concentration of 0.3% by weight based on the first hydroxypropylmethylcellulose. The internal temperature was controlled to 79 ℃ and depolymerization was performed for 160 minutes to obtain a second (low polymerization degree, after depolymerization) hydroxypropylmethylcellulose. The thus obtained second hydroxypropyl methylcellulose was ground using a Jet impact Mill "Jet Mill" (a product of japan pneumatic manufacturers) to obtain a ground second hydroxypropyl methylcellulose intended to be obtained. The powder characteristics of the milled second hydroxypropyl methylcellulose and the tablet characteristics of the tablet obtained by dry direct compression in the same manner as in example 1 are shown in table 1.

< example 4>

A first (high polymerization degree, before depolymerization) hydroxypropylmethylcellulose was obtained in the same manner as in example 1, except that 15.2kg of an aqueous 49% by weight sodium hydroxide solution, 12.2kg of methyl chloride and 1.7kg of propylene oxide were used. The obtained first hydroxypropylmethylcellulose had a degree of substitution with methoxy groups of 29.5% by weight and a degree of substitution with hydroxypropoxy groups of 6% by weight.

To the first hydroxypropylmethylcellulose was added a 12% by weight aqueous hydrochloric acid solution in an amount such as to have a concentration of 0.3% by weight based on the first hydroxypropylmethylcellulose. The internal temperature was controlled to 79 ℃ and depolymerization was performed for 140 minutes to obtain a second (low polymerization degree, after depolymerization) hydroxypropylmethylcellulose. The thus obtained second hydroxypropyl methylcellulose was ground using a Jet impact Mill "Jet Mill" (a product of japan pneumatic manufacturers) to obtain a ground second hydroxypropyl methylcellulose intended to be obtained. The powder characteristics of the milled second hydroxypropyl methylcellulose and the tablet characteristics of the tablet obtained by dry direct compression in the same manner as in example 1 are shown in table 1.

< example 5>

A first (high polymerization degree, before depolymerization) hydroxypropylmethylcellulose was obtained in the same manner as in example 1, except that 12.4kg of an aqueous 49% by weight sodium hydroxide solution, 10.0kg of methyl chloride and 0.8kg of propylene oxide were used. The obtained first hydroxypropylmethylcellulose had a degree of substitution with methoxy groups of 29.5% by weight and a degree of substitution with hydroxypropoxy groups of 3.1% by weight.

To the first hydroxypropylmethylcellulose was added a 12% by weight aqueous hydrochloric acid solution in an amount such as to have a concentration of 0.3% by weight based on the first hydroxypropylmethylcellulose. The internal temperature was controlled to 79 ℃ and depolymerization was performed for 160 minutes to obtain a second (low polymerization degree, after depolymerization) hydroxypropylmethylcellulose. The thus obtained second hydroxypropyl methylcellulose was ground using a Jet impact Mill "Jet Mill" (a product of japan pneumatic manufacturers) to obtain a ground second hydroxypropyl methylcellulose intended to be obtained. The powder characteristics of the milled second hydroxypropyl methylcellulose and the tablet characteristics of the tablet obtained by dry direct compression in the same manner as in example 1 are shown in table 1.

< example 6>

The ground second hydroxypropyl methylcellulose intended was obtained in the same manner as in example 5 except that the gap and grinding pressure in the classification zone were changed by using a Jet Mill "under grinding conditions. The powder characteristics of the milled second hydroxypropyl methylcellulose and the tablet characteristics of the tablet obtained by dry direct compression in the same manner as in example 1 are shown in table 1.

< comparative example 1>

The second hydroxypropyl methylcellulose was obtained in the same manner as in example 1. The second hydroxypropyl methylcellulose was used without milling by using a high speed rotary impact Mill "victoriy Mill". The powder characteristics of the second hydroxypropylmethylcellulose and the tablet characteristics of the tablet obtained by dry direct compression in the same manner as in example 1 are shown in table 1.

TABLE 1

As is apparent from table 1, the tablets comprising the hydroxypropylmethylcellulose obtained in each of examples 1 to 6 and obtained by dry direct compression exhibited high hardness even when the added amount was as small as 5% by weight, but no significant delay in disintegration time was observed.

< example 7>

The following powder mixture containing the milled second hydroxypropyl methylcellulose obtained in example 1 was dry granulated by using Roller compact MINI (product of Fowler Corp.) at a Roller pressure of 6MPa, a Roller speed of 4rpm and a screw speed of 5 rpm.

Composition of powder mixture

Fine acetaminophen powder (product of yamamoto corporation): 10.0 parts by weight

Lactose hydrate (trade name "Pharmatose 200M", product of DFE Pharma): 79.0 parts by weight

Hydroxypropyl methylcellulose: 10.0 parts by weight

Light silicic anhydride: 0.5 part by weight

Magnesium stearate: 0.5 part by weight

To the obtained granules, 0.5 part by weight of magnesium stearate was added, mixed for 30 seconds, and compressed under the following conditions to prepare tablets. The tablet properties of the tablets prepared are shown in table 2.

Tabletting conditions

A tablet press: rotary tablet press (trade name "VIRGO"; product of Japanese chrysanthemum)

Tablet size: 200 mg/tablet, diameter (D)8mm and radius of curvature (R)12mm

Tabletting pressure: 10kN

Tabletting speed: 20rpm

< example 8>

Dry granulation was performed in the same manner as in example 7, except that hydroxypropylmethylcellulose obtained in example 2 was used. To the obtained granules, 0.5 part by weight of magnesium stearate was added, mixed for 30 seconds, and compressed under the following conditions to prepare tablets. The tablet properties of the tablets prepared are shown in table 2.

< comparative example 2>

Dry granulation was performed in the same manner as in example 7, except that hydroxypropylmethylcellulose obtained in comparative example 1 was used. To the obtained granules, 0.5 part by weight of magnesium stearate was added, mixed for 30 seconds, and compressed under the following conditions to prepare tablets. The tablet properties of the tablets prepared are shown in table 2.

TABLE 2

As is apparent from table 2, compared with the results of comparative example 2, the tablets comprising the hydroxypropylmethylcellulose obtained in each of examples 7 to 8 and obtained by dry granulation tableting exhibited high hardness, but no delay in disintegration time was observed.