KR20010005746A - Chemically and thermally stable norastemizole formulations - Google Patents

Abstract

The present invention relates to a potent anti-histamine norastimazole pharmaceutical composition which is chemically and thermally stable. The composition is characterized by being lactose-free, non-hygroscopic, anhydrous, consisting of large particles or inert coated nolastemizol or a pharmaceutically acceptable salt thereof, which is stable and easy to manufacture.

Description

Chemically and thermally stable nolastemisol compositions {CHEMICALLY AND THERMALLY STABLE NORASTEMIZOLE FORMULATIONS}

Including the stability of the drug substance, the potential interactions between the drug substance and the inactive ingredient, the manufacturing process, packaging, environmental conditions encountered during shipping, storage and processing, the time it takes to manufacture and use, and the dosage form. Many factors affect the stability of pharmaceuticals. In addition to the physical stability, the chemical stability of the pharmaceutical substance should also be considered. Knowing the physical and chemical stability of pharmaceutical compositions is very important for at least three reasons.

First, pharmaceuticals must be new and have a professional approach. Changes in color and physical state, such as fading, color changes, and blurring, can cause patients to lose confidence in the drug. Second, some drugs are dispensed in a multi-dose container, so it is necessary to be able to dose the drug evenly over time. For example, non-uniform dosage patterns can be seen by blurry solutions, labile emulsions, uncolored tablets and capsules, and the like. Third, the therapeutic ingredient should be available to the patient for the expected shelf life of the drug. If the physical or chemical integrity of the drug is broken, the bioavailability of the therapeutic ingredient may be degraded or altered.

Various pharmaceutical forms have been used to successfully administer a variety of commercially available drugs. U.S. Common pharmaceutical dosage forms listed in the Pharmacopeia / National Formulary (USP / NF) include aerosols, capsules, cachets, eye washes, creams, emulsions, tablets, tablets, gels, inhalants, infusions, lotions, magma, milk, ointments Contains, plasters, pellets or transplanted tissue, powders, solutions, eye drops, oral medications, ear solutions, pastilles, topical solutions, alcohols, suppositories, suspensions, sublingual tablets, syrups, tablets, tinctures, pills, fragrant water, etc. But it is not limited to this. For oral administration, syrups, solutions, suspensions, pills, tablets and capsules are preferred. However, pills, tablets, and hard and soft gel capsules are most preferred for easier administration, to make delivery easier, and to better manage the patient according to the prescribed dosage. In some cases, tablets are preferred over capsules because pills are easier to swallow.

Pills, tablets and capsules include excipients such as drug compositions, diluents, lubricants and the like, which are known in the art. Examples of well-known excipients include coatings, dyes, desiccants, emulsions, solubilizers, fragrances, anti-agglomerates, plasticizers, suspensions, viscosity increasing agents, binders, diluents, wetting agents and the like.

Lactose is most widely used as a diluent or excipient. Spray-dried lactose is a commonly used form of lactose, which is widely used as a direct compression excipient. Since spray-dried lactose has been used, its use as an excipient has skyrocketed. Rapid acceptance of spray-dried lactose is because it can be easily integrated into a direct compression tablet. In this application, the spray-dried lactose is in ready-to-use form and does not require the introduction of complex processing procedures and does not require additional granulation processes. Spray-dried lactose can be added directly to the drug to achieve the desired dilution ratio. Thereafter, the combination of lactose and drug may be dry compressed into tablets or formed into pills or capsules with other excipients if necessary.

Whether spray-dried or not, lactose is in equilibrium between the alpha and beta forms, which continues to convert between them. α-lactose is a disaccharide of β-D-galactose and α-D-glucose. β-lactose is a disaccharide of β-D-galactose and β-D-glucose. β-lactose appears only in the anhydride form, while α-lactose can be obtained in the anhydride form or in the hydroxide form.

During the conversion between alpha and beta of lactose, an aldehyde intermediate composition is formed, which is known to be incompatible with most primary amines. Primary amines are bonded to the carbonyl carbon of the aldehyde to form imines:

The incompatibility of most primary amines with lactose is well known. Castello et al., J. Pharm. Sci., 51 (2): 106-108 (Feb. 1962). See also, Blaug et al., J. Pharm. Sci., 61 (11): 1770-1775 (Nov. 1972); Hartauer et al., Drug Dev. and Indust. See Pharm., 17 (4): 617-630 (1991).

Castello et al. Tested the compatibility of lactose with amphetamine sulfate. They found that the mixture of lactose and amphetamine sulfate was not colored, especially in the presence of an alkaine lubricant such as magnesium sterate. Blaug et al. Tested spray-drying lactose and dextroamphetamine sulfate (primary amine salt). They found that lactose forms a siphon base (eg, imine) in the presence of fluoroamphetamine sulfate. Hartauer et al. Found incompatibility between aminophylline and lactose, especially when heated to about 60 ° C., which turned out not to be colored. Aminophylline comprises two molecules of theophylline (secondary amine) for one molecule of ethylene diamine (primary amine). However, Hartauer et al. Tested this component and found that theophylline (secondary amine) does not react with lactose, regardless of whether it is heated to 60 ° C or not, and ethylene diamine reacts with lactose when heated to 60 ° C. . Therefore, it can be seen that lactose and aminophylline are not compatible due to the incompatibility between the primary amine component of aminophylline and ethylenediamine and lactose.

Astemizole, secondary amine, can be combined with lactose, HISMANAL in tablet dosage form containing lactose It is marketed by. Physician's Desk Reference, 50th Edition, Medical Economics Co., Montvale, NJ, p. According to 1293 (1996), Hismanal Each tablet of contains 10 mg astemisol, lactose, corn starch, microcrystalline cellulose, gelled starch, povidone K90, magnesium stearate, colloidal silicon dioxide and sodium lauryl sulfate.

As such, the major metabolite of nolastemizole, other secondary amines, and astemisol must be combined with lactose, especially when not heated. Nolastemizol has been reported to be more potent and less toxic than astemizol. Therefore, nolastemizol can replace asemizol to treat allergic diseases. Astemisol and nolastemizole are antihistamines containing 1/2 of a secondary amine: However, nolastemizole contains two secondary amines, while astemisol contains only one secondary amine. .

This application is a continuation of 08 / 851,786, filed May 6, 1997, and a continuation of 08 / 824,477, filed March 26, 1997, the entire contents of which are incorporated herein by reference.

The present invention relates to chemically and thermally stable pharmaceutical compositions comprising nolastemisol.

BRIEF DESCRIPTION OF THE DRAWINGS FIG.

FIG. 2 is a bar graph showing the change in the initial efficacy of the dosage form of norastimazole and various pharmaceutical excipients when the dosage form is exposed to a temperature of 60 ° C. at 75% relative humidity using a non-welded container.

Applicants have found that decolorization reactions between primary amines and lactose occur in norastimazole even without heating. Thus, it is believed that there is an incompatibility between secondary amines, nolastemizol and lactose not recognized until now. Therefore, it is preferable to formulate lactose-free nolastemizol. In addition, the Applicant has discovered that the instability of lactose and nolastemizol can be initiated or accelerated when the nolastemizol / lactose composition is exposed to water (humidity), including atmospheric moisture. Instability is also initiated or accelerated upon exposure to heat above 60 ° C. Moreover, the Applicant has found that the instability of lactose and nolastemizol is initiated or accelerated due to the high surface area of the small nolastemisol particles conventionally used in pharmaceutical compositions upon exposure of the nolastemizol / lactose composition. In addition, the Applicant has found that the instability of lactose and nolastemizol can be prevented by coating the nolastemisol particles prior to the combination of nolastemizole and lactose, which is a reactive excipient.

In the PCT application PCT / US93 / 08349 known from WO94 / 07494 a nolastemizole composition is proposed in Example 4, which is lactose deficient. Compositions A, B and C of Example 4 each comprise 1.0 wt% magnesium stearate BP, 94.0, 89.0 and 79.0 wt% starch 1500 (pre-gelatinized starch available from colorcon, Ltd.) and the remaining ingredients It is a metabolite of astemizol (norastemizol). However, magnesium stearate BP and starch 1500 would be incompatible at published weight ratios and would not produce or utilize the lactose-free composition of Example 4. In other words, the composition of Example 4 of the PCT application is not suitable for practical pharmaceutical use. In addition, the publication neither discloses nor suggests the incompatibility of norastamazole and lactose as evidenced by the lactose containing tablet composition of norastimazole in Example 5.

In view of the problems associated with pharmaceutical compositions containing secondary amines, nolastemizol and lactose, it is desirable to prepare stable solid pharmaceutical compositions of nolastemizole that prevent incompatibility between nolastemisol and lactose. The present invention provides a lactose-type nolastemizol composition.

There is a need for a stable, high performance nolastemizole based on the pharmaceutical advantages of nolastemizol as compared to astemizol. To date, there are no stable nolastemisol compositions commercially available. However, the inventors have found that the lactose-free nolastemisol composition is chemically, physically and thermally stable by removing lactose and using another component. Such stability can be achieved by the present invention without loss of ease of manufacture or performance.

Thus, one aspect of the present invention is to provide a chemical and thermally stable pharmaceutical composition comprising a carrier or excipient that contains or does not utilize lactose and norastimazole or a pharmaceutically acceptable salt thereof. Lactose has been widely used in the pharmaceutical industry because of its ease of manufacture. However, Applicants have found that compositions containing noracemazole and lactose are unstable over time and deteriorate quickly upon exposure to heat and moisture.

Secondary amines are soluble with lactose at ambient temperatures with minimal exposure to heat (below 60 ° C). Astemisol drugs are commercially available under the trademark Hismanal as tablets containing lactose and other excipients.

It has been found that there is a physical or chemical incompatibility between secondary amines, nolastemizol and lactose. The incompatibility between nolastemisol and lactose may be due to the formation of enamines due to the reaction between the aldehyde intermediate of lactose and the secondary amine.

C-CH = O + HNR ₂ → C = C-NR ₂ (enamine) + H ₂ O

It has also been found that incompatibilities exist even at ambient temperatures (below 60 ° C) and principal surface humidity. In addition, the Applicant has found a highly stable pharmaceutical composition containing nolastemizole without using lactose, a widely used excipient.

According to one aspect of the present invention norastamazole is provided in a lactose-type pharmaceutical composition. The composition has antihistamine efficacy and is useful for the treatment of various conditions. Examples of such conditions include allergic rhinitis, asthma and dizziness, motion sickness, vestibular disorders (Meniere's disease), retinopathy caused by diabetes mellitus, and other allergic disorders including diabetic disorders associated with diabetes.

Such lactose-like compositions provide a stable and convenient dosage form for administering nolastemizol to humans. The lactose composition of the present invention has a stable and long shelf life. In addition, the compositions of the present invention remain stable even when exposed to warm temperature and humidity changes. In addition, although the composition is lactose-free, it is easy to manufacture the composition and the composition has desirable administration performance. The composition of the present invention comprises a solid unit dosage composition comprising nolastemizol or a salt thereof and at least one non-lactose type excipient. The composition also includes other therapeutic ingredients, binders / fillers, lubricants, disintegrants, anti-cake forming agents, preservatives, film coatings, sweeteners, colorants, fragrances, desiccants, plasticizers, dyes, dispersants or surfactants. However, these accessory ingredients are compatible with nolastemisol and secondary amines to ensure stability of the composition.

The no lactose-type nolastemizole composition prepared according to the present invention comprises nolastemisol and at least one non-lactose type excipient. Examples of such excipients are known in the art and are listed in USP (XXI) / NF (XVI). Non-lactose nolastemizole dosage forms prepared according to the present invention also include lubricants, binders / fillers, and nolastemizole in pharmaceutically acceptable amounts. The non-lactose nolastemisol dosage compositions prepared according to the present invention also include nolastemisol, microcrystalline cellulose, pre-gelatinized starch and magnesium stearate.

Other sugars, such as fructose and sucrose, have been found to result in lactose-like degradation when used in combination with nolastemizole containing compositions. Thus, in another embodiment, the lactose-free pharmaceutical composition comprises nolastemizol or a salt thereof and at least one excipient and does not contain monosaccharides or disaccharide excipients including glucose, fructose and sucrose.

Nolastemisol compositions containing lactose disintegrate rapidly upon exposure to unbound water (humidity or humidity). The addition of water (eg 5%) is widely accepted in the pharmaceutical field as a means of simulating long-term storage in order to measure properties such as shelf life or stability of the composition over time (Jens T. Carstensen, Drug Stability: Principles & Practice, 2d.Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80). Indeed, water and temperature facilitate research.

Moreover, the effect of water on the composition is very important because the hygroscopic conditions (humidity or humidity) are frequently encountered during the manufacture, handling, packaging, storage, shipping and use of the composition. Therefore, the use of lactose in pharmaceutical compositions containing nolastemizol should be avoided due to the significant contact with moisture or humidity experienced by the composition under the conditions of manufacture, packaging and storage.

Moreover, although excipients other than lactose can be readily used in the preparation of lactose-free nolastemisol compositions without affecting the preparation and therapeutic performance of the composition, spray-dried lactose can continue to be used as excipients. In spray-dried form, lactose is the best of all direct compression fillers in flowability and is very effective in small dosage compositions (<50 mg / dose) when the compatibility of the active ingredient does not play a significant role (R. Shangraw, Selection of Manufacturing Process and Excipients with an Emphasis on Direct Compression, Course material from Granulation, Tableting, and Capsule Technology, Center for Professional Advancement, East Brunswick, NJ, 1996). Therefore, it is desirable to include lactose in solid dosage forms or compositions of nolastemizol.

Therefore, in another aspect of the present invention there is provided a thermally and chemically stable pharmaceutical composition, in particular a solid composition, comprising at least one excipient comprising norastimazole or a salt thereof and lactose, the lactose containing composition being anhydrous. That is, there is no unbound water.

The present invention also encompasses thermal and chemically stable non-hygroscopic pharmaceutical compositions composed of one or more excipients or components, including norastimazole or salts thereof and lactose. These stable, anhydrous or non-hygroscopic pharmaceutical compositions are based on the discovery that the incompatibility between nolastemisol and lactose or other disaccharides or polysaccharides is promoted or initiated by exposure of the composition to unbound water. Thus, the preparation of pharmaceutical compositions without unbound water prevents the accelerated degradation of nolastemisol, which occurs when reactive excipients are used and unbound water is present.

Thus, when lactose is an excipient that requires it, another aspect of the present invention relates to a non-hygroscopic or anhydrous pharmaceutical composition comprising nolastemizol, lactose and additional excipients or components, wherein the resulting pharmaceutical composition is free of unbound water. It features. Non-hygroscopic or anhydrous compositions can be prepared by standard methods if a suitable excipient is selected so that the resulting pharmaceutical composition is non-bonded and the process is carried out at low humidity conditions.

Anhydrous nolastemisol pharmaceutical compositions prepared according to the present invention must be prepared and stored so as to maintain their anhydrous properties. Thus, these compositions are packaged using materials known in the art to prevent pharmaceutical compositions from being exposed to water and are included in suitable kits. Such packaging is a sealed foil or plastic, unit dose container, blister pack or strip pack.

A second aspect of the present invention is a method for preparing a solid pharmaceutical composition comprising norastamazole and lactose, the method comprising mixing lactose with norastamazole or a salt thereof under anhydrous or low humidity conditions, wherein the components are non-bonded water It is characterized by none. The present invention includes the step of packaging the anhydrous or non-hygroscopic solid nolastemisol composition under low humidity conditions. The use of these conditions reduces the risk of contact with water and prevents decomposition of nolastemisol during processing and storage. In addition, the final packaged product is free of unbound water to improve stability and prevent degradation. Such compositions may be provided in sealed packaging such as vials, sealed packets, blister packs and other vacuum sealed, moisture free containers.

When the pharmaceutical composition is prepared, the active ingredient or therapeutic agent (eg, norastimazole) is ground and screened to narrow the particle size distribution and reduce the particle size. This is done to optimize various physicochemical properties of the composition such as dissolution, uniformity of content, bioavailability of the active ingredient. In the case of nolastemisol, solubility is very low (10 mg / mL) at pH 3-4 and pH 4 so that dissolution is an important problem. However, the interaction between nolastemizol and reactive excipients (such as lactose) may be affected by the surface area of nolastemizole in the pharmaceutical composition.

Accordingly, in another embodiment of the present invention there is provided a pharmaceutical composition comprising a large noracemazole particle or a salt thereof and a carrier and treating histamine induced disorders. Suitable carriers for use in this composition are one or more excipients selected from inert excipients such as lactose or other monosaccharides or disaccharides and reactive excipients. Large nolastemisol particles have adequate physicochemical properties (dissolution, content uniformity, bioavailability) but show no incompatibility with reactive excipients such as lactose.

In a preferred embodiment, the nolastemizol or salt thereof present in the composition has a particle size distribution such that at least 40% by weight of nolastemizol or a salt thereof comprises particles having a size of at least 200 μm, in particular at least 250 μm.

Another means of preventing the interaction between nolastemisol and reactive excipients such as lactose in pharmaceutical compositions is to prevent contact of nolastemisol with reactive excipients of the composition. One method is to coat the nolastemisol particles with an inert or non-reactive coating prior to compounding with the reactive excipient. Inert coatings should not significantly affect the pharmaceutical properties of the composition (efficacy time, in vivo absorption time).

Accordingly, another aspect of the present invention relates to a solid pharmaceutical composition comprising a nolastemizol or salt thereof and a carrier coated with an effective amount of an inert coating for the treatment of histamine induced disorders. In a preferred embodiment, the nolastemizol or salt thereof is granulated with an inert excipient (eg starch) and the resulting granules are coated with an inert or non-reactive coating. The coated nolastemisol is then blended with other excipients, including reactive excipients.

Suitable inert coatings and methods for coating the particles or granules are known in the art. Inert coatings include inert film formers dispersed in suitable solvents and may include auxiliary ingredients such as colorants and plasticizers. In particular nolastemisol particles or granules are coated using aqueous and non-aqueous film coating techniques or microencapsulation. Suitable inert film formers include celluloses such as methyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, and sodium carboxymethyl cellulose; Vinyl such as polyvinyl pyrrolidone; Glycols such as polyethylene glycol; Acrylics such as dimethylaminoethyl methacrylate-methacrylic acid copolymer and ethylacrylate-methylmethacrylate copolymer; Carbohydrate polymers such as maltotextrin and polytextrose. Inert coatings in particular include hydrophilic film formers such as hydroxypropyl methylcellulose such that absorption in vivo is not significantly delayed.

After the nolastemisol particles or granules are coated with an inert coating, the coated nolastemisol is combined with a reactive excipient such as lactose or an inert excipient using standard techniques such as blending, granulation, compression or a combination thereof to provide tablets, caplets Make various dosage forms, such as capsules and pills.

The amount of noracemazole in all dosage forms prepared according to the invention should be effective and pharmaceutically acceptable for treatment. The actual dosage level of nolastemizol in the pharmaceutical composition of the present invention may be adjusted to such an amount as to achieve the therapeutic response required for a particular patient, the pharmaceutical composition of nolastemizol, and the dosage form without toxicity to the patient.

Selected levels and frequencies of administration of the compositions of the present invention may be determined by the route of administration, time of administration, rate of secretion of the therapeutic agent, including nolastemizol, duration of treatment, other drugs, compounds or substances used in combination with nolastemizol, age, sex, It depends on many factors, including weight, condition and medical history of the patient being treated. For example, the method of administration is different for pregnant women, nursing mothers, children and healthy adults.

Surgeons of ordinary skill in the art can readily determine and prescribe the effective amount of the required composition. For example, the administration of nolastemizol in the composition of the present invention can be started lower than the amount necessary to achieve the required therapeutic effect and gradually increased until the required effect is achieved.

The daily dose of nolastemizol is the lowest effective amount to produce the required therapeutic effect. This effective amount depends on the various factors described above. For example, the unit dose of the no lactose type nolastemizol is 1 to 200 mg, especially 2 to 100 mg. In addition, unit dosages may be formulated in a norastamazole content of 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg or 62.5 mg. If necessary, the effective daily dose of nolastemizol can be separated at daily intervals of 2, 3, 4, 5, 6 or more. Preferred dosage forms are tablets, caplets, capsules, pills, pastilles, pills, lozenges, syrups, capsules. However, powders, granules and pellets may be used.

All ingredients, including norasemizole dosage forms prepared according to the invention, meet or exceed the standards for pharmaceutical ingredients of USP / NF and combinations thereof. The purpose of the USP / NF is to provide standards for substances and jet methods used in the therapeutic field. The USP / NF establishes titles, definitions, descriptions, and standards, quality, strength, purity, packaging and labeling, bioavailability, stability, handling and storage procedures, inspection methods, and methods of manufacture.

Non-lactose, non-hygroscopic, large anhydrous particles, coated nolastemisol dosage forms meet the pharmaceutical standards described in USP / NF (USP XXI / NF XVI). The nolastemizole dosage forms are prepared using pharmaceutically acceptable ingredients in combination with at least the amounts described in USP XXI / NF XVI. In addition, nolastemizole can be prepared according to the method disclosed in US patent application 08 / 182,685 (1994.1.18).

The stability of a product is defined as the ability of a particular composition in a particular container to remain within physical, chemical, microbiological, therapeutic and toxicological criteria and to maintain a potential level of at least 90%. Thus, the shelf life is the time that the product remains stable when stored under the recommended conditions.

Various factors affect the stability of the product, including the stability of the therapeutic ingredient and the potential interactions between the therapeutic and inactive ingredients (eg norastimazole and excipients).

"Carrier" is synonymous with carrier. "Muractose type" means that the amount of lactose present is insufficient to result in incompatibility between noratemizole and lactose, and thus does not drop to less than 90% of the initial efficacy during shelf life. "Unbound water" means water that is not present in the form of a stable hydrate of one or more components of the pharmaceutical composition, such as alpha lactose monohydrate. "Anhydrous" means that the amount of unbound water present is insufficient to initiate or accelerate the incompatibility between nolastemisol and lactose. In addition, "anhydrous" means "anhydrous" or "anhydrous nature" means that there is no unbound water, including moisture. "Non-hygroscopic" means that the entire composition is non-hygroscopic and does not provide enough unbound water to initiate or promote incompatibility between reactive excipients such as norastimazole and lactose. "Additive" is used the same meaning as "excipient". The term "virtually free" means less than 5% by weight, in particular less than 1% by weight, even less than 0.1% by weight. "Large particles" means that the nolastemisol comprises at least 40% by weight of nolastemisol particles or salts thereof having a size of at least 200 μm, especially at least 250 μm. "Coated" "inert coating" or "inert coated" means that an inert coating is used to coat nolastemisol particles to prevent interaction with reactive excipients such as lactose. Conventional active coatings may be used in the lactose-free, non-hygroscopic, anhydrous and large particle compositions of the present invention, but the coating used is inert, thus preventing the interaction between nolastemisol and reactive excipients.

"Pharmaceutically acceptable" means suitable for use in contact with tissues and fluids of humans and animals without excessive toxicity, inflammation, allergic reactions, and the like. It also means that there is no chemical or physical incompatibility between nolastemizol (or salt thereof) and the excipient component. For example, an inappropriate chemical reaction is one in which the efficacy of nolastemizol is badly increased or decreased by the addition of excipients. Another example of an inappropriate chemical reaction is that only norastimazole (or a salt thereof) is over sweetened or soured. Each excipient must be "acceptable" in terms of compatibility with other ingredients and must not harm the patient.

Physical incompatibility refers to the incompatibility between nolastemisol (or salt thereof) and an excipient. For example, the combination of excipients and nolastemizole may form a mixture that is excessively hygroscopic or excessively separated so that the form of the composition (tablets, capsules, etc.), stability cannot be sufficiently maintained.

Antihistamines, such as astemisol or nolastemizol, are administered orally in solid dosage forms such as tablets, capsules, and caplets. In addition, capsules such as hard gelatin capsules and soft gelatin capsules may be used. However, tablets are preferred because they give the patient benefits (dose accuracy, compressibility, portability, easy administration, soft taste) and benefit the manufacturer (simplification and economy of manufacture, convenience and stability of packaging, shipping and bonsai). Tablets are solid dosage forms containing therapeutic drugs.

The crystalline or powdered material has numerous physical properties in order for the therapeutic material of the present invention (pressure-free, non-hygroscopic, anhydrous, large particle or coated nolastemisol dosage form) to be prepared in a solid dosage form (tablet) by applying pressure. It is necessary to have These characteristics include the property of freely flowing as a powder during compression and easily demolding from a tool. Since most materials do not have or have only some of these properties, methods for making tablets have been developed that give the material the properties of being compacted in tablets or similar dosage forms.

In addition to the drug or therapeutic ingredient, dosage forms such as tablets include additives. These additives are classified according to their role in dosage forms such as tablets, caplets, capsules and the like. Additives include binders, diluents (fillers), disintegrants and lubricants.

Although various additives used in the present invention may be mentioned for the non-lactose type, they may also be used in non-hygroscopic, anhydrous, large particle or coated compositions. In addition, the non-hygroscopic, anhydrous, large particulate or coated pharmaceutical compositions of the present invention may include lactose or other monosaccharides or disaccharides as excipients. In another embodiment, inorganic bisulfate may be used to improve the stability of the nolastemisol composition.

Care should be taken in the selection of excipients and additives in the case of non-hygroscopic compositions such that there is no tendency to adsorb moisture without proper control. For example, excipients used in such compositions are alpha lactose monohydrate, minitol.

In the case of anhydrous compositions anhydrous or low humidity excipients or additives such as AVICEL-PH-103 ^™ and Starch 1500 LM should be used.

The binder is used to provide a powder that flows free from the tablet component mixture to allow the material to flow when used in the purifier. The binder provides cohesiveness to the nolastemisol tablets. Too little binder results in problems with fluidity and results in tablets that do not maintain integrity. Too much binder adversely affects the release (dissolution rate) of the drug from the tablet. Therefore, the tablet must contain an amount of binder sufficient to provide a free flowing mixture of tablet components without adversely affecting the rate at which the drug component dissolves from the tablet. The amount of binder used depends on the form of the composition and the mode of administration.

Suitable binders for use in the non-lactose, non-hygroscopic, anhydrous, large particle or coated dosage compositions prepared according to the present invention include corn starch, potato starch or other starch, gelatin, acacia, sodium alginate, alginic acid, starvation. Alginate, powdered tragacanth, guar gum, cellulose and its derivatives (ethylulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized Natural and synthetic gums such as starch, hydroxypropyl methyl cellulose (2208, 2906, 2910), microcrystalline cellulose or mixtures thereof.

Suitable forms of microcrystalline cellulose are those sold under the AVICEL-PH-101, AVICEL-PH-103 and AVICEL-PH-105 (FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, PA., USA). . Exemplary suitable binders are carboxymethyl cellulose sodium mixtures such as AVICEL RC-581 available from microcrystalline cellulose and FMC.

The most commonly used tablets weigh about 100 mg to about 500 mg. Thus, for most potent drugs, including nolastemisol dosage forms, fillers are the majority of tablets. Fillers (eg, diluents) are used to provide powder volumes (eg, in tablets or capsules) to make tablets, capsules or other desired flavors of appropriate size. In general, therapeutic ingredients are combined to produce diluents in conventional dosage forms of the appropriate size. In the case of using the binder together, the binder is bound to the filler and affects the bioavailability. As a result, although a sufficient amount of filler should be used, the desired dilution ratio can be obtained without adversely affecting the release of the drug substance in the form containing the filler. In addition, fillers should be used that are in physical form comparable to the therapeutic ingredients. Thus, as noted, lactose should not be used with nolastemizole to make the nolastemisol dosage forms made according to the present invention, unless care is taken to remove unbound water. The nolastemisol dosage forms that do not include lactose according to the present invention suitably do not include monosaccharides or disaccharides, including but not limited to glucose, sucrose, fructose. The amount of filler used varies depending on the type of dosage form, the method of administration, and the like, which can be well recognized by those skilled in the art.

Suitable fillers that may be used in the nolastemisol formulations that do not contain lactose according to the present invention include talc, calcium carbonate (particles or powders), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, salicylic, Sorbitol, starch, pre-gelatinized starch or mixtures thereof.

The binder / filler in the pharmaceutical composition of the present invention will generally be about 50-99 wt% of the pharmaceutical composition.

Disintegrators are used to decompose the tablet when exposed to an aqueous environment. If there are too many disintegrants, atmospheric humidity will make tablets that decompose in the bottle, and the unbound water will initiate or accelerate the nolastemisol lactose interaction. In addition, too little disintegrant will not cause sufficient degradation, thus altering the rate and extent of drug release in the dosage form. Thus, a sufficient amount of disintegrant, not too much or too little, to make no adverse effect on the release of the drug component is used to make the nolastemisol dosage form according to the invention. The amount of disintegrant used varies widely depending on the type of dosage form and the mode of administration, which is well known to those skilled in the art. In general, pharmaceutical compositions include about 0.5 to about 15 wt%, suitably about 1 to 5 wt% disintegrant.

Suitable disintegrating agents used to make lactose-free nolastemisol formulations according to the invention include agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polyacrylic potassium, glycolate starch Include, but are not limited to, sodium, potato or tapioca starch, other starches, other ilgin, other celluloses, gums, or mixtures thereof.

Based on the physicochemical properties of nolastemizol, a non-hygroscopic, anhydrous, large particle or coated nolastemisol pharmaceutical composition that does not contain lactose, so that it dissolves rapidly when administered to an individual such as the stomach of the individual. It is generally preferable to prepare. Thus, in suitable embodiments, lactose-free, non-hygroscopic, anhydrous large particles or coated pharmaceutical compositions of the present invention include, but are not limited to, croscarmellose sodium or glycolate sodium. It includes.

Whatever the weak form, do not allow the weak component to adsorb to the punch of the machine making the powder. For example, in the case where a drug (such as nolastemizol) accumulates on the punch surface, a hole is formed in the weak surface and cannot be used. In addition, if a drug or other weak ingredient is stuck in this manner, an unnecessary release force must be used when removing the tablet from the die. Not to mention the wear of the die when using excessive ejection force, high destruction rate and production costs are raised. In practice, it may be possible to reduce the sticking by using a large amount of lubricant such as magnesium stearate or by wet-mashing. However, one method is to minimize this problem by selecting drug salts with good anti-adsorbent properties.

As mentioned above, the use of lubricants can enhance the transfer of lactose-free nolastemisol tablet powder mixtures to the tablet making machine and prevent the tablets from sticking to the die after the tablets are compressed. Using too much lubricant results in tablets that do not produce satisfactory tablets and that have a hydrophobic coating that, if used too much, will not penetrate water. Since lubricants are always hydrophobic materials such as stearic acid, magnesium stearate and calcium stearate, a hydrophobic coating will be formed that will not penetrate water if too much lubricant is used. In addition, hydrophobic coatings that do not penetrate the water prevent tablets from breaking down and prevent the drug from dissolving. Therefore, a sufficient amount of lubricant should be used to release the compressed tablets from the die without creating a hydrophobic coating that does not penetrate water, which will critically interfere with the desired degradation or dissolution of the drug component.

Suitable lubricants that may be used in the nolastemisol formulations that do not contain lactose according to the present invention include calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, la Usyl sulfate sodium, talc, hydrogenated vegetable oils (e.g. peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar or its Mixtures include, but are not limited to. Additional lubricants include Siloid Silica Gel (AEROSIL 200, manufactured by WR Grace Co. of Baltimore MD), Synthetic Silkyra Solidified Aerosol (Deaussa Co. of Plano, Texas), and CAB-O-SIL (Cabot Co. of Boston). , Pyrogenic silicon dioxide products sold by Mass) or mixtures thereof. Lubricants are optional additions and are generally included in less than about 1 wt% of the pharmaceutical composition.

Other types of additives used in nolastemisol dosage forms include, but are not limited to, agglomeration agents, antimicrobial preservatives, coatings, colorants, hygroscopics, flavoring and fragrances, plasticizers, viscosity increasing agents, sweeteners, buffers, wetting agents, and the like.

Suitable agglomeration agents for use in the nolastemisol formulations that do not contain lactose according to the present invention include, but are not limited to, silicate calcium, silicate magnesium, silicon dioxide, colloidal silicon dioxide, talc or mixtures thereof.

Suitable antimicrobial preservatives for use in nolastemisol formulations that do not contain lactose according to the present invention include benzalkonium chloride solution, benzetonium chloride, benzoic acid, benzyl alcohol, butyl paraben, cetylpyridium chloride, chlorobutanol, cresol , Dehydroacetic acid, ethyl paraben, methyl paraben, phenol, phenylethyl alcohol, phenyl mercury acetate, phenyl mercury nitrate, potassium sorbate, propyl paraben, benzoate sodium, dehydroacetate sodium, sodium propionate, sorbic acid, tee Mersol, thymol or mixtures thereof, including but not limited to.

Suitable coatings that may be used in the nolastemisol dosage forms that do not contain lactose according to the present invention include carboxymethyl cellulose sodium, cellulose acetate phthalate, ethylcellulose, gelatin, pharmaceutical glazes, hydroxypropyl cellulose, hydroxypropyl methylcellulose (E.g., 2208, 2206, 2910), hydroxy methyl cellulose phthalate (e.g., 200731, 220824), methylcellulose, polyethylene glycol, polyvinyl acetate phthalate, shellec, sucrose, titanium dioxide, carnuba wax, microcrystalline wax or Mixtures thereof, including but not limited to. The amount of coating and carrier (water soluble or non-water soluble) used will vary depending on the type of formulation and the mode of administration, but will be appreciated by those skilled in the art.

The polymer forming the film can optionally be provided for the nolastemisol tablets (capsule-shaped tablets are often called caplets) according to the invention, such as conventional coating pans, Accelacota, High-Cola or Worster air flotation columns. Use Such jeans generally have an exhaust system to remove dust, solvents or water vapor so that they dry quickly. Spray guns or other suitable atomization equipment may be used in the coating pan to provide a spray pattern to provide a fast and homogeneous coating to the tablets. Typically, the film coating solution is dried by providing heated or cold dry air over the tablet phase in a continuous or intermittent manner. For non-hygroscopic, anhydrous large particles or coated pharmaceutical compositions comprising reactive excipients such as lactose, a non-water soluble operation such as a non-water soluble coating should be used.

The coating solution can be sprayed using a positive hydraulic pretreatment or peristaltic pump system in a continuous or intermittent spray-drying process. The particular form of spraying is chosen depending on the drying efficiency of the coating pan.

In most cases, the coating material is sprayed onto the lactose-free, non-hygroscopic, anhydrous large particles or coated nolastemisol tablets until the desired tablet shape is made in the desired thickness. Various types of coatings may be used, such as enteric coatings, sustained release coatings, or types that dissolve rapidly for fast acting tablets. Suitably, use of a coating that dissolves quickly allows the active ingredient to be released quickly. The coating thicknesses of the polymers forming the films provided for tablets vary widely. However, it has a similar appearance, feel (texture and oral sensation) to gelatin capsules. In the case where the therapeutic substance is desired to be released more quickly or delayed, those skilled in the art will appreciate the type of film based on the basic characteristics such as the desired blood concentration of the active ingredient, the release rate, the solubility of the active ingredient, the desired function of the dosage form, and the like. The thickness may be easily determined.

Suitable materials for forming a suitable film used to coat lactose-free, non-hygroscopic, anhydrous, large formulations or coated nolastemisol dosage forms, such as methylcellulose, hydroxypropyl methyl cellulose (PHARMACOAT 606 6 cps), Polyvinylpyrrolidone (povidone), ethylcellulose (ETHOCEL 10 cps), various methacrylic acid and methacrylic acid ester derivatives, cellulose acetate phthalate or mixtures thereof, including but not limited to.

Suitable colorants for use in nolastemisol formulations that do not include lactose in accordance with the present invention include, but are not limited to, pharmaceutically acceptable colorants or scarlet pigments, caramel, red ferric oxide, yellow ferric oxide, or mixtures thereof. Desiccants that can be used in anhydrous, large particles or coated nolastemisol formulations that do not contain lactose according to the present invention include, but are not limited to, calcium chloride, calcium sulfate, silica gel, or mixtures thereof.

Suitable fragrances that can be used in the nolastemisol formulations containing no lactose according to the present invention include acacia, tragatan, almond oil, anetol, anise oil, benzaldehyde, caraway, caraway oil, cardamom oil, cardamom Seeds, Compound Cardamom Tincture, Cherry Juice, Cinnamon, Cinnamon Oil, Clove Oil, Cocoa, Coriander Oil, Eriodithione, Eriodiction Liquid Extract, Ethyl Acetate, Lavender Oil, Lemon Oil, Menthol, Methyl Salicylate, Glutamate Monosodium, nutmeg oil, orange flower oil, orange flower water, orange oil, sweet orange peel tincture, compound orange essence, peppermint, peppermint oil, peppermint essence, fine needle oil, rose oil, strong rose can, spearmint, spear Mint oil, thymol, tolu balsam tincture, vanilla, vanilla tincture, vanillin or mixtures thereof It is not limited to me.

Suitable plasticizers which may be used in the nolastemisol dosage forms without lactose according to the invention include castor oil, diacetylated monoglycerides, diethyl phthalate, glycerin, mono and di-acetylated monoglycerides, polyethylene glycol , But not limited to, propylene glycol, triacetin or mixtures thereof.

Suitable viscosity increasing materials that can be used in the nolastemisol formulations that do not contain lactose according to the present invention include acacia, agar, aramimic acid, monostearate aluminum, bentonite, bentonite magma, carbomer 934, carboxymethylcellulose calcium, carboxymethyl Sodium cellulose, sodium carboxymethylcellulose 12, carrageenan, cellulose, microcrystalline cellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxy methylcellulose (number 2208, 2906, 2910), silicate alunium Magnesium, methylcellulose, pectin, polyvinyl alcohol, povidone, silica gel, colloidal silicon dioxide, sodium alginate, tragatan, xanthan gum, or mixtures thereof.

Suitable sweeteners used in the nolastemisol dosage forms not containing lactose according to the present invention include, but are not limited to, aspartame, dexrate, mannitol, saccharin, saccharin calcium, saccharin sodium, sorbitol, sorbitol solution, or mixtures thereof. Do not.

Suitable buffers that can be used in the nolastemisol dosage forms that do not contain lactose according to the present invention include, but are not limited to, magnesium hydroxide, aluminum hydroxide or the like. Suitable humectants include, but are not limited to, glycerol, other humectants, or mixtures thereof. Norastemisol formulations of the invention include one or more of the following materials; (1) solution retardants such as paraffin; (2) absorption accelerators, such as quaternary ammonium compounds; (3) wetting agents, such as cetyl alcohol, glycerol monostearate; (4) absorbents such as kaolin and bentonite clay; (5) Water soluble antioxidants (such as ascorbic acid, hydrogen chloride cysteine, sodium disulfide, metabisulfate sodium, sulfite sodium, fat soluble antioxidants (such as ascorbyl palmitate, hydroxyanisol (BHA), butyl) Antioxidants such as hydroxylated hydroxy toluene (BHT), lecithin, propyl gallate, alpha-tocopherol, etc.) (6) metal chelating agents, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

The lactose-free, non-hygroscopic, anhydrous large particles or coated nolastemisol formulations according to the invention are provided as such as hard or soft gelatin caps and include various excipients as mentioned in tablets. In order to form tablets, nolastemizol may contain one or more excipients (e.g., diluents, binders, disintegrants, dispersants, surface-active substances, lubricants, coating materials, flavors, colorants, solvents, viscosity increasing agents, suspending agents, sweetening agents, Colorants, dyes, etc.) are mixed homogeneously using equipment to make known tablets such as twin cells or "V" type mixers. The exact amount of each of the various excipients may be determined by one of ordinary skill in the art of pharmacy.

The lactose-free, non-hygroscopic, anhydrous large particles or coated nolastemisol formulations according to the present invention may be used in addition to therapeutic drug ingredients in addition to diluents, binders, lubricants, disintegrants, colorants, flavors, sweeteners and the like. It further requires similar materials or mixtures thereof. The combination of such substances or other additives results in a variety of dosage forms (eg tablets, capsules, caplets, troches, etc.). These include hard gelatins, caplets, sugar-coated tablets, enteric-coated tablets to delay action, multiple compressed tablets, long-acting tablets, solution tablets, foaming agents, ball and sublingual tablets, and trophies. Included. It is appropriate that the sugar-coating does not contain lactose or monosaccharides or disaccharides, but in the case of sugar norastamazole there should be no unbound water.

The lactose-free, non-hygroscopic, anhydrous large particles or coated nolastemisol tablets according to the present invention are made using methods of molding, compression or general tableting. Thus, compressed tablets are usually made by large-scale production and molded tablets are made by small-scale operation. For example, there are generally three methods for preparing tablets for making nolastemisol formulations; (1) wet-granulation methods; (2) dry-granulation methods; (3) direct compression. These three methods are known and are referred to the following references; Remington's Pharmaceutical Sciences, 16th and 18th Eds., Mack Publishing Co., Easton, Pennsylvania (1980 and 1990). See also U.S. Pharmacopeia XXI, U.S. Pharmacopeial Convention, Inc., Rockville, Maryland (1985), in the case of non-hygroscopic or anhydrous formulations, preferably does not utilize a wet depletion process.

The lactose-free, non-hygroscopic, anhydrous large particles or coated nolastemisols according to the invention can be made into various formulations. This includes sugar-coated tablets, film coated tablets, enteric coating tablets, multiple compressed tablets, long acting tablets, and the like. Lactose-free, non-hygroscopic, anhydrous large particles or inert coated noracemazole sugar-coated tablets (SCT) are compressed tablets comprising a sugar coating. Such coatings may be colored and are beneficial to cover drugs with an unpleasant taste or smell or to protect oxidation sensitive materials. Lactose-free, non-hygroscopic, anhydrous large particles or coated nolastemisol film coated tablets (FCT) are compressed tablets coated with a water-soluble material film or a thin layer. Many polymeric materials having film forming properties are used. Film coating has the same general characteristics as in the case of sugar-coating and has the added advantage of significantly reducing the time required for coating operations. Lactose-free, non-hygroscopic, anhydrous large particles or coated nolastemisol enteric coatings (ECT) are compressed tablets that do not degrade in the stomach but degrade in the intestine. Enteric skin is used in the case of tablets that contain drugs that degrade or break down in the gastrointestinal tract, which is resistant to delayed release means or mucous membranes of the drug.

Lactose-free, non-hygroscopic, anhydrous large particles or coated nolastemisol multiple compressed tablets (MCT) are compressed tablets made in more than one compression process, such as layered tablets or press-coated tablets. do. Tablets with layers are made by compressing tablet granules in addition to the previously compressed tablets. This operation is repeated until a multilayer tablet with two, three or more layers is made. In general, certain tablet presses require tablets with layers. See, for example, US Pat. No. 5,213,738.

Press coated tablets are another form of multiple compressed tablets. Such tablets are also referred to as dry-coated tablets, which are made by feeding the compressed tablets back to the machine making the tablets, and compressing another excess layer around the preformed tablet. Such lactose-free, non-hygroscopic, anhydrous nolastemisol formulations have all the advantages of compressed tablets and retain sugar-coated tablets to hide the taste of drug substance in the core tablets. Squeezed coatings are also used to separate drugs that are incomparable to each other. In addition, they are used to provide enteric skin for core tablets. These two nolastemisol tablets (eg, layered tablets and compression-coated tablets) can be used to make long-acting dosage forms.

Lactose-free, non-hygroscopic, anhydrous large particles or coated nolastemisol long-acting tablets consist of compressed tablets that are formulated to release the drug in a manner that can have long-term efficacy. There are several types of tablets, including tablets that have a delayed action, such that the release of the drug is delayed until after a certain period of time after administration, or until a specific physiological condition is present. Repeated action tablets allow the complete release of the drug periodically into the gastrointestinal fluid. Prolonged release tablets are those in which the drug contained in the stomach is continuously increased and released.

The method of preparing the additives bound to the lactose-free, non-hygroscopic, anhydrous large particles or coated nolastemisol formulations is intended to have the desired physical characteristics to enable rapid tablet compression. After compression, the tablet should have additional various features such as appearance, hardness, degradability, homogeneity, which are made by the preparation method and the additives present in the tablet formulation.

The basic unit in all tablet pressing equipment consists of a lower punch, a subsequent eye, and an upper punch, which have the same shape and directivity as the lower punch, and from the top to the die hole when the material forming the tablet is filled into the die hole. Enter Tablets are made by the pressure exerted on the punch. In succession, tablets are released from the die. The weight of the tablet is determined by the volume of material that is opened in the die holes.

The lactose-free, non-hygroscopic, anhydrous large particles or coated nolastemisol formulations that move freely into the die cavity, or the ability of the dosage form, are of great importance for homogeneously filling. The excess fluidity is of great importance for the continuous movement of granules from the feedstock or feed hopper. In addition, in the case where the tablet granules do not have cohesiveness, they are crushed after pressing and are difficult to operate. In addition, because the punch must move freely in the die and the tablet must be released from the punch side, the material from which the tablet is made has a certain degree of lubrication to minimize friction and lubricity to remove the compressed tablet. Must have Granulation can be carried out by adding granules. The amount of granules used will vary depending on the type of formulation and the mode of administration, as will be appreciated by those skilled in the art. Generally, the pharmaceutical composition contains about 5-15 wt% of the granulating agent. Suitably, when lactose is present in the anhydrous or non-hygroscopic composition of the present invention, the granulating agent should be water-insoluble.

In addition, stable lactose-free, non-hygroscopic, anhydrous large particles or coated nolastemisol tablets or other formulations have their own size, shape, weight and color during their half-life under normal operating and storage conditions. Thus, for example, cracks or blemishes on the bottom of the container, the tablet side, or excess powder or solid particles on the container wall indicate that the uncoated tablet is physically unstable. Thus, moderate homogeneous regenerating stirring and tumbling is carried out so that the tablets can be physically sufficiently stable. Tablet strength is determined using a commercially available strength tester. In addition, the availability of the active ingredient in vitro should not change over time.

The lactose free pharmaceutical compositions of the invention should be prepared in soft gelatin capsule unit dosage form using methods known to those skilled in the art (Ebert, Pharm. Tech., 1 (5): 44-50 (1977)). Soft elastic gelatin capsules are slightly thicker spherical shells and softer capsules than hard gelatin capsules, and gelatin is plasticized by adding glycerin, sorbitol or similar polyols. The strength of the capsule shells is varied by varying the amount of gelatin and plasticizer and water. Soft gelatin shells contain preservatives such as methyl and propylparaben and sorbic acid to prevent mold growth. The active ingredient is dissolved or suspended in a liquid carrier or carrier, the carrier being a vegetable or mineral oil, polyethylene glycol, propelin glycol, glycols such as triglycerides, surfactants such as polysorbates or combinations thereof.

Tablets or other dosage forms of the pharmaceutical compositions of the present invention may be coated on dragees, capsur pills, granules, etc. using enteric coating or other coatings known in the pharmaceutical art.

Pharmaceutical compositions of the invention can be prepared to control or delay the release of the active ingredient, e.g. using hydroxymethylcellulose in varying proportions to achieve a desired release profile or to utilize other polymeric metrics, liposomes or microspheres. Can be.

Unless stated otherwise, all ratios specified herein are in weight ratios based on the total weight of all components of the particular formulation.

The lactose-free, non-hygroscopic, anhydrous large particles or coated nolastemisol compositions of the present invention further comprise analgesics, anti-inflammatory agents, cough suppressants or expectorants.

The incompatibility of lactose and nolastemisol is shown in Table 1 below. At various temperatures (25 ° C, 40 ° C, 60 ° C) and various relative humidity (60%, 75%), levels for various times (0, 1 week, 1 month, 2 months, 3 months, 6 months, 9 months) The effect of lactose on nolastemizole in rats was evaluated. Each evaluation result is shown in Table 1. Impurity levels in the capsules tested were measured using HPLC and are shown in Table 1 as percentage of the drug form tested. In the initial opaque appearance, discoloration is indicative of the incompatibility of noracemazole and lactose, which is evident by the increased percentage of impurities detected by HPLC.

Thus, according to the results, when the EK was prepared with lactose, filled into hard gelatin capsules, and stored in a sealed container without being sealed, the preparation was chemically unstable at high temperature and humidity. In addition, even at 25 ° C. and 60% relative humidity conditions, nolastemizol / lactose capsules increased impurities after 6 months and 9 months, and decreased in vitro capacity, indicating an incompatibility between nolastemisol and lactose. will be.

To identify excipients, in addition to lactose, suitable excipient performances for use with nolastemizol have been made on a variety of other excipients. The types of excipients tested include corn starch, dihydrate calcium sulfide, calcium stearate, sucrose, fructose, calcium carbonate, microcrystalline cellulose, maltodextrin, CaHPO ₄ 2H ₂ O, CaHPO ₄ stearate magnesium, starch 1500 , Croscarmellose sodium or mixtures thereof.

The effect of the various excipients on the decomposition of nolastemizole is shown in FIG. 2, which is a non-sealed seal when the nolastemizol / excipient complex is exposed to 60 ° C. and 75% relative humidity and under conditions commonly used in excipient suitability studies. It may be stored in a container.

As can be clearly seen in FIG. 2, nolastemizol and lactose are obviously inadequate because the drug's ability drops dramatically. However, there was no such drastic reduction between the other excipients tested and norastimazole. However, as illustrated in FIG. 2, it is necessary to adjust the dosage form daily to account for capacity changes between the various excipients.

FIG. 2 also shows to some extent that monosaccharides and disaccharide excipients should be avoided in making nolastemisol formulations, which can be seen as degradation in the case of nolastemisol / suscrose combinations.

The results were obtained using screw top containers, high temperature, high humidity and such conditions are generally accepted conditions for determining the interaction of excipients and compounds under accelerated conditions. Applicants have also found that norastimazole alone is stable for a significant time when stored under high humidity conditions (and therefore when exposed to many unbound water). Another study evaluated the effect of levels on lac / norastemisol interactions.

In a 20 ml Amber glass crimp-top vial, the following samples were prepared;

Nolastemizol alone

Norasteemisol 20% / Lactose 80%

Nolastemizol 20% / Lactose 80% + H ₂ O 5%

Nolastemizole 1% / lactose 99%

Nolastemizol 1% / Lactose 99% + H ₂ O 5%

The vial was fixed at 60 ° C. for 14 days and tested for nolastemizol.

According to the results, the incompatibility of nolastemisol and lactose was significantly reduced when no unbound water was present and when the vessel was sealed. In addition, the influence of moisture on the reaction rate is quite large. When unbound water was not deliberately added to the sealed container, there was no significant difference from the baseline when norasemisol was present alone. It can be seen that the capacity was decreased in unbound water, and in the absence of unbound water, the ability to compare to lactose-free or nolastemisol alone was reduced.

Nolastemizol% (Test Results)

Nolastemizol alone 96.90

Nolastemizol 20% / Lactose 80% 98.33

Nolastemizol 20% / Lactose 80% + H ₂ O 50% 65.16

Nolastemizol 1% / Lactose 99% 92.59

Nolastemizol 1% / Lactose 99% + H ₂ O 5% 77.22

Lactose-free, non-hygroscopic, anhydrous large particles or coated nolastemizol formulations, such as troches, tablets or capsules, may be used with nolastemizol or a pharmaceutically acceptable salt thereof and one or more of the above-mentioned pharmaceutical acceptable Possible excipients are made in combination with a pharmaceutically acceptable yam, eg, unit dosage form of norastemizol, comprising from 1 mg to 200 mg nolastemizole, suitably from about 2 mg to about 100 mg nolastemizol You can make Tablet, troche or capsule dosage forms can be made by methods known in the art, including wet granulation, dry granulation or press molds. In addition, wet granulation is not useful in non-hygroscopic or anhydrous formulations. Other known methods used to make tablets, troches or capsules may be used. However, compression molding is suitable for making tablets and troches. In the case of capsules, hard gelatin capsule shells are suitable for filling norastimazole and one or more excipients.

STARCH 1500 Is a pre-gelatinized starch manufactured by Colorcon Ltd. It is recommended not to use more than 87wt%. In addition, magnesium stearate is a lubricating agent STARCH 1500 When used with magnesium stearate is not used in excess of 0.25wt% because side effects occur during dissolution. STARCH 1500 like this Side effects in dissolving and using more than 0.25% magnesium stearate are important for relatively low water soluble compounds such as noracemazole.

DESCRIPTION OF THE PREFERRED EMBODIMENTS In order to explain the present invention, suitable embodiments according to the claims of the present invention are described as follows. The examples are illustrative only and not intended to be limiting.

The present invention relates to a stable pharmaceutical weak form of nolastemizol which prevents the incompatibility between nolastemisol and lactose. First, the present invention relates to a lactose-free pharmaceutical composition comprising nolastemisol, a pharmaceutically acceptable salt and a pharmaceutically acceptable non-lactose excipient. In another embodiment, the present invention is directed to a solid pharmaceutical composition comprising norastimazole or a pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient, wherein the excipient is not lactose.

In one preferred embodiment the at least one pharmaceutically acceptable non-lactose excipient is a binder, filler or mixture thereof. In another preferred embodiment, the excipient comprises a lubricant, a proteolytic material or mixtures thereof. In another preferred embodiment, the excipient is croscarmellose, microcrystalline cellulose, gelled starch and magnesium stearate. In a preferred embodiment, the tablet digest is a supertablet. In another embodiment, the pharmaceutical composition does not include all monosaccharides or disaccharide excipients.

The present invention relates to a heat-stable, solid pharmaceutical composition which is lactose free consisting of norastamazole, a pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient. In another embodiment, the present invention relates to a chemically stable pharmaceutical composition free of lactose, wherein the composition comprises about 1% to 50% by weight of nolastemizol or a pharmaceutically acceptable salt and comprises at least one pharmaceutically acceptable About 99% to 50% by weight of the excipient.

In a second embodiment, the present invention includes a non-hygroscopic pharmaceutical composition consisting of nolastemisol, a pharmaceutically acceptable salt and at least one pharmaceutically acceptable excipient. Non-hygroscopic pharmaceutical compositions according to the present invention may contain pharmaceutically acceptable excipients that are free of water, i.e., water, which can be used for the nolastemizol / excipient reaction, including all reactions of lactose with nolastemizol. . The present invention provides a chemically, thermally stable, non-hygroscopic pharmaceutical composition consisting of nolastemisol and at least one pharmaceutically acceptable excipient, wherein the excipient may comprise lactose or other monosaccharides or disaccharides.

In other words, the norastamazole composition according to the invention comprises (a) lactose free (no monosaccharides or disaccharides), (b) unbound water free excipients, and the excipients include alpha-lactose monohydrate or other Lactose, such as monosaccharides or polysaccharides, and (c) large particles coated with an inert agent, together with excipients comprising lactose, such as alpha-lactose monohydrate or other monosaccharides or disaccharides. Applicants have found very stable nolastemisol compositions. In addition, the composition of the present invention, which is not absorbent, may contain a part of a moisture absorbent component; However, the overall composition is hardly hygroscopic. In addition, the non-hygroscopic pharmaceutical composition according to the present invention may use a hydroxide component.

In another embodiment, the present invention comprises an anhydrous pharmaceutical composition, which composition consists of norastimazole, a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers or excipients which may include lactose. . The composition can be formulated with anhydrides or low moisture containing components that utilize low moisture or low humidity conditions so that the resulting pharmaceutical composition is an anhydride. The present invention also provides a chemically, thermally stable, anhydrous pharmaceutical composition comprising nolastemizole and at least one pharmaceutically acceptable excipient, wherein the excipient may comprise lactose or other monosaccharides or disaccharides.

The present invention also encompasses pharmaceutical compositions for treating histamine-induced diseases consisting of norastimazole, pharmaceutically acceptable salts and pharmaceutically acceptable excipients. The present invention provides a chemical, thermally stable pharmaceutical composition having large particles of nolastemisol and at least one pharmaceutically acceptable excipient, the excipient comprising lactose or other monosaccharides or disaccharides.

In a preferred embodiment, about 40 wt% of nolastemisol particles or pharmaceutically acceptable salts comprise particles having a size of at least 200 μm. In one embodiment of the invention, the large particle pharmaceutical composition may comprise lactose as a pharmaceutically acceptable excipient.

The present invention includes a solid pharmaceutical composition for treating a histamine-induced disease consisting of a therapeutically effective amount of coated nolastemizol, or a pharmaceutically acceptable salt, which is a pharmaceutically acceptable coating coated with nolastemizol, an inactive agent. Salts and pharmaceutically acceptable excipients. The present invention provides a coated chemically and thermally stable pharmaceutical composition that prevents incompatibility between nolastemisol and lactose, the excipients comprising lactose or other monosaccharides or disaccharides.

In an embodiment of the invention, the excipient comprises lactose. In another embodiment, the coated nolastemisol or pharmaceutically acceptable salt comprises granular nolastemisol, a pharmaceutically acceptable salt and a pharmaceutically acceptable inert excipient, wherein the granular composition is coated with an inert coating. In a preferred embodiment, the inert coating comprises an inert film-forming agent in the solvent. In another preferred embodiment, the inert membrane-formulating agent is methylcellulose, hydroxymethyl cellulose, carboxymethyl cellulose, hydroxypropylmethylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, carboxymethyl Sodium cellulose and mixtures thereof.

In an embodiment of the present invention, the amount of norastimazole is about 1 mg to 200 mg. In a more preferred embodiment, the amount of nolastemizol is about 2 mg to 100 mg. In another preferred embodiment, the nolastemizol is an amount effective to treat an allergic disease. In another preferred embodiment, the therapeutically effective amount is sufficient to treat or prevent a person with allergic disease.

The present invention relates to a solid pharmaceutical composition comprising nolastemisol or a pharmaceutically acceptable salt, microcrystalline cellulose, gelled starch, magnesium stearate, and croscarmellose sodium. In an embodiment of the invention, the solid pharmaceutical composition is provided in tablet or capsule dosage form.

The present invention relates to a method for treating an allergic disease in a mammal by administering an amount appropriate for treating one of the compositions. In a preferred embodiment, the mammal is a human. In a more preferred embodiment, the allergic disease is allergic rhinitis.

Fill the active ingredient and mix with the excipients listed. The mixture is filled into two engineered hard gelatin capsules of appropriate size using methods and machines known in the art. See Remington Pharmaceutical Science, 16th or 18th Editions. Other dosage forms may be prepared by changing the size of the capsule as needed or by changing the weight of the filler. Non-hygroscopic, anhydrous and gelatin capsule compositions are made without any lactose.

Example 4

The active ingredient is sieved using an appropriate sieve and mixed until homogeneously mixed. The dry mixture is screened and mixed with magnesium stearate. The resulting powder mixture is compressed into tablets of the desired shape and size. Tablets of different strengths can be prepared by varying the ratio of excipients to the active ingredient (eg norastimazole) or by varying the weight of the tablets.

Example 5

The active ingredient is sieved through an appropriately sized screen and mixed until homogeneously mixed with a non-lactose excipient (except for cross carmelose (or glycolate starch sodium) and all microcrystalline cellulose). After drying, the granules are screened, mixed with microcrystalline cellulose and simply mixed with the remaining croscarmellose or glycolate starch sodium and magnesium stearate. The resulting freely moving powder is compressed into tablets of the desired size and shape. Tablets of different strengths can be prepared by varying the ratio of excipients to the active ingredient (eg norastimazole) or by varying the weight of the tablets.

Example 6

The active ingredient is sieved through a screen of appropriate size and mixed until homogeneously mixed with a non-lactose excipient (except magnesium stearate). The dried mixture is screened and the magnesium stearate mixed briefly. The resulting powder mixture is compressed into tablets of the desired size and shape. Tablets of different strengths can be prepared by varying the ratio of excipients to the active ingredient (eg norastimazole) or by varying the weight of the tablets.

While the invention has been described in particular embodiments, those skilled in the art will recognize that various changes and modifications can be made without departing from the scope of the invention.

Claims (42)

Lactose-free pharmaceutical composition characterized by comprising lactose-free nolastemizol or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient other than lactose A solid pharmaceutical composition consisting of nolastemizol or a pharmaceutically acceptable salt thereof, at least one pharmaceutically acceptable excipient, wherein the excipient is not lactose. The solid pharmaceutical composition of claim 1 or 2, further comprising a lubricant, a disintegrant, or a mixture thereof. The composition of claim 1, wherein the at least one non-lactose pharmaceutically acceptable excipient consists of croscarmellose sodium, macrystalline cellulose, pre-gelatinized starch and magnesium stearate. The composition of claim 1 or 2, wherein the pharmaceutical composition does not contain monosaccharides or disaccharides. A thermally stable solid pharmaceutical composition comprising no lactose consisting of norastimazole or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. A chemically stable solid pharmaceutical comprising no lactose consisting of about 1 to about 50 wt% nolastemizol or a pharmaceutically acceptable salt thereof and about 99% to about 50 wt% of at least one pharmaceutically acceptable excipient. Composition. 8. The composition of claim 1 or 7, wherein the nolastemizol is present in an amount from about 1 mg to about 200 mg. The composition of claim 8, wherein the nolastemizol is present in an amount from about 2 mg to about 100 mg. 8. The composition of claim 1 or 7, wherein the nolastemizol is present in a therapeutically effective amount effective for treating an allergic disease. A solid pharmaceutical composition, characterized in that it comprises norastimazole, or a pharmaceutically acceptable salt thereof, microcrystalline cellulose, pre-gelatinized starch, magnesium stearate and croscarmellose sodium. The pharmaceutical composition of claim 11, wherein the solid composition is provided in tablet or capsule dosage form. The pharmaceutical composition according to claim 2, further comprising enteric skin. A method for treating an allergic disease in a mammal, characterized by administering a therapeutically effective amount of the pharmaceutical composition according to claim 1. The method of claim 14, wherein the mammal is a human. The method of claim 14, wherein the allergic disease is allergic rhinitis. Anhydrous pharmaceutical composition, characterized in that it consists of norastimazole or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. 18. The anhydrous pharmaceutical composition according to claim 17, wherein at least one pharmaceutically acceptable excipient is lactose. A solid pharmaceutical composition consisting of nolastemizol or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient and lactose, wherein the composition is substantially free of unbound water. 20. The pharmaceutical composition of claim 17 or 19, wherein at least one pharmaceutically acceptable excipient is selected from low-moisture or minor excipients. Anhydrous pharmaceutical composition, characterized in that it does not include lactose consisting of about 1 to about 50 wt% nolastemizol or a pharmaceutically acceptable salt thereof and about 99% to about 50 wt% of at least one pharmaceutically acceptable excipient. A solid unit dosage form comprising the anhydrous composition according to claim 20 or 21 contained in a sealed foil, a sealed container, a foam pack or a strip pack. A non-hygroscopic pharmaceutical composition, characterized in that it consists of norastimazole or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient. The non-hygroscopic pharmaceutical composition of claim 23 wherein the one or more pharmaceutically acceptable excipients is lactose. Non-hygroscopic pharmaceutical composition consisting of nolastemizol or a pharmaceutically acceptable salt thereof, lactose and at least one pharmaceutically acceptable excipient, wherein the composition does not actually contain unbound water. Pharmaceutical compositions. A solid, non-hygroscopic pharmaceutical composition, characterized in that it consists of nolastemizol or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient and lactose. The pharmaceutical composition of claim 24 or 25, wherein the one or more pharmaceutically acceptable excipients are selected from non-hygroscopic or low moisture excipients. The pharmaceutical composition of claim 23, 24, 25, or 26, wherein the lactose is hydrated. A method for treating an allergic disease in a mammal, characterized in that the method comprises administering a therapeutically effective amount of the pharmaceutical composition according to claim 24. 30. The method of claim 29, wherein the mammal is a human. 30. The method of claim 29, wherein the allergic disease is allergic rhinitis. A pharmaceutical composition for treating histamine-induced disease, wherein the composition comprises norasemizole large particles or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. 33. The pharmaceutical composition of claim 32, wherein the excipient consists of lactose. 33. The pharmaceutical composition of claim 32, wherein at least about 40 wt% of nolastemizol large particles or pharmaceutically acceptable anti salts thereof have a particle size of 200 μm or more. In a pharmaceutical composition for treating histamine-induced disease, it comprises a therapeutically effective amount of a coated nolastemizol or a pharmaceutically acceptable salt thereof, which is coated with an inert coating, or a norastimazole, A pharmaceutical composition characterized by consisting of an acceptable salt and a pharmaceutically acceptable excipient. 36. The solid pharmaceutical composition of claim 35, wherein the excipient is lactose. The composition of claim 35, wherein the coated nolastemizol or a pharmaceutically acceptable salt thereof consists of granulated nolastemizol or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable inert excipient, wherein the granulated composition is A pharmaceutical composition characterized by being coated with an inert coating. 38. The pharmaceutical composition of claim 35 or 37, wherein the inert coating is composed of an inert film-forming material in a solvent. 39. The method of claim 38, wherein the inert-film forming material is methylcellulose, hydroxymethyl cellulose, carboxymethyl cellulose, hydroxymethylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, methylhydroxyethylcellulose, carboxymethylcellulose sodium, And mixtures thereof. 36. A method of treating an allergic disease in a mammal, characterized in that it comprises administering a therapeutically effective amount of the composition according to claim 32 or 35. 41. The method of claim 40, wherein the mammal is a human. 41. The method of claim 40, wherein the allergic disease is allergic rhinitis.