CN1257431A - Chemically and thermally stable norastemizole formulations - Google Patents

Abstract

The present invention relates to chemically and thermally stable pharmaceutical formulations of the potent antihistamine, norastemizole. The compositions are lactose-free, non-hygroscopic, or anhydrous, or comprise large particles or inertly coated norastemizole, or a pharmaceutically acceptable salt thereof, and are stable and easily manufactured.

Description

Chemistry and thermally stable norastemizole formulations

The cross reference of related application

The application is to be that the part of pending application 08/851786 on May 6th, 1997 is follow-up the applying date, and the latter is that the part of pending application 08/824477 on March 26th, 1997 is follow-up for the applying date again, and the full content of two parts of applications all clearly is incorporated herein for reference.

Field of the present invention

The present invention relates to contain the chemistry and the heat-staple pharmaceutical composition of Tecastemizole (norastemizole).

Background of the present invention

The stability of many factor affecting drug products, the stability that comprises the medicine component, latent effect between medicine component and the inactive ingredients, preparation method, packing, the environmental condition that transport, storage and operating period is run into, preparation and use between time span and the type of dosage form.Except physical stability, should consider the chemical stability of drug products.For three chief reasons, the physics of pharmaceutical preparation and the knowledge of chemical stability are very important.

At first, drug products preferably should show freshly, exquisite and professional.Any change of physical appearance and color comprise fade, color change, fuzzy outward appearance or the like all can make patient that product is lost confidence.Secondly, because some product is prepared with multi-dose container, the uniform medicament of All Time internal therapy agent must be guaranteed.For example, uneven medicament pattern shows as turbid solution, has divided emulsion, the tablet of variable color or the capsule of variable color etc. of layer.The 3rd, in the whole storage life of dosage form expection, the medicine component must be able to be used by patient.Dosage form all can cause harmful change of the shortage or the medicine component bioavailability of bioavailability the destruction aspect physics or the chemical globality.

Various pharmaceutical dosage forms are successfully used to give many marketed drug.The conventional pharmaceutical dosage forms of listing in American Pharmacopeia/National Formulary (USP/NF) includes but not limited to aerosol, capsule, cachet, collyrium, cream, Emulsion, extractum, liquid extractum, gel, inhalant, injection, lotion, magma, milk, ointment, paste, pill or implant, powder, solution, ophthalmic solution, oral administration solution, otic solution, pastille, topical solution, spirit, suppository, suspending agent, Sublingual lozenge, syrup, tablet, tincture, lozenge, aromatic water etc.For oral administration, syrup, solution, suspending agent, lozenge, tablet and capsule are preferred.Yet in order to be easier to administration, easy to carry and patient is taken medicine according to the dosage of doctor formula, dragee, tablet and hard, soft capsule are most preferred.In some cases, tablet is preferable over capsule, because tablet is easier to swallow sometimes.

Typically, dragee, tablet and capsule comprise drug component, diluent and other excipient, as known in the art lubricant etc.For example known excipient comprises coating materials, coloring agent, desiccant, emulsifying agent, cosolvent, correctives, anti-caking agent (anti-caking), plasticizer, suspending agent, thickening agent, binding agent, diluent, wetting agent etc.

Lactose is normally used diluent or excipient.Spray-dired lactose is normally used lactose form, and it is widely used as the excipient of direct compression.Because the appearance of spray-dried lactose, it has also enlarged as the application of excipient.Spray-dried lactose is why such to be approved fastly, and partly cause is that its mixes in direct compression easily.In this was used, spray-dired lactose was the tabletting step that has and needn't further granulate or adopt complexity with its backup form.Spray-dired lactose also can be at an easy rate and is mixed into easily in dragee and the capsule.Spray-dired lactose can directly be added in the medicine, obtains needed thinner ratio thus.After this, for example, the mixture dry method of lactose and medicine tablet be can be pressed into, perhaps, if desired, dragee or capsule be made with other excipient.

Typically, all there are the balance between α type and the β type in spray drying or non-spray drying type lactose, and wherein, the change between these configurations is constantly ongoing.Alpha-lactose is the disaccharide that is made of β-D-galactose and alpha-D-glucose.Beta lactose is by β-D-galactose and disaccharide that β-the D-glucose constitutes.Beta lactose only exists with its anhydrous form, and alpha-lactose can obtain an anhydrous form or a hydrated form.

In the change process of α type and β type lactose, form the aldehyde intermediate, it is known that it is incompatible with most of primary amine.Primary amine is added to and forms imines on the carbonyl carbon of aldehyde (or ketone):

The incompatibility of most of primary amine and lactose is known.See Castello etc., J.Pharm.Sci., 51 (2): 106-108 (in February, 1962).Also see J.Pharm.Sci. such as Blaug, 61 (11): 1770-1775 (in November, 1972); Hartauer etc., Drug Dev.and Indust.Pharm., 17 (4): 617-630 (1991).

Castello etc. have tested the compatibility of amphetamine sulfate (a kind of primary amine salt) with lactose.They find that the mixture variable color gradually of lactose and amphetamine sulfate is particularly in the presence of alkaline lubricant such as magnesium stearate.Blaug etc. have tested dextroamphetamine sulfate (a kind of primary amine) and spray-dried lactose.They find that in the presence of dextroamphetamine sulfate, lactose forms Schiff alkali (being imines).Hartauer etc. have tested aminophylline and lactose, and find to exist between aminophylline and lactose some incompatibility, and particularly when heating down for about 60 ℃, this point can show by variable color.Aminophylline comprises the ratio of 2 molecule theophylline (secondary amine) and 1 molecule ethylenediamine (primary amine).Yet Hartauer etc. have tested these components and have found, are heating or be not heated under 60 ℃, and single theophylline (secondary amine) does not react with lactose, and ethylenediamine but reacts with lactose, particularly when being heated to 60 ℃.Therefore, the incompatibility of aminophylline and lactose is to be produced by primary amine component ethylenediamine in the aminophylline and lactose.

Medicine astemizole (secondary amine) is seemingly compatible with lactose, because it can HISMANAL ^, lactinated Tabules is bought from market.According to Physician ' s Desk Reference, 50th Edition, Medical Economics Co., Montvale, NJ, P.1293 (1996), every Hismanal ^Contain 10mg astemizole, lactose, corn starch, microcrystalline Cellulose, pregelatinized starch, 30 POVIDONE K 30 BP/USP 90, magnesium stearate, silica sol and sodium lauryl sulfate.

Similarly, expection Tecastemizole (main metabolites of another secondary amine and astemizole) should be compatible with lactose, particularly when not heating.It is reported that Tecastemizole is more effective and low toxicity than astemizole.Therefore, Tecastemizole is the medicine of attractive replacement astemizole in treat ing bronchial anaphylactic disease.Should be realized that astemizole and Tecastemizole all are the antihistaminics that contains the secondary amine part; Yet Tecastemizole has two secondary amine parts, and astemizole has only one.

The present invention's general introduction

The present invention relates to the stable pharmaceutical dosage form of Tecastemizole, it has avoided the incompatibility between Tecastemizole and the lactose.On the one hand, the present invention relates to a kind of lactose-free pharmaceutical composition, it comprises Tecastemizole or its officinal salt and the pharmaceutically acceptable excipient of at least a non-lactose.In another embodiment, the present invention relates to a kind of solid composite medicament, it comprises Tecastemizole or its officinal salt and at least a pharmaceutically acceptable excipient, and wherein said excipient is not a lactose.

In an embodiment preferred, the pharmaceutically acceptable excipient of at least a non-lactose is binding agent, filler or its mixture.In another embodiment preferred, at least a pharmaceutical excipient is binding agent, filler or its mixture.In a more preferred embodiment, above-mentioned excipient further comprises lubricant, disintegrating agent or its mixture.In a more preferred embodiment, excipient is croscarmellose, microcrystalline Cellulose, pregelatinized starch and magnesium stearate.In preferred embodiments, disintegrating agent is superfine disintegrating agent.In another embodiment, pharmaceutical composition is substantially free of all monosaccharide or disaccharide excipient.

The present invention also relates to not contain lactose, thermodynamically stable solid composite medicament, it comprises Tecastemizole or its officinal salt and at least a pharmaceutically acceptable excipient.In another embodiment, the present invention relates to not contain lactose, chemically stable solid composite medicament, it comprises the heavy Tecastemizole of about 1%-50% or its officinal salt and the about heavy at least a pharmaceutically acceptable excipient of 99%-50%.

In second embodiment, the present invention relates to the non-hygroscopic pharmaceutical composition, it comprises Tecastemizole or its officinal salt and at least a pharmaceutically acceptable excipient.Non-hygroscopic pharmaceutical composition of the present invention can comprise pharmaceutically acceptable excipient, described pharmaceutically acceptable excipient is substantially free of unbound water, promptly participate in the interactional water of Tecastemizole/excipient, described interaction comprise but do not limit and lactose and Tecastemizole between any interaction.The present invention also be provided at chemically with thermodynamics on stable non-hygroscopic pharmaceutical composition, it comprises Tecastemizole and at least a pharmaceutically acceptable excipient, wherein, described excipient can comprise lactose or other monosaccharide or disaccharide.

That is to say; Tecastemizole compositions of the present invention is that (a) is substantially free of lactose (and preferably being substantially free of monosaccharide or disaccharide); (b) comprise the excipient that is substantially free of unbound water; this excipient can comprise lactose such as alpha-lactose monohydrate or other monosaccharide or disaccharide; or (c) comprise bulky grain or by a kind of inert agents coated granules and excipient, described excipient can comprise lactose such as alpha-lactose monohydrate or other monosaccharide or disaccharide.In arbitrary form, the applicant has found high stability Tecastemizole preparation.In addition, should be noted that non-hygroscopic compositions of the present invention still can comprise some hygroscopic elements; Yet whole compositions must be non-hygroscopic basically.And non-hygroscopic pharmaceutical composition of the present invention also can use the hydrate component.

In another embodiment, the present invention relates to anhydrous pharmaceutical composition, described compositions comprises Tecastemizole or its officinal salt and one or more pharmaceutically suitable carrier or excipient, comprises lactose.Can use low water content or low dampness condition to prepare said composition by using anhydrous components or low water content component, like this, resulting pharmaceutical composition be anhydrous basically.In addition, the invention provides chemically with thermodynamics on stable anhydrous pharmaceutical composition, it comprises Tecastemizole and at least a pharmaceutically acceptable excipient, wherein, described excipient can comprise lactose or other monosaccharide or disaccharide.

The present invention also comprises the pharmaceutical composition that is used for the treatment of the disease that histamine causes, it comprises bulky grain Tecastemizole or its officinal salt and a kind of pharmaceutically acceptable excipient.The present invention also be provided at chemically with thermodynamics on stable pharmaceutical composition, it contains bulky grain Tecastemizole and at least a pharmaceutically acceptable excipient, wherein, described excipient can comprise lactose or other monosaccharide or disaccharide.

In preferred embodiments, about 40% heavy or more bulky grain Tecastemizole or its officinal salt comprise having 200 μ m or bigger granule.In another embodiment, the bulky grain pharmaceutical composition can comprise lactose as pharmaceutically acceptable excipient.

The present invention also comprises the solid composite medicament that is used for the treatment of the disease that histamine causes, it is included in coating Tecastemizole or its officinal salt of effective dose on the therapeutics, and it comprises Tecastemizole or its officinal salt and a kind of pharmaceutically acceptable excipient with inertia coating materials coating.The present invention further provides chemically with thermodynamics on the pharmaceutical preparation of stable coating Tecastemizole, it has avoided the incompatibility between Tecastemizole and the lactose, wherein, described excipient can comprise lactose or other monosaccharide or disaccharide.

In one embodiment, excipient comprises lactose.In another embodiment, the Tecastemizole of coating or its officinal salt further comprise granular preparation and a kind of pharmaceutically acceptable inert excipient of Tecastemizole or its officinal salt, and wherein, described granular preparation is with inertia coating materials coating.In an embodiment preferred, the inertia coating materials is included in inertia film former in the solvent.In a more preferred embodiment, the inertia film former is selected from methylcellulose, hydroxy methocel, carboxymethyl cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, methyl hydroxyethylcellulose, sodium carboxymethyl cellulose and composition thereof.

In one embodiment, Tecastemizole exists with the amount of about 1-200mg.In a more preferred embodiment, Tecastemizole exists with the amount of about 1-100mg.In another embodiment preferred, Tecastemizole is effectively measured with treatment anaphylactic disease on the therapeutics and is existed.In another embodiment preferred, effectively measuring on the therapeutics is enough to prevention or treatment humans allergic disease.

The present invention also relates to solid composite medicament, it comprises starch, magnesium stearate and the sodium carboxymethyl cellulose of Tecastemizole or its officinal salt, microcrystalline Cellulose, pregelization.An embodiment, solid composite medicament provides with tablet or capsule formulation.

The present invention also relates to one of a kind of above-mentioned composition by treating effective dose and treat the method for at least a mammal anaphylactic disease.In preferred embodiment, mammal is the people.In a more preferred embodiment, anaphylactic disease is an allergic rhinitis.

The accompanying drawing summary

Fig. 1 describes the chemical constitution of Tecastemizole.

The bar diagram that the initial effectiveness of dosage form Tecastemizole and various drug excipient changed when Fig. 2 represented that dosage form uses unsealed container (that is the bottle of screw lid) to expose under 60 ℃ of temperature and 75% humidity.

The present invention describes in detail

Surprisingly, the applicant finds even in situation about not heating, the metachromasia that primary amine and lactose occur also exists in Tecastemizole. Therefore, at secondary amine, as if also there is undesirable incompatibility mentioned above between Tecastemizole and the lactose. So it is desirable preparing lactose-free Tecastemizole formulation. And the applicant finds that also the unstability of lactose and Tecastemizole can start because Tecastemizole/lactose preparation is exposed to water (comprising atmospheric moisture, such as humidity) and/or promote. Unstability is also because starting and/or promote being higher than under about 60 ℃ temperature heating. And the applicant finds that also the unstability of lactose and Tecastemizole can expose Tecastemizole/lactose preparation and start and/or promote because of the high surf zone of granule Tecastemizole commonly used in the pharmaceutical composition. In addition, the applicant finds that also the unstability of lactose and Tecastemizole can be by suppressing to the Tecastemizole granule coating or avoiding before preparation Tecastemizole and the excipient that reacts such as lactose.

In publication number is the embodiment 4 of PCT application PCT/US93/08349 of WO94/07495, propose the Tecastemizole preparation, wherein do not contain lactose. Among preparation A, the B and C of embodiment 4, all contain 1.0% weight dolomol BP, the starch 1500 that contains respectively 94.0,89.0 and 79.0 % weight (can be from Colorcon, the starch,pregelatinized that Ltd buys), the remainder of composition is the metabolin (such as, Tecastemizole) of astemizole. Yet, in practice, do not prepare or use the preparation of lactose-free embodiment 4, because dolomol BP and starch 1500 are inconsistent at described percentage by weight. In other words, the preparation of the disclosed embodiment 4 of this PCT is unsuitable for actual drug use. And the document is both not open does not advise that Tecastemizole and lactose are inconsistent yet, and this is because wherein embodiment 5 is the tablets that contain the Tecastemizole of lactose.

For mentioned above with comprise secondary amine, the undesirable problem that Tecastemizole is relevant with the lactose pharmaceutical preparation needs preparation avoid inconsistent stable Tecastemizole solid pharmaceutical preparation between Tecastemizole and the lactose. The present invention recognizes valuably and lactose-free Tecastemizole preparation is provided.

Because the pharmacological action of Tecastemizole is better than astemizole, need the Tecastemizole formulation of stability and high efficiency. Up to the present, there is not commercially available stable Tecastemizole preparation. Yet the present inventor is by eliminating lactose and using other component described herein to find, the lactose-free formulation of Tecastemizole all is stable on chemistry, physics and thermodynamics unexpectedly. The present invention can obtain this stability and not affect easiness and the medicament characteristic of preparation.

Therefore, feature of the present invention provides stable pharmaceutical preparation on chemistry and thermodynamics, and it comprises Tecastemizole or its officinal salt and a kind of pharmaceutically suitable carrier or excipient, and described carrier or excipient do not comprise or do not use any type of lactose. Because produce easily, lactose is widely used for pharmaceuticals industry especially. Yet the applicant finds valuably, the preparation that comprises Tecastemizole and lactose As time goes on unstable and when meet heat and when moist degraded faster.

Thought before that secondary amine was compatible with lactose, particularly at room temperature or in the situation of being heated minimum (for example being lower than about 60 ℃) or keeping from heat. For example, as mentioned above, the medicine astemizole can commodity Hismanal by name^, contain lactose and other excipient Tabules and buy.

Find that at present physics and/or chemical incompatibility are present between secondary amine Tecastemizole and the lactose. Although without being limited by theory, be sure of that the incompatibility of Tecastemizole and lactose is to form enamine by reaction between the aldehyde intermediate of lactose and the secondary amine to cause:

Also find this incompatibility even be present under room temperature (for example, being lower than about 60 ℃ temperature) and the indoor relative humidity. In addition, the applicant has also found high stability pharmaceutical composition, and it comprises Tecastemizole and does not use the excipient lactose of extensive employing.

One of feature of the present invention provides lactose-free Tecastemizole pharmaceutical composition. These compositions have effective anti-histamine activity and are used for the treatment of various diseases. For example, these diseases comprise allergic rhinitis, asthma and other anaphylactia, dizzy, motion sickness, vestibular function imbalance (for example Meniere's disease), diabetes type retinopathy, other little vascular diseases relevant with diabetes.

The more important thing is, these lactose-free compositions provide stable and easily formulation in order to discharge Tecastemizole in human body. The lactose-free composition of the present invention is stable especially, and they have effective storage period. In addition, even run into slight temperature and room temperature variation, it is stable that the present composition still keeps. And although the present composition is lactose-free, said composition is easily preparation still, and said composition has needed Dose Characteristics. The present composition comprises the solid unit dose preparation, and it comprises Tecastemizole or its officinal salt and the pharmaceutically acceptable excipient of at least a non-lactose. Said composition also can comprise or not contain other treatment component, adhesive/filler, disintegrant, lubricant, anti-caking agent, anticorrisive agent, film coating agent, sweetener, colouring agent, flavouring, drier, plasticizer, dyestuff, dispersant and/or surfactant. Yet any these dispensable components must be compatible with Tecastemizole (a kind of secondary amine) in order to guarantee the stability of preparation.

Preferably, the lactose-free formulation according to the Tecastemizole of the present invention preparation comprises Tecastemizole and at least a non-lactose excipient. The example of this excipient is well known in the art and lists among USP (XXI)/NF (XVI), is incorporated herein its full content for reference. More preferably, that comprise Tecastemizole, pharmaceutically compatible according to the lactose-free formulation of Tecastemizole of the present invention preparation and pharmaceutically adhesive/filler and the lubricant of Sq. More preferably, the formulation according to the lactose-free Tecastemizole of the present invention preparation comprises Tecastemizole, microcrystalline cellulose, pregelatinized starch and dolomol.

Also have been found that when using in the composition that is containing the Tecastemizole preparation, other sugar, the degraded that causes similarly, caused by lactose such as fructose and sucrose, although not as above-described effect serious. Therefore, in another embodiment, the pharmaceutical composition that does not conform to lactose comprises Tecastemizole or its officinal salt and the pharmaceutically acceptable excipient of at least a non-lactose, and does not contain any monose or disaccharides excipient, includes, but are not limited to glucose, sucrose and fructose.

As mentioned above, lactinated Tecastemizole preparation runs into unbound water, and for example when moisture and moisture, it is faster to degrade. Simulate long term storage in order to measure the preparation characteristic such as the method for storage period or stability and time relationship as a kind of, pharmaceutical field adopts the method (for example adding 5% water) that adds water widely. See Jens T.Carstensen, Drug Stability:Principles ﹠ Practice, 2d.Ed., Marcel Dekker, NY, NY, 1995, pp.379-80. In fact, water and temperature are all accelerated this research.

And water is quite tangible to the effect of preparation, because help the condition of moisture absorption, for example moisture and/or dampness all may run in production, processing, packing, storage, transportation and the use of preparation usually.Therefore, apparent, owing under ordinary production, packing and storage requirement, in fact exist and the contacting of moisture and/or dampness, should be avoided in the pharmaceutical composition that contains Tecastemizole or the preparation and use lactose.

And, the productivity and the therapeutic that do not influence compositions although the excipient except lactose can easily be used for preparing the lactose-free Tecastemizole pharmaceutical composition of the disclosure, spray-dired lactose remains selected excipient.In spray-dried forms, lactose is mobile best and to be lower than low dosage formulation (for example≤50mg/ agent) be very effective in all direct compression filleies, and in said preparation, main effect is not brought into play in the compatibility of active component.For example, see R.Shangraw, Selection of ManufacturingProcess and Excipients with an Emphasis on Direct Compression, Course material from Granulation, Tableting, and CapsuleTechnology, Center for Professional Advancement, EastBrunswick, NJ, 1996.Therefore, if possible, in the solid dosage forms or the effective excipient of pharmaceutical composition of Tecastemizole, comprise lactose.

Therefore, in addition, the present invention comprises thermodynamics and chemically stable pharmaceutical composition, solid pharmaceutical preparation particularly, it comprises Tecastemizole or its officinal salt and one or more pharmaceutically acceptable excipient of not essential ground, includes, but are not limited to lactose, it is anhydrous wherein containing the lactose preparation, promptly is substantially free of unbound water.

The present invention further comprises thermodynamics and chemically stable non-hygroscopic pharmaceutical composition, and it comprises Tecastemizole or its officinal salt and one or more excipient or component, includes, but are not limited to lactose.Although be not subjected to the restriction of any theory, but these stable anhydrous or non-hygroscopic pharmaceutical composition parts are based on applicant's discovery, promptly when described preparation runs into unbound water, promote and/or may cause incompatible between Tecastemizole and lactose or other monosaccharide or the disaccharide.Therefore, prepare the pharmaceutical composition that is substantially free of unbound water will stop the Tecastemizole that takes place when using reactive excipient and having unbound water accelerated degradation.

Therefore, if lactose is a kind of excipient of needs, so, the present invention relates to non-hygroscopic or anhydrous pharmaceutical composition on the other hand, it comprises Tecastemizole, lactose and not essential ground one or more other excipient or components, and wherein resulting pharmaceutical composition does not conform to unbound water basically.Should be realized that, can prepare non-hygroscopic or anhydrous formulation by standard method, preceding topic condition is to select suitable excipient to make resulting pharmaceutical composition be substantially free of unbound water, and uses the low humidity condition to be prepared.

Should prepare and store the anhydrous Tecastemizole pharmaceutical composition for preparing according to the inventive method so that keep no aqueous.Therefore, with using the pharmaceutical composition that prevents well known in the art to meet the material of water moisture absorption and pack these pharmaceutical compositions, they are packaged in the suitable Medicine box (formulary kits).This packing includes, but are not limited to by the aluminium foil of encapsulating method sealing, plastics etc., unit-dose container, blister or bar packing.

Therefore, second aspect present invention comprises that preparation comprises the method for the solid pharmaceutical preparation of Tecastemizole and lactose, this method is included under anhydrous or low moisture and/or the dampness condition mixes Tecastemizole or its officinal salt and lactose, and wherein said component is substantially free of unbound water.This method can further comprise or not be contained in the described anhydrous or nonhygroscopic solid Tecastemizole preparation of packing under the low humidity condition.By using such condition, the danger that contacts with water reduces and prevents and in fact reduce the degraded of Tecastemizole in processing and storage process.In addition, the product of final packaging have seldom or do not contain unbound water, in fact this improved stability and prevented degraded.Said composition can provide packages sealed, well known to a person skilled in the art vacuum-packed and does not contain in the container of moisture as bottle, sealing deck, blister and other.

According to traditional method, when pharmaceutical compositions or preparation, active component or therapeutic agent (for example Tecastemizole) are milled and/or sieved so that reduce granularity and/or dwindle particle size distribution.Usually, doing like this is optimization such as dissolution, uniformity of dosage units, bioavailability for the various physicochemical properties that make preparation such as active component.Dissolution and Tecastemizole have special relation because when PH 3-4, dissolubility relatively low (approximately 10mg/ml) and when PH4 is above dissolubility lower.Although be not bound by any particular theory, the applicant be sure of that Tecastemizole and reactive excipient can be subjected to the influence of Tecastemizole granule surface area in pharmaceutical composition or the preparation as the interaction between the lactose.

Therefore, another embodiment of the present invention comprises and is used for the treatment of the inductive disease medicament compositions of histamine, and it comprises bulky grain Tecastemizole or its officinal salt and pharmaceutically suitable carrier.The pharmaceutically suitable carrier that is applicable to these compositionss comprises following carrier, and they can comprise one or more and be selected from inert excipient and reactive excipient, as the excipient of lactose or other monosaccharide or disaccharide.These " bulky grain " Tecastemizole pharmaceutical compositions have suitable physicochemical property (at aspects such as dissolution, uniformity of dosage units and bioavailability), and do not show and reactive excipient, as the incompatibility of lactose.

In preferred embodiments, existing Tecastemizole or its officinal salt have following particle size distribution in the compositions, wherein, it is 200 μ m or bigger granule that about 40% heavy or more substantial Tecastemizole or its officinal salt comprise granularity, is preferably greater than about 250 μ m.

Suppressing or prevent Tecastemizole and reactive excipient in the pharmaceutical composition, is to prevent that Tecastemizole contacts with any reactive excipient in the compositions as interactional other method between the lactose.A method of accomplishing this point be with the preparation of reactive excipient before, with Tecastemizole with inertia or non-reacted coating materials coating.Preferably, the inertia coating materials should not influence the pharmacodynamic profiles (for example trap in onset time and the body) of compositions significantly.

Therefore, another embodiment of the present invention relates to the solid composite medicament that is used for the treatment of the inductive disease of histamine, it comprises coating Tecastemizole or its officinal salt for the treatment of effective dose, and it comprises Tecastemizole or its officinal salt and pharmaceutically suitable carrier with inertia coating materials coating.In embodiment preferably, at first, Tecastemizole or its officinal salt are granulated with inert excipient (for example starch), then, with resulting granules with inertia or non-reacted coating materials coating.Then, resulting coating Tecastemizole and other excipient are comprised reactive mixed with excipients.

Suitable inertia coating materials is well known in the art with the method that is used for coated granule.Typically, the inertia coating materials comprises the inertia film former that is dispersed in the The suitable solvent, and can further comprise other pharmaceutically acceptable adjuvant, as coloring agent and plasticizer.Preferably, with moisture or do not contain moisture film packaging technique or microencapsulation method coating Tecastemizole granule.Suitable inertia film former comprises, but is not restricted to cellulose such as methylcellulose, hydroxy methocel, carboxymethyl cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, methyl hydroxyethylcellulose and Carboxymethyl cellulose sodium; Ethylene such as polyvinylpyrrolidone; Dihydroxylic alcohols such as Polyethylene Glycol; Acrylic acid such as dimethylaminoethyl methacrylate-methacrylate copolymer and ethyl propylene acid esters-methylmethacrylate copolymer; With other carbohydrate polymer, as maltodextrin and polyglucose.Preferably, the inertia coating materials contains hydrophilic film former, as hydroxypropyl emthylcellulose, so that can obviously not postpone its absorption in vivo.

In case behind the granule or granular preparation with inertia coating materials coating Tecastemizole; can use standard technique to prepare the Tecastemizole of coating; described standard technique comprises; but be not restricted to and other inertia and/or reactive excipient; as the combination of lactose mixing, granulation, tabletting or these steps so that prepare various dosage forms, as tablet, caplet, capsule, dragee etc.

The preferred amounts of Tecastemizole is its treatment effective dose in all dosage forms of the present invention's preparation, and this amount also is its medically suitable amount.The actual dose level of Tecastemizole can change so that obtain needed given patient being had the treatment effect in pharmaceutical composition of the present invention, the pharmaceutical composition of Tecastemizole and medication and to the Nore Ah imidazoles amount of patient's nonhazardous.

The dosage level of selected pharmaceutical composition of the present invention and give the frequency and will depend on various factors, comprise route of administration, administration time, therapeutic agent comprise Tecastemizole discharge rate, treatment persistent period, merge other medicines, chemical compound and/or the material, age, sex, body weight, situation, general health situation and the patient's that treats that use various factorss known in the art such as treatment history with Tecastemizole.For example, for health adult, dosage changes because of anemia of pregnant woman, nursing women and child use usually.

Doctor with ordinary skill can determine and specify the treatment effective dose of required pharmaceutical composition easily.For example, the doctor brings into use the Tecastemizole dosage that is lower than in the pharmaceutical composition of the present invention of finishing required therapeutic effect and increases this dosage gradually up to reaching required effect.

Dosage every day that Tecastemizole is suitable is the Tecastemizole that produces required therapeutic effect minimum effective dose.The effective dosage of this treatment depends on factor mentioned above usually.For example, the unit dose of lactose-free Tecastemizole is about 1 milligram to about 200 milligrams, preferably approximately 2 milligrams to about 100 milligrams.For example unit dose can be mixed with the Tecastemizole of 2.5 milligrams, 5 milligrams, 10 milligrams, 12.5 milligrams, 15 milligrams, 20 milligrams, 25 milligrams, 30 milligrams, 35 milligrams, 40 milligrams, 45 milligrams, 50 milligrams or 62.5 milligrams.If desired, with respectively administration of suitable interval, optionally unit dosage forms is divided into 2,3,4,5,6 or more a plurality of sub-doses unit to effective daily dose of Tecastemizole in all day.As mentioned above, preferred dosage form is tablet, caplets, lozenge, pastille, pill, lozenge, syrup, capsule etc.Yet other pharmaceutically acceptable dosage form such as powder, granule, dragee etc. also can use.

Should be noted that all the components that contains in the Tecastemizole dosage form among the present invention preferably meets or surpass the standard of USP/NF Chinese medicine component and compositions thereof.The purpose of USP/NF provides the material of use in the medical field practice and the authoritative standard and the explanation of material and preparation thereof.USP/NF has formulated the standard of exercise question, definition, explanation and discriminating, quality, intensity, purity, Packaging and Labeling, and when feasible, and bioavailability, stability, suitable operation and storage method and inspection method and manufacturing or preparation scheme are provided.

The dosage form that as herein described and claimed Tecastemizole does not contain lactose, non-hygroscopic, anhydrous, bulky grain and coating meets each component of regulation among the USP/NF (as USPXXI/NF XVI) and the pharmaceutical standards that does not contain lactose, non-hygroscopic, anhydrous, bulky grain or coated dosage form for preparing with these components.In fact; pharmaceutically acceptable dosage form and pharmaceutically acceptable amount that the dosage form that Tecastemizole does not contain lactose, non-hygroscopic, anhydrous, bulky grain or coating is known as by pharmaceutically acceptable component preparation in the pharmaceutically acceptable compositions meet specified standard among the USPXXI/NF XVI at least, and the full content of described document all is incorporated herein for reference.In addition, it should be noted that Tecastemizole can prepare according to methods known in the art, comprise that those are disclosed in the unsettled U. S. application 08/182685 on January 18th, 1994 in the applying date, the document is incorporated herein for reference as the purpose of instruction preparation Tecastemizole method.

The particular formulations that the stability of drug products can be defined as in special container keeps its physics, chemistry, microorganism, treatment and toxicity characteristic (although exception is arranged) and maintenance about at least 90% to demarcate the ability of effort levels.Therefore, for example effect duration is defined in that drug products keeps the stable time when storing under the condition of recommendation.

The stability of many factor affecting drug products comprises ability to function between the stability for the treatment of component, treatment component and the inactive ingredients (as Tecastemizole and excipient) etc.Physical factor can cause or promote chemical reaction as heat, light and moisture.

For convenience, employed some term of this paper is defined as follows.Term used herein " carrier " is the synonym of " excipient ".Term used herein " does not contain lactose " and means if present, the quantity not sufficient of lactose is to cause Tecastemizole that the inventor finds and the incompatibility between the lactose in the Tecastemizole dosage form, surpass this dosage form storage life, the adverse effect that Tecastemizole is renderd a service is lower than 90% of initial effectiveness.Term used herein " unbound water " means the water that does not have one or more pharmaceutical composition stable components hydrate forms, as the alpha lactose monohydrate.Similarly, term used herein " anhydrous " means the quantity not sufficient of the unbound water that has (if any) in the Tecastemizole dosage form to cause and/or to promote the incompatibility between Tecastemizole and the lactose.And " anhydrous " used herein, " anhydrous condition " or " anhydrous characteristic " mean and are substantially free of unbound water and comprise moisture.It is non-moisture absorption basically that term used herein " non-hygroscopic " means whole preparation, and the unbound water that is enough to cause and/or promote the incompatibility between Tecastemizole and the reactive excipient (as lactose) promptly is not provided.Term " additive " is a synonym with term used herein " excipient ".Term " is substantially free of " to mean and is lower than about 5% weight, preferably is lower than about 1% weight, more preferably less than about 0.1% weight.Term used herein " bulky grain " means the Tecastemizole compositions and comprises about 40% weight or have 200 μ m or bigger more, is preferably greater than the Tecastemizole of about 250 μ m sizes or the granule of its officinal salt.Term used herein " coating ", " the inertia coating " or " carrying out the inertia coating " mean and use the inertia coating materials to wrap up the Tecastemizole granule and suppress granule and the interaction of reactive excipient (as lactose).Be applicable to that also the present invention does not contain lactose, non-hygroscopic, anhydrous and bulky grain preparation use although be applicable to the non-inertia coating that conventional medicine uses, preferably employed any coating material all is inert and suppresses the interaction of Tecastemizole and any reactive excipient.

Term used herein " pharmaceutically acceptable " refers to be suitable in correct medical diagnosis scope to give and is used for contacting with body fluid with the tissue of humans and animals and does not have over-drastic toxicity, zest, anaphylaxis or other problem or complication, has those chemical compounds, material, compositions and/or the dosage form of rational medicine Sexual health beneficial effect/dangerous ratio.

In addition, use term " pharmaceutically acceptable " excipient, meaning between any excipient composition of Tecastemizole (or its salt) and generation dosage form does not have disadvantageous chemistry or physical incompatibility.For example, disadvantageous chemical reaction is for reducing or increase the effectiveness of Tecastemizole (or its salt) nocuously because of adding one or more excipient.That another example of disadvantageous chemical reaction is that the taste of Tecastemizole (or its salt) dosage form becomes is excessively sweet, acid etc. and make dosage form not good to eat.Excipient with other component compatibility meaning of Tecastemizole preparation on and not injure on the patient must all be " acceptable ".

Physical incompatibility refers to the incompatibility of each composition in the dosage form such as Tecastemizole (or its salt) and any excipient.For example, the combination of excipient and Tecastemizole can form the mixture or the excessive isolated mixture of excessive moisture absorption, therefore can not fully keep the required shape of dosage form (tablet, lozenge etc.), its stability etc., can not be by the relieve pain said preparation of required regulation.

Modally be, by the mode orally give antihistaminic of solid dosage forms (as tablet, capsule, lozenge, caplets etc.), as astemizole or Tecastemizole.In addition, also can use capsule formulation such as hard gelatin capsule, Perle etc.Yet tablet remains preferred dosage form because for patient (as, dosage is accurate, tight, light, taste is gentle and be easy to take medicine) and all be favourable to maker (easy and economic as preparing, stable and packing, transport and distribute conveniently).Tablet is a solid pharmaceutical dosage formulation, contains medicine and is with or without suitable additive.

For with medicine of the present invention or the treatment component (promptly; do not contain lactose, non-hygroscopic, anhydrous, bulky grain or coating Tecastemizole dosage form) be with or without under the diluent condition; make solid dosage forms (as tablet) through spendable equipment pressurization, need have the crystallization of various physical characteristics or the material of powder type.These characteristics for example comprise as powder and are easy to free-pouring ability so that punching press is bonding, and are easy to take out in the slave unit.Because most of materials do not have or these characteristics slightly, the preparation of tablet and preparation method are developed into gives these Ideal Characteristics and these materials is pressed into tablet or similar dosage form.

Should be noted that tablet and similar dosage form can contain the various materials that are called additive except medicine or treatment component.These additives can be classified according to its effect in preparing dosage form such as tablet, caplet, capsule, lozenge etc.One group of additive comprises but is not limited to binding agent, diluent (filler), disintegrating agent and lubricant.

Although that hereinafter discusses variously is used for additive of the present invention and is specifically related to lactose-free dosage form, the further classification that it will be readily appreciated by those skilled in the art that each class all comprises the additive that is applicable to non-hygroscopic of the present invention, anhydrous, bulky grain or coated drugs compositions.In addition, non-hygroscopic of the present invention, anhydrous, bulky grain or coated drugs compositions also can comprise lactose or other list or the disaccharide as excipient.In another embodiment, inorganic bisulfites can be used for improving the stability of any Tecastemizole compositions of this paper.

For the non-hygroscopic preparation, to note selecting excipient and additive especially, under the situation that lacks proper environment control, there is not the tendency of moisture absorption so on the whole.For example, the excipient that is used for said preparation includes but not limited to alpha lactose monohydrate, mannitol etc.

For anhydrous formulation, should use the excipient described below or the additive of suitable anhydrous or low moisture form, for example, AVICEL-PH-103 ^TMWith Starch 1500 LM.

The use binding agent makes the mixture of tablet ingredients form free-pouring powder and material is flowed on pelleter.Binding agent also provides the caking property of Tecastemizole sheet.Binding agent can produce flow field problem very little and make tablet can not keep its integrity.Binding agent can have a negative impact to the release (dissolution rate) of medicine from tablet too much.Therefore, the binding agent that should mix q.s in tablet produces free-pouring tablet ingredients mixture and the dissolution rate of drug component from tablet is not had a negative impact.For low-dose tablets, required good compressibility may be eliminated to a certain degree because of the suitable dilution adjuvant that use is called as compression aids.The amount of employed binding agent depends on the type and the mode of administration of preparation, and those skilled in the art are easy to determine.

Be suitable for the present invention and do not contain lactose; non-hygroscopic; anhydrous; the binding agent that the Tecastemizole preparation of bulky grain or coating uses includes but not limited to corn starch; potato starch or other starch; gelatin; natural or synthetic natural gum such as arabic gum; sodium alginate; alginic acid; other alginate; the powdery tragakanta; guar gum; cellulose and derivant thereof are (as ethyl cellulose; cellulose acetate; carboxymethylcellulose calcium; sodium carboxymethyl cellulose); polyvinylpyrrolidone; methylcellulose; starch,pregelatinized; hydroxypropyl emthylcellulose (as, the 2208th; 2906; No. 2910); microcrystalline Cellulose or its mixture.

The material that the microcrystalline Cellulose of suitable form is for example sold with AVICEL-PH-101, AVICEL-PH-103 and AVICEL-PH-105 (can be available from FMC Corp., American ViscoseDivision, Avicel Sales, Marcus Hook, PA., USA).An example of proper adhesive is microcrystalline Cellulose and the sodium carboxymethyl cellulose mixture of being sold by FMC Corp. as AVICEL RC-581.

Modal heavily is from about 100 milligrams to about 500 milligrams.Therefore, comprise the Tecastemizole dosage form for many effective medicines, filler occupies the major part of tablet.Use filler (as diluent) to obtain powder (in tablet or capsule) volume so that produce tablet, capsule or other the ideal dosage form that to accept size.In general, in the regular dosage form of suitable size, the treatment component is by mixed diluent formation therein.When having binding agent, the bonding of medicine and filler can take place and influence bioavailability.So, should use the filler of capacity to reach required dilution ratio and drug component is not discharged from the dosage form that contains filler and have a negative impact.In addition, should use physics and chemically with the filler of the treatment component compatibility of dosage form.Therefore, should be noted that if do not note eliminating uncombined water, lactose should not be used from preparation Tecastemizole dosage form of the present invention with Tecastemizole one.The yet preferred lactose-free Tecastemizole dosage form of the present invention does not comprise list or disaccharide, as, but be not limited to glucose, sucrose and fructose.The amount of employed filler depends on the type of preparation and the mode of administration, and those of ordinary skills are easy to determine.

The example of the suitable filler that uses in the lactose-free Tecastemizole dosage form of the present invention includes but not limited to Pulvis Talci, calcium carbonate (as granule or powder), microcrystalline Cellulose, Powderd cellulose, dextrate, Kaolin, mannitol, silicic acid, sorbitol, starch, starch,pregelatinized or its mixture.

Binding agent/filler in the pharmaceutical composition of the present invention exists with the content of pharmaceutical composition weight about 50% to about 99% usually.

Use disintegrating agent to make tablet disintegrate when being exposed to aqueous environment.Disintegrating agent will produce too much can be in bottle be enough to cause and/or promote the interaction of Tecastemizole lactose because of the unbound water of the tablet of atmospheric water disintegrate and existence.Disintegrate may be not enough to produce very little and rate of release and the degree of drug component from dosage form may be therefore changed.Therefore, should use the neither also not many very little disintegrating agent that changes the capacity of drug component release nocuously to form Tecastemizole dosage form of the present invention.The amount of employed disintegrating agent depends on the type and the administering mode of preparation, and those of ordinary skills are easy to determine.Usually, in pharmaceutical composition, use the disintegrating agent of about 0.5 to 15% weight, preferably approximately the disintegrating agent of 1 to 5% weight.

Can be used for forming the suitable disintegrating agent that the present invention do not contain lactose dosage form Tecastemizole and comprise, but be not restricted to agar, alginic acid, calcium carbonate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, cross-linked pvp, polacrilin potassium, glycolic acid Starch Sodium, potato starch or tapioca, other starch, clay, other algin, other cellulose, natural gum or its mixture.

Physicochemical property based on Tecastemizole; typically; need preparation not contain the Tecastemizole pharmaceutical composition of lactose, non-hygroscopic, anhydrous, bulky grain or coating, make them, for example in patient's stomach, considerably dissolve soon when giving the patient with them.Therefore, in preferred embodiments, the pharmaceutical composition of the present invention that does not contain lactose, non-hygroscopic, anhydrous, bulky grain or coating comprises super disintegrant, and it includes, but are not limited to crosslinked Carboxymethyl cellulose sodium or glycolic acid Starch Sodium.

No matter how much dose must avoid the adhesion of component and tablet machine in the dosage form.For example, when the surface aggregation of medicine (for example Tecastemizole) at punch die, it makes the sheet sub-surface form pit and therefore is out of favour.In the method, when being released, tablet do not need too high release power from punch die yet.Too high release power can improve breakage rate and increase producing cost, let alone excessive to punch die.In fact, can pass through wet granulation (wet massing) or pass through to use high-load lubricant, for example magnesium stearate reduces viscosity.Yet the salt of selecting to have the adhesive medicine of good resistance also can be reduced to minimum with these problems.

As mentioned above, make with lubricator increase the mobile of the lactose-free Tecastemizole tabletting powder mixture that flows in the tablet machine and prevent tabletting after slice, thin piece adhere in film.Lubricant can not be prepared gratifying tablet very little, and too much lubricant can be prepared the tablet with waterproof hydrophobic coatings.Because lubricant is lyophobic dust such as stearic acid, magnesium stearate, calcium stearate etc. normally, so, can form waterproof hydrophobic coatings by using too much lubricant.And waterproof hydrophobic coatings can suppress the disintegrate of tablet and the stripping of drug component.Therefore, should use the lubricant of q.s, disintegrate and/or stripping that this amount makes institute's tabletting can not form desired drug component from releasing towards film easily produce the waterproof hydrophobic coatings of ill effect.

The suitable lubricant that uses in the lactose-free Tecastemizole dosage form of the present invention's preparation comprises, but be not restricted to calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, Sorbitol, mannitol, Polyethylene Glycol, other glycol, stearic acid, sodium laurylsulfate, Pulvis Talci, hydrogenated vegetable oil (for example Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, Oleum Helianthi, Oleum sesami, olive oil, Semen Maydis oil and Oleum Glycines), zinc stearate, ethyl oleate, ethyl laurate, agar or its mixture.For example other lubricant comprises syloid silica gel (AEROSIL 200, produce by W.R.Grace Co.of Baltimore MD), synthetic silica solidify aerosol (by Deaussa Co.of Plano, Texas sells), CAB-O-SIL (by the pyrogenicity silica product of Cabot Co.of Boston sale) or its mixture.Typically, can add or not add the lubricant that is less than about pharmaceutical composition weight 1% amount.

Other class additives that use in this Tecastemizole dosage form comprise, but are not restricted to anti-caking agent, anti-microbial preservative, coating materials, coloring agent, desiccant, correctives and spice, plasticizer, thickening agent, sweeting agent, buffer agent, wetting agent etc.

The suitable anti-caking agent that uses in the lactose-free Tecastemizole dosage form of the present invention's preparation comprises, but is not restricted to calcium silicates, magnesium silicate, silicon dioxide, silica sol, Pulvis Talci or its mixture.

The suitable anti-microbial preservative that uses in the lactose-free Tecastemizole dosage form of the present invention's preparation comprises, but is not restricted to Benasept solution, benzyl rope chloramines, benzoic acid, benzyl alcohol, butoben, western pyrrole chloramines, chlorobutanol, cresol, dehydroacetic acid, ethyl hydroxybenzoate, methyl hydroxybenzoate, phenol, phenethanol, phenylmercuric acetate, phenylmercuric nitrate, potassium sorbate, propylparaben, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosal (thimersol), thymol or its mixture.

The suitable coating materials that uses in the lactose-free Tecastemizole dosage form of the present invention's preparation comprises, but be not restricted to sodium carboxymethyl cellulose, cellulose acetate-phthalate, ethyl cellulose, gelatin, medicinal glaze, hydroxypropyl cellulose, hydroxypropyl emthylcellulose (Nos.:2208 for example, 2906,2910), Hydroxypropyl Methylcellulose Phathalate (for example Nos.:200731,220824), methylcellulose, Polyethylene Glycol, the phthalic acid polyvinyl acetate, Lac, sucrose, titanium dioxide, Brazil wax, microwax, or its mixture.When the type of preparation and route of administration change, the amount of the coating materials that uses and mounting medium (moisture or water-free) also change, and those of ordinary skills are easy to determine.

Can the film forming polymer coating be used in the Tecastemizole sheet of the present invention (for example, the tablet of the capsule shape of so-called caplet) by coating pan, Accelacota, High-Cola or the Worster air suspension post that uses a kind of equipment such as routine.Typically, this equipment has gas extraction system so that remove dust and solvent or water vapour promote rapid drying.Spray pistol or other suitable atomising device can be introduced in the coating pan and help rapidly emulsion sheet bed equably so that provide with spray pattern.Usually, will heat by continuous or over-over mode spraying circulation or the air of cool drying is introduced sheet bed top so that the drying of quickening film coating solution.For the pharmaceutical composition of the non-hygroscopic of the present invention that contains reactive excipient such as lactose, anhydrous, bulky grain or coating, preferably not moisture operation for example should be used not moisture coating.

Can pass through employing aerating displacement or peristaltic pump system spray coating solution continuously or in the circulation of spray drying intermittently.Select the particular type of spraying according to the drying efficiency of coating pan.

In most of the cases, the spray coating material up to do not contain lactose, non-hygroscopic, bulky grain, anhydrous or coating Tecastemizole tablet by even coating to desired thickness and reach the required outward appearance of tablet.The coating of many dissimilar coatings all can adopt the quick dissolution type coating that as enteric, slowly discharges coating or snap action tablet.Preferably, use quick dissolution type coating, cause quick acting so that allow to discharge more quickly active component.The coating thickness that is coated on the film forming polymer on the tablet can change.Yet preferably thickness is simulated outward appearance, sensation (sense of touch and mouthfeel) and the function of gelatine capsule.Need quicker or when postponing to discharge therapeutic agent, those skilled in the art should easily recognize the type and the thickness of film, even have, use according to the rate of release of the required blood levels of active component, active component and dissolubility and the required performance of dosage form.

Do not contain the various suitable film former that uses in the tablet coating of Tecastemizole preparation of lactose, non-hygroscopic, anhydrous, bulky grain or coating and comprise for example derivant, cellulosic phthalic acetate or its mixture of methylcellulose, hydroxypropyl emthylcellulose (PHARMACOAT 606 6 cps), polyvinylpyrrolidone (povidone), ethyl cellulose (EThxel 10cps) first acrylic acid and first acrylate as containing the present invention in final dosage form.

The used suitable coloring agent of the lactose-free dosage form of Tecastemizole of the present invention includes but not limited to pharmaceutically useful dyestuff and color lake, caramel, red iron oxide, flavin ferrum oxide or its mixture.The used suitable desiccant of Tecastemizole dosage form that the present invention does not contain lactose, anhydrous, bulky grain or coating includes, but are not limited to calcium chloride, calcium sulfate, silica gel or its mixture.

Tecastemizole of the present invention does not contain the used suitable fragrance of lactose dosage form and includes but not limited to arabic gum, the tragakanta, almond oil, anethole, Oleum Anisi Stellati, benzaldehyde, Fructus cari carvi, caraway oil, cardamom oil, cardamom seed, Fructus Amomi Rotundus chemical compound tincture, cherry juice, Cortex Cinnamomi, Oleum Cinnamomi, Oleum Caryophylli, cocoa, Fructus Coriandri oil, mountain balsam, the mountain balsam liquid extract, ethyl acetate, the vanillin ethyl ester, by oil, Oleum Anisi Stellati, Radix Glycyrrhizae, pure Radix Glycyrrhizae extract, the Radix Glycyrrhizae liquid extract, Essential lavender oil, Fructus Citri Limoniae oil, menthol, methyl salicylate, sodium glutamate, Semen Myristicae oil, orange blossom oil, aqua aurantii florum, orange oil, Fructus Citri sinensis peel tincture, chemical compound orange spirit, Herba Menthae, Oleum menthae, the Herba Menthae spirit, Masson Pine pin oil, Oleum Rosae Rugosae, strong rose water, Mentha viridis L, oleum menthae viridis, thymol, balsam of Tolu face cream tincture, Rhizoma et radix valerianae, plain or its mixture of tincture of vanilla and Rhizoma et radix valerianae.

The used suitable plasticizers of the lactose-free dosage form of Tecastemizole of the present invention includes but not limited to monoglyceride, diethyl phthalate, glycerol, list and diacetylation monoglyceride, Polyethylene Glycol, propylene glycol and glyceryl triacetate or its mixture of Oleum Ricini, diacetylation.

The used appropriate viscosity dose of the lactose-free dosage form of Tecastemizole of the present invention includes but not limited to arabic gum, agar, aramine acid (alamic acid), aluminum monostearate, bentonite, bentonite magma, carbomer 934, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, sodium carboxymethyl cellulose 12, carrageenin, cellulose, microcrystalline Cellulose, gelatin, guar gum, hydroxyethyl-cellulose, hydroxypropyl cellulose, hydroxypropyl emthylcellulose the (the 2208th; 2906; 2910), aluminium-magnesium silicate, methylcellulose, pectin, polyvinyl alcohol, polyvidone, silica gel, colloidal silica, sodium alginate, tragakanta and xanthan gum or its mixture.

The used suitable sweeting agent of the lactose-free dosage form of Tecastemizole of the present invention comprises but is not limited to aspartame, dextrate, mannitol, glucide, Calcium o-benzolsulfimide, saccharin sodium, sorbitol, sorbitol solution or its mixture.

The used suitable buffer agent of the lactose-free dosage form of Tecastemizole of the present invention includes but not limited to magnesium hydroxide, aluminium hydroxide etc. or its mixture.Suitable wetting agent includes but not limited to glycerol, other wetting agent or its mixture.Tecastemizole dosage form of the present invention can further comprise one or more following ingredients: (1) stripping delayer, as paraffin; (2) absorption enhancer, quaternary ammonium compound; (3) wetting agent is as spermol and glyceryl monostearate; (4) adsorbent is as Kaolin and POLARGEL NF; (5) antioxidant, as water solublity antioxidant (as, ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulphate, sodium sulfite etc.), oil-soluble antioxidant (as, ascorbyl palmitate, BHA (BHA), butylated hydroxy-methylbenzene (BHT), lecithin, propyl gallic acid ester, alpha-tocopherol etc.); (6) metal-chelator is as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid etc.

For example, also can form together with the various excipient of mentioning in the suitable material of gelatin or other and the previous relevant tablet firmly or the soft capsule form provide the present invention not contain the Tecastemizole dosage form of lactose, non-hygroscopic, anhydrous, bulky grain or coating.With regard to the preparation of tablet, by using traditional preforming device such as double-walled or " V " blender, according to known method, with Tecastemizole and one or more excipient (for example diluent, binding agent, disintegrating agent, dispersant, surfactant, lubricant, coating material, correctives, coloring agent, solvent, thickening agent, suspending agent, sweeting agent, colorant, dyestuff etc.) with various mixed prepare chemically with thermodynamics on stable dosage form (for example tablet, capsule etc.), comprise uniform distribution and blended therapeutic agent in the described dosage form.Those of ordinary skill in the pharmaceutical field can be measured the accurate amount of various excipient at an easy rate.

Except the medicine component; large-scale production the present invention does not contain the Tecastemizole dosage form of lactose, non-hygroscopic, anhydrous, bulky grain or coating also will add following additive, include, but are not limited to diluent, binding agent, lubricant, disintegrating agent, coloring agent, correctives, sweeting agent, etc. or its mixture.Because the adding of these additives or other additive can prepare various dosage forms (for example tablet, capsule, caplet, dragee etc.).For example these dosage forms comprise hard gelatin capsule, caplet, the coated tablet of delay action, the casing sheet of delay action, the repeatedly tablet of Ya Zhi tablet, prolongation effect, solution sheet, effervescent tablet, cheek and Sublingual tablet, dragee etc.Preferably, sugar-coat does not comprise lactose or monosaccharide or disaccharide, except in being substantially free of the Tecastemizole preparation of unbound water.

Usually, prepare the Tecastemizole dosage form that the present invention does not contain lactose, non-hygroscopic, anhydrous, bulky grain or coating with mold pressing, tabletting or the tablet forming method that adopts usually.Therefore, usually, prepare compressed tablet, and molded tablet prepares with small-scale usually relevant with large scale production method.For example, three kinds of flaking methods that prepare the Tecastemizole dosage form are arranged usually: (1) wet granulation; (2) dry granulation and (3) direct compression.These methods are well known to those skilled in the art.See Remington ' s Pharmaceutical Sciences, 16th and18th Eds., Mack Publishing Co., Easton, Pennsylvania (1980and 1990).Also see American Pharmacopeia XXI, U.S.Pharmacopeial Convention, Inc., Rockville, Maryland (1985).For non-hygroscopic or there is not water aqua type, preferably do not use wet granulation.

The Tecastemizole dosage form that does not contain lactose, non-hygroscopic, anhydrous, bulky grain or coating that can prepare various tablet forms according to the present invention.These preparations comprise Tabules such as coated tablet (SCT), film coated tablet, casing sheet, the tablet of repeatedly compacting, the tablet of prolongation effect etc.The Tecastemizole coated tablet (SCT) that does not contain lactose, non-hygroscopic, anhydrous, bulky grain or inert material coating is pressed into the tablet that contains sugar-coat.This sugar-coat can be painted and be being covered aspect the medicine with tedious taste and abnormal smells from the patient and preventing that aspect the oxidizable material oxidation be useful.With do not contain lactose, non-hygroscopic, anhydrous, bulky grain or or Tecastemizole film coated tablet (FCT) compacting of coating in flakes, with the thin layer or the film coating of the insoluble material of this sheet water.Can use the polymer that has film property in a large number.The film clothing has the identical general character with sugar-coat, and has the advantage that reduces the coating required time greatly.The casing sheet also is applicable to the present invention.The Tecastemizole casing sheet (ECT) that does not contain lactose, non-hygroscopic, anhydrous, bulky grain or coating is pressed into preventing stripping in gastric juice and in intestinal the tablet of the material coating of disintegrate.Contain the tablet of easy deactivation under one's belt or destructive drug component, the tablet of stimulating mucosal or the method that conduct postpones the medicine wet method, can use enteric coating.

With the Tecastemizole that do not contain lactose, non-hygroscopic, anhydrous, bulky grain or coating repeatedly compressed tablet (MCT) be pressed into by once above tabletting such as lamination or the tablet of pressing the clothing method to make.Laminate is by on the granule of compression moulding formerly other tablet and powder being suppressed up preparation.Can repeat this operation so that produce two-layer, three layers or multiwalled multilayer tablet.Typically, the prepared layer tabletting needs specific sheet press.For example, see U.S. Patent No. 5,213,738, be incorporated herein it for reference in full.

Pressing garment piece is repeatedly the another kind of form of compressed tablet.This tablet is also referred to as the dry-method coating sheet, and it is to be added in the tablet machine and to suppress another granular layer again around the tablet of molding by the tablet that will before suppress to prepare.These do not contain lactose, non-hygroscopic or anhydrous Tecastemizole sheet and have the advantage of all compressed tablets, and punching, monogram, disintegration rate etc. are promptly arranged, and have also kept coated tablet can cover the speciality of label Chinese medicine component taste simultaneously.Press garment piece also can be used to separate immiscible medicine.In addition, they can be used for providing a casing to label.For example, when the design long-acting dosage form, the Tecastemizole of two kinds of forms (being synusia and pressure garment piece) can use.

The Tecastemizole DAT that does not contain lactose, non-hygroscopic, anhydrous, bulky grain or coating can comprise the compressed tablet that discharges drug component in the mode through medicine just is provided after a while.A large amount of tablet types are arranged, comprise the tablet of delay action, in this tablet, after administration, stop drug release in a period of time or just discharge medicine up to certain physiological condition of existence.Can prepare the tablet with repeat function, it regularly discharges the drug component of full dosage in gastro-intestinal Fluid.Also can prepare the tablet that continues release, its discharges the increment of contained drug component continuously in gastro-intestinal Fluid.

Select preparation method and be mixed into not contain the additive in lactose, non-hygroscopic, anhydrous, bulky grain or the coating Tecastemizole sheet so that obtain having the required physical property tablet of tabletting rapidly simultaneously.Behind the tabletting, preferably, tablet should have many other characteristics such as outward appearance, hardness, disintegrate ability and uniformity, and they are subjected to the influence of the additive that exists in preparation method and the tablet.

The elementary cell of all preforming devices comprises the low punch that enters punch die from the bottom and has upper punch common and identical shaped in a state of excitement down and diameter that it enters behind the film chamber at the tabletting material, enters towards the film chamber from the top.By pressurization preparation tablet on drift.Subsequently, slice, thin piece is from releasing towards film.The weight of the stereometry slice, thin piece by being filled into the material in the film chamber.

Guaranteeing aspect the even filling that not containing lactose, non-hygroscopic, anhydrous, bulky grain or coating Tecastemizole sheet or dosage form granule, to flow freely into towards the ability in film chamber be important.Particulate flowability is guaranteeing that granule is from also being important aspect feed source or the loading hopper continuous-flow.And, if tablet and powder does not have cohesiveness, so, behind the tabletting, slice, thin piece when handling with cracked and scatter.In addition, because drift must move freely in film and slice, thin piece must be easily released from punch head surface, all tabletting materials must have lubricity so that friction is minimized and compressed tablet is released.Granulating agent can be added so that promote granulating.The amount of the granulating agent of using changes with preparation type and administering mode and is to discern easily to those skilled in the art.Typically, in pharmaceutical preparation, use the granulating agent of about 5%-15% weight.Preferably, when containing lactose in or the non-hygroscopic compositions anhydrous in the present invention, granulating agent should be anhydrous.

In addition, Tecastemizole tablet or its other dosage form of not containing lactose, non-hygroscopic, anhydrous, bulky grain or coating of pays attention stably keep its original size, shape, weight and color in the whole storage life under normal operation and condition of storage.Therefore, excessive powder or solid particle, the crack of tablet surface or the crystallization outward appearance on bits sheet or tablet surface or the chamber wall of container bottom is the sign of uncoated tablets physical instability.Therefore, the appropriateness of tablet, all shaking with rolling effect of even reproduction should guarantee that tablet has enough physical stabilities.The hardness of tablet can be determined by the hardness tester that is purchased.In addition, obvious variation should not take place in active component availability in glass tubing in time.

The lactose-free pharmaceutical composition of the present invention also can by use conventional method well known in the art be mixed with soft resilient gelatine capsule (as referring to, Ebert, Pharm.Tech., 1 (5): 44-50 (1977)).Soft resilient gelatine capsule has soft, the spheric gelatin shell thicker slightly than hard gelatin capsule, and wherein gelatin comes plasticising by adding glycerol, sorbitol or similar polyhydric alcohol.The hardness of capsule shells can be regulated by the type of change gelatin and the amount of plasticizer and water.Soft gelatin shell can contain antiseptic (as methyl and propyl para-hydroxybenzoate and sorbic acid) and prevent conk.Active component dissolves in or is suspended in liquid excipient or carrier, as vegetable oil or mineral oil, dihydroxylic alcohols such as Polyethylene Glycol and propylene glycol, triglyceride, surfactant such as polysorbate or its compositions.

The tablet of pharmaceutical composition of the present invention and other dosage form such as dragee, capsule, pill and granule be indentation or coating and add shell randomly, as known enteric coating in the medicine formulation art and other coating.

It is slow or sustained release that pharmaceutical composition of the present invention also can be formulated into active component, for example wherein uses as hydroxypropyl emthylcellulose (its ratio of scalable is to produce required release mode), other polymeric material, liposome and/or microsphere.

All percentage ratios as herein described all are based on the percentage by weight of whole composition gross weights of particular dosage form, except as otherwise noted.

The Tecastemizole compositions that the present invention does not contain lactose, non-hygroscopic, anhydrous, bulky grain or coating can further contain just like analgesics, Decongestant, antitussive or expectorant.

The incompatibility of explanation Tecastemizole and lactose in the infra Table I.Estimated at various temperatures (as 25 ℃, 40 ℃ and 60 ℃), various relative humidity level (as, 60% and 75% relative humidity) and each time (as, 0,1 week, 1 month, 2 months, 3 months, 6 months and 9 months) lactose is to the influence of Tecastemizole.The result of this evaluation is presented in the Table I.Use impurity level in high pressure liquid chromatography (HPLC) the experiment with measuring capsule, and with the percentages show of test dosage form in Table I.Attention shows incompatibility between Tecastemizole and the lactose by the appearance color change of initial White-opalescent, and the increase of the impurity percent of measuring by HPLC confirms.

Table I *

The capsular stability of Tecastemizole

Temperature (℃)	Relative humidity (%)	Time	Outward appearance	HPLC impurity (%)	HPLC measures (%)
						????25	????60	????0	The White-opalescent capsule	????0.10	????101.0
????25	????60	1 week	The White-opalescent capsule	????0.12	????97.1
						????25	????60	January	The White-opalescent capsule	????0.25	????99.3
????25	????60	February	The White-opalescent capsule	????0.39	????95.7
						????25	????60	March	The White-opalescent capsule	????0.35	????99.9
????25	????60	June	Yellow/White-opalescent capsule	????1.53	????96.8
						????25	????60	JIUYUE	Cream-coloured opaque capsule	????1.63	????94.7
????40	????75	1 week	The White-opalescent capsule	????0.46	????98.5
						????40	????75	January	The White-opalescent capsule	????1.45	????98.9
????40	????75	February	The White-opalescent capsule	????3.42	????95.0
						????40	????75	March	The cream-coloured capsule of duskiness	????7.40	????88.2
????40	????75	June	Brown opaque capsule	????18.80	????78.5
						????40	????75	JIUYUE	Brown opaque capsule	????22.92	????70.7
????60	????75	1 week	The White-opalescent capsule	????13.90	????83.0
						????60	????75	January	The White-opalescent capsule	????36.87	Undetermined

The stability of Tecastemizole when * being filled in the hard gelatin capsule of lactose, about 25 milligrams of Tecastemizoles and 4.975 gram lactose; Even in the time of 25 ℃, 6 months and capsule demonstration impurity increase (HPLC impurity) and effectiveness minimizing (HPLC mensuration) in glass tubing after 9 months show that lactose and Tecastemizole are incompatible.

Therefore, the result shows Tecastemizole and lactose preparation, is filled in the hard gelatin capsule and when being stored in non-air-locked sealed container, and preparation is a chemically unstable in the temperature of rising and dampness following time.And, even when 25 ℃ and 60% relative humidity, 6 months and after 9 months Tecastemizole/lactose capsule show that impurity increases and in glass tubing, render a service and reduce, show that lactose and Tecastemizole are incompatible.

In the trial of the excipient of determining to be suitable for to use except that lactose, use various types of other excipient to carry out excipient research with Tecastemizole.Example by the test excipient comprises corn starch, calcium sulfate dihydrate, calcium stearate, sucrose, fructose, calcium carbonate, microcrystalline Cellulose, maltodextrin, CaHPO ₄2H ₂O, CaHPO ₄, magnesium stearate, starch 1500 ^, cross-linking sodium carboxymethyl cellulose or its mixture.

Various excipient are described among Fig. 2 the influence of Tecastemizole degraded, wherein the compositions of Tecastemizole/excipient is exposed under 60 ℃ of temperature and 75% relative humidity and stores in non-air-locked sealed container, and this is the representative condition that carries out the excipient Study on Compatibility.

As clearly shown in Figure 2, Tecastemizole and lactose are obviously incompatible, because the effectiveness of medicine sharply descends.Yet, between the excipient of Tecastemizole and other test, as seen do not render a service fierce decline.Yet, dosage every day need be regulated with the usefulness variation in the excipient that meets shown in Figure 2 and explanation.

Fig. 2 also provides some indication list and disaccharide excipient also should preferably avoid being present in the Tecastemizole preparation, shown in the Degradation that Tecastemizole/sucrose compositions is observed.

Use the screw lid container, they are acceptable widely chemical compound and interactional methods of excipient measured under acceleration environment obtaining The above results under high temperature and the high humility.When the applicant finds that also Tecastemizole stores separately under high humidity (therefore being exposed to tangible unbound water), extremely stable for a long time.Carrying out another studies and estimates moisture varying to the interactional influence of lactose/Tecastemizole.

In the bottle that curls in 20ml amber glass top, prepare following sample:

Pure Tecastemizole

Tecastemizole 20%/lactose 80%

Tecastemizole 20%/the contain lactose 80% of 5% water

Tecastemizole 1%/lactose 99%

Tecastemizole 1%/the contain lactose 99% of 5% water

The bottle that curls was descended placement 14 days and measured Tecastemizole at 60 ℃.

The result shows that when not existing unbound water and seal of vessel airtight, the incompatibility of Tecastemizole and lactose reduces greatly.In fact, the humidity effect response speed is conspicuous.If intentionally unbound water is not added in the container of abundant sealing, difference is different from contrast basically, promptly pure Tecastemizole.When containing unbound water, can be observed effect and reduce, simultaneously, when not containing unbound water, compare with free from lactose or pure Tecastemizole, also can be observed effect and reduce.

% Tecastemizole (measurement result)

Pure Tecastemizole 96.90

Tecastemizole 20%/lactose 80% 98.33

Tecastemizole 20%/the contain lactose 80% 65.16 of 5% water

Tecastemizole 1%/lactose 99% 92.59

Tecastemizole 1%/the contain lactose 99% 77.22 of 5% water

Can pass through mixed with excipients with the pharmaceutically compatible as mentioned above of Tecastemizole or its officinal salt and one or more pharmaceutically compatible amounts; generation comprises about 1mg-200mg Tecastemizole, and the unit dose Tecastemizole dosage form that preferably comprises about 2mg-100mg Tecastemizole prepares free from lactose, non-hygroscopic, anhydrous, bulky grain or coating Tecastemizole dosage form such as dragee, tablet or capsule.For example, can comprise by means commonly known in the art that wet granulation, dry granulation or tabletting molding prepare tablet, dragee or capsule dosage form.And wet granulation is not suitable for non-hygroscopic or anhydrous formulation.Can use other method of preparation tablet well known in the art, dragee and capsule.Yet the tabletting molding is preparation tablet and dragee preferable methods.For capsule, preferably fill the hard gelatin capsule shell of Tecastemizole and one or more excipient.

STARCH 1500 ^Be a kind of pregelatinized starch of producing by Colorcon Ltd., advise that its use amount is no more than 75% of weight.In addition, when with STARCH 1500 ^Use together, during as lubricant, the amount of the magnesium stearate of using should be not more than weight 0.25% with magnesium stearate.Because this may have ill effect to stripping.At STARCH 1500 ^In preparation greater than 0.25% weight magnesium stearate, for chemical compound with relative low water solubility such as Tecastemizole, this ill effect is a particular importance.

After having described the present invention, the following example is used for illustrating the disclosed preferred specific embodiments of the present invention.Known, described embodiment be used to illustrate and be not used in the scope that limits claim of the present invention.

Embodiment 1: hard gelatin capsule unit dosage forms (free from lactose)

Component	2.5mg capsule (unit: mg)	5mg capsule (unit: mg)	20mg capsule (unit: mg)
				Tecastemizole	????2.5	????5.0	????20.0
Microcrystalline Cellulose	????90.0	????90.0	????90.0
				Pregelatinized starch	????100.3	????97.8	????82.8
Cross-linked carboxymethyl cellulose	????7.0	????7.0	????7.0
				Magnesium stearate	????0.2	????0.2	????0.2

Embodiment 2: hard gelatin capsule unit dosage forms (non-hygroscopic)

Component	2.5mg capsule (unit: mg)	5mg capsule (unit: mg)	20mg capsule (unit: mg)
				Tecastemizole	????2.5	????5.0	????20.0
The alpha-lactose monohydrate	????197.3	????144.8	????179.8
				Magnesium stearate	????0.2	????0.2	????0.2

Embodiment 3: hard gelatin capsule unit dosage forms (anhydrous)

Component	2.5mg capsule (unit: mg)	5mg capsule (unit: mg)	20mg capsule (unit: mg)
				Tecastemizole	????2.5	????5.0	????20.0
??AVICEL-PH-103	????50.0	????50.0	????50.0
				Starch 1500LM	????97.3	????94.8	????79.8
Alpha-lactose (anhydrous)	????50.0	????50.0	????50.0
				Magnesium stearate	????0.2	????0.2	????0.2

Active component sieved and with listed mixed with excipients, utilize suitable machinery and method well known in the art that this mixture is filled in two parts hard gelatin capsule of suitable size.See Remington ' s Pharmaceutical Sciences, 16th or 18thEdition all is incorporated herein it for reference.If desired, can prepare other dosage by changing loading and changing the capsule size.Above-mentioned any stable, free from lactose, non-hygroscopic and anhydrous hard gelatin capsule preparation can prepare.

Embodiment 4: press sheet formulation (free from lactose)

Component	2.5mg capsule (unit: mg)	5mg capsule (unit: mg)	20mg capsule (unit: mg)
				Tecastemizole	?????2.5	?????5.0	?????20.0
Microcrystalline Cellulose	?????90.0	?????90.0	?????90.0
				Pregelatinized starch	?????100.3	?????97.8	?????82.8
Cross-linked carboxymethyl cellulose	?????7.0	?????7.0	?????7.0
				Magnesium stearate	?????0.2	?????0.2	?????0.2

Active component sieved by suitable sieve and with non-lactose mixed with excipients until forming uniform mixture.This dry mixture is sieved and mix with magnesium stearate.Then, resulting mixture of powders is pressed into the tablet of required shape and size.Ratio by changing active component (being Tecastemizole) and excipient or the weight that changes tablet can prepare the tablet of other intensity.

Embodiment 5: wet granulation (free from lactose)

Component	Every weight (mg)
					Preparation A	Preparation B	Formulation C
Tecastemizole	????25	????50	????100
				Pregelatinized starch	????100-150	????100-125	????50-100
Microcrystalline Cellulose	????0-75	????0-50	????0-50
				Polyvinylpyrrolidone	????7.5	????…	????7.5
Polyethylene Glycol	????…	????10-30	????…
				Cross-linked carboxymethyl cellulose	????10	????…	????10
The glycolic acid Starch Sodium	????…	????5-15	????…
				Magnesium stearate	????1.5	????1.5	????1.5
The yellow #2 of FDC color lake	????1.25	????1.25	????1.25

Active component sieved by suitable sieve and mix until the uniform mixture of formation with non-lactose excipient (comprise half carboxymethyl cellulose (or sodium starch glycollate) and all microcrystalline Cellulose).The water that adds appropriate volume is also granulated this powder.After the drying, granule is sieved and mix and mix with magnesium stearate simply with microcrystalline Cellulose, remaining carboxymethyl cellulose or glycolic acid Starch Sodium.Then, free-pouring powder is pressed into the tablet of required shape and size.Ratio by changing active component (being Tecastemizole) and excipient or the weight that changes tablet can prepare the tablet of other intensity.

Embodiment 6: direct compression

Component	Every amount (mg)
				Preparation A	Preparation B
Tecastemizole	????25	????50
			Pregelatinized starch	????12.5	????12.5
Microcrystalline Cellulose	????205	????180
			Silicon dioxide	????0.625	????0.625
Sodium lauryl sulfate	????1.25	????1.25

Cross-linked carboxymethyl cellulose	????2.5	????2.5
			Magnesium stearate	????2	????2
The yellow #2 of FDC color lake	????1.25	????1.25

Active component is sieved by suitable sieve and mix until the uniform mixture of formation with non-lactose excipient (except that magnesium stearate).Dried mixture is sieved and mix with magnesium stearate simply.Then, resulting mixture of powders is pressed into the tablet of required shape and size.Ratio by changing active component (being Tecastemizole) and excipient or the weight that changes tablet can prepare the tablet of other intensity.

Those skilled in the art are apparent, although described the present invention with regard to particular, still can carry out various changes and modification, this and defined spirit and scope of the invention in the claim.

Claims (42)

1, a kind of lactose-free pharmaceutical composition, it comprises Tecastemizole or its officinal salt and the pharmaceutically acceptable excipient of at least a non-lactose.

2, a kind of solid composite medicament, it comprises Tecastemizole or its officinal salt and the pharmaceutically acceptable excipient of at least a non-lactose, and wherein, described excipient is not a lactose.

3, claim 1 or 2 compositionss, it further comprises lubricant, disintegrating agent or its mixture.

4, claim 1 compositions, wherein, the pharmaceutically acceptable excipient of described at least a non-lactose comprises crosslinked sodium carboxymethyl cellulose, microcrystalline Cellulose sodium, pregelatinized starch and magnesium stearate.

5, claim 1 or 2 compositionss, wherein said pharmaceutical composition is substantially free of all monosaccharide or disaccharide.

6, lactose-free thermodynamically stable pharmaceutical composition, it comprises Tecastemizole or its officinal salt and at least a pharmaceutically acceptable excipient basically.

7, lactose-free chemically stable pharmaceutical composition, it comprises the Tecastemizole of about 1%-50% weight or the pharmaceutically acceptable excipient of its officinal salt and at least a about 99%-50% weight.

8, claim 1 or 7 compositionss, wherein, described Tecastemizole exists with the amount of about 1mg-200mg.

9, claim 8 compositions, wherein, described Tecastemizole exists with the amount of about 2mg-100mg.

10, claim 1 or 7 compositionss, wherein, described Tecastemizole exists with the treatment effective dose of treatment anaphylactic disease.

11, a kind of solid composite medicament, it comprises Tecastemizole or its officinal salt, microcrystalline Cellulose, pregelatinized starch, magnesium stearate and cross-linking sodium carboxymethyl cellulose.

12, claim 11 solid composite medicament, wherein said solid composite provides with tablet or capsule dosage form.

13, claim 2 pharmaceutical composition, it further comprises enteric coating.

14, the method for treatment mammal anaphylactic disease, it comprises the claim 1 or 2 compositionss for the treatment of effective dose.

15, claim 14 method, wherein said mammal is the people.

16, claim 14 method, wherein said anaphylactic disease are allergic rhinitis.

17, anhydrous pharmaceutical composition, it comprises Tecastemizole or its officinal salt and at least a pharmaceutically acceptable excipient.

18, claim 17 anhydrous pharmaceutical composition, wherein said at least a pharmaceutically acceptable excipient is a lactose.

19, a kind of solid composite medicament, it comprises Tecastemizole or its officinal salt, at least a pharmaceutically acceptable excipient and lactose, and wherein said compositions is substantially free of unbound water.

20, claim 17 or 19 pharmaceutical compositions, wherein said at least a pharmaceutically acceptable excipient is selected from low humidity or anhydrous excipient.

21, anhydrous pharmaceutical composition, it comprises the Tecastemizole of about 1%-50% weight or one or more pharmaceutically acceptable excipient of its officinal salt and about 99%-50% weight.

22, a kind of solid unit dosage form, it comprises and is sealed in the aluminium foil, is sealed in claim 20 or 21 anhydrous compositions in container, vesicle packing or the bar packing.

23, a kind of non-hygroscopic pharmaceutical composition, it comprises Tecastemizole or its officinal salt and one or more pharmaceutically acceptable excipient.

24, claim 23 non-hygroscopic pharmaceutical composition, wherein said one or more pharmaceutically acceptable excipient are lactose.

25, a kind of non-hygroscopic pharmaceutical composition, it comprises Tecastemizole or its officinal salt, lactose and one or more pharmaceutically acceptable excipient, and wherein said compositions is substantially free of unbound water.

26, a kind of solid non-hygroscopic pharmaceutical composition, it comprises Tecastemizole or its officinal salt, at least a pharmaceutically acceptable excipient and lactose.

27, claim 24 or 25 pharmaceutical compositions, but wherein said one or more drug excipients are selected from non-hygroscopic or low humidity excipient.

28, claim 23,24,25 or 26 pharmaceutical compositions, wherein said lactose is a hydrate.

29, a kind of method for the treatment of the mammal anaphylactic disease, it comprises the claim 24 or 25 compositionss for the treatment of effective dose.

30, claim 29 method, wherein said mammal is the people.

31, claim 29 method, wherein said anaphylactic disease are allergic rhinitis.

32, a kind of pharmaceutical composition for the treatment of the inductive disease of histamine, it comprises bulky grain Tecastemizole or its officinal salt and pharmaceutically acceptable excipient.

33, claim 32 bulky grain pharmaceutical composition, wherein excipient comprises lactose.

34, claim 32 bulky grain pharmaceutical composition, wherein about 40% weight or more bulky grain Tecastemizole or its officinal salt comprise and have 200 μ m or bigger granule.

35, a kind of solid composite medicament for the treatment of the inductive disease of histamine, comprising treatment effective dose coating Tecastemizole or its officinal salt, it comprises Tecastemizole or its officinal salt and pharmaceutically acceptable excipient with inertia coating materials coating.

36, claim 35 solid composite medicament, wherein said excipient comprises lactose.

37, claim 35 solid composite medicament, wherein the Tecastemizole of coating or its officinal salt comprise Tecastemizole or granular preparation that its officinal salt becomes and pharmaceutically acceptable inert excipient, wherein described one-tenth granular preparation are used inertia coating materials coating.

38, claim 35 or 37 solid composite medicaments, wherein the inertia coating materials is included in the inertia film former in the solvent.

39, claim 38 solid composite medicament, wherein said inertia film former is selected from methylcellulose, hydroxy methocel, carboxymethyl cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose, methyl hydroxyethylcellulose, cross-linking sodium carboxymethyl cellulose and composition thereof.

40, a kind of method for the treatment of the mammal anaphylactic disease, it comprises treats effective dose claim 32 or 35 compositionss.

41, claim 40 method, wherein said mammal is the people.

42, claim 40 method, wherein said anaphylactic disease are allergic rhinitis.

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