CN1964724A - Solid dosage form of wetted heparin - Google Patents

Abstract

The present invention relates to a solid pharmaceutical composition (such as a solid dosage form) comprising a delivery agent and wetted heparin. The inclusion of wetted heparin rather than un-wetted heparin in the solid pharmaceutical composition results in increased delivery of the heparin. Without being bound by any particular theory, applicants believe that because the polymer chain of the wetted heparin is already in an ''open'' form, while un-wetted heparin is not, less of the wetted heparin is broken down in the gastrointestinal tract and is more readily absorbed in the stomach.

Description

The solid dosage forms of wetted heparin

The provisional application sequence number that the application has required to submit on May 6th, 2004 is 60/569,475 U. S. application, the provisional application sequence number of submitting on May 19th, 2004 are 60/572,679 U. S. application and the provisional application sequence number of submitting on August 4th, 2004 are 60/598, the priority of 978 U. S. application, these applications here all are incorporated herein by reference.

Technical field

The application relates to the solid dosage forms of wetted heparin and delivery agent.

Background technology

For the prevention and initial stage treatment of venous thromboembolism, heparin is most widely used anticoagulant, and said venous thromboembolism comprises that dvt forms (DVT) and pulmonary infarction (PE).Estimate that PE every year only just can make people more than 300,000 be admitted to hospital and makes people's death of about 50,000 to 250,000 every year in the U.S..Heparin product (classification and unfraction heparin) has been approved for many indications, but also has many indications not granted.The embolic incident is normally treated or prevented to its therapeutic goal.

Heparin is a kind of effective anticoagulant, and its chemical constituent comprises the mixture of the repetition disaccharide unit that some are made up of glycosamine and L-iduronic acid or D-glucuronic acid.Heparin is a kind of naturally occurring glycosaminoglycans, and it is separated by pulmonis Bovis seu Bubali and pig intestinal mucosa commercial the most commonly.It is sulphation, anionic form and has very high acidity.

Effects of heparin cause the reaction of blood coagulation and be also referred to as the formation of the fibrin clot of thrombosis.It has suppressed some coagulation factors that are activated, particularly factor Xa and prothrombin a by combining with plasma protein enzyme inhibitor Antithrombin III.It is by desulfuration acidify and depolymerisation and by the part metabolism.

Heparin comprises unassorted heparin and low molecular weight heparin, and for example, dalteparin sodium, Enoxaparin, booth are pricked heparin (tinzaparin).Show that heparin can prevent patient's dvt after the ischemic complication, prevention hip or knee reattachment surgery in unstable angor and the non-q wave myocardial infarction to form (DVT) and prevents to have the DVT of patient's abdominal postoperative of thromboembolic complication risk.Risky abdominal operation patient comprise these ages surpass 40 years old, fat, surpass in the persistent period and to undergo surgery under 30 minutes the general anesthesia or have other risks and assumptions such as malignant tumor or DVT is arranged or the patient of pulmonary infarction history.But also show the DVT of movable serious limited medical patient during the heparin prophylaxis of acute disease, and can be used for treating the DVT that has or do not have pulmonary infarction.

The anticoagulation of heparin need exist Antithrombin III to promote and 1: 1 complex of thrombin formation.Heparin as catalytic templating can increase by 1 with the formation speed of thrombin-Antithrombin III complex, and 000-times, heparin both can combine with inhibitor, can combine with thrombin again.The conformation change in the anticoagulant enzyme has also been induced in the combination of heparin, and it makes this reactive site easier to be approaching by thrombin.Antithrombase combines with heparin by the sulfate group on the specific pentasaccharide sequence of finding in about 30% heparin molecule.Plasma thromboplastin component, X, XI and XII that this heparin-the Antithrombin III complex can also suppress to be activated.In case thrombin combines with antithrombase, heparin molecule just is released from this complex.For example, when the heparin concentration in the blood plasma is about 0.1 to 1.0IU/mL the time, thrombin, prothrombin a and factor Xa are suppressed by Antithrombin III rapidly.As recording with activated partial thrombin time (aPTT), thrombin time, anticoagulin IIa and anticoagulin xa activity, consequently blood coagulation time increases.

At present, heparin is by continuously or intermittent intravenous input or depths subcutaneous injection and by parenteral.Heparin self can not be absorbed by gastrointestinal tract well.

US patent 6,458,383 discloses the pharmaceutical dosage form that a kind of delay that is used for the oral administration of hydrophilic medicament discharges.This dosage form comprise low-molecular-weight heparin, bile salt or bile acid and at least a hydrophilic surfactant active of being selected from, lipophilic surfactant with and composition thereof surfactant.

Still need also can be provided by oral administration the weight heparin medicament composition of the heparin response (promptly can pass through gastrointestinal tract and make the heparin oral administration that bioavailability increases) of increase.This based composition will provide a kind of administrated method more easily for the patient who uses heparin.Oral heparin also will increase patient's compliance, particularly can increase the compliance that needs prophylactic treatment to prevent the patient of serious venous thromboembolism sexual behavior part.Do not need the fact of injecting very attractive, and will reduce the infection that the destruction of skin complete is produced owing to injection for the patient with pin.

General introduction of the present invention

The present invention relates to a kind of solid composite medicament that comprises delivery agent and wetted heparin.Comprising wetted heparin rather than not wetted heparin in solid composite medicament can increase the transmission of heparin.Be not subjected to the constraint of any particular theory, the applicant thinks because the polymer chain of wetted heparin has been " opening " form, and not wetted heparin is quite different, and a small amount of wetted heparin decomposes in gastrointestinal tract and can more easily be absorbed under one's belt.This solid composite medicament can be unit dosage forms, as tablet, capsule, oral cavity disintegration tablet and bar, granule, powder fractional pack and patch.

According to an embodiment preferred; said solid composite medicament comprises (i) and is selected from N-[8-(2-hydroxy benzoyl)-amino] sad with and the delivery agent and the (ii) wetted heparin of pharmaceutically useful salt (as its single sodium salt) (being collectively referred to as " SNAC " hereinafter).Said wetted heparin comprises heparin and solvent.Said solvent can also be partly dissolved said SNAC.Find that not dissolved SNAC can be used as good gellant and comes this SNAC of common gelling and wetted heparin.Said solid composite medicament has promoted the oral delivery of heparin, and the heparin not wetted with comprising equivalent compared the bioavailability that has increased heparin with the administration of the tablet of SNAC.

Another embodiment of the invention is a kind of method that heparin is delivered medicine to the transmission that needs the individual of its or promotion heparin by orally give solid composite medicament of the present invention.

Another embodiment is the thrombotic method that its individuality was treated or need to be prevented to a kind of solid composite medicament of the present invention by orally give antithrombotic formation effective dose.Can comprise that without limitation dvt forms (DVT) and pulmonary infarction (PE) with the thrombosis of said medicine composite for curing or prevention any kind.

Another embodiment is the method for the serious venous thromboembolism sexual behavior part of a kind of solid composite medicament of the present invention that forms effective dose by orally give antithrombotic individuality of need preventing it.Such patient comprise these recently (for example in about 1 week or 2 weeks) patient, especially these ages of having carried out hip or knee reattachment surgery or abdominal operation surpassed 40 years old fat or the persistent period above the patient who undergos surgery or have other risks and assumptions such as malignant tumor or DVT or PE history under 30 minutes the general anesthesia situation.

Another embodiment is a kind of by delivery agent, heparin and wetting agent formation semisolid admixed together or gel combination being prepared the method for solid composite medicament of the present invention.For example, the admixture of delivery agent and heparin can be joined wetting agent solution (adding separately or together) and form a kind of semisolid or gel combination.This solid composite medicament can also further be configured to unit dosage forms, as preparing by said composition is packaged in the capsule.

Another embodiment be a kind of comprise delivery agent (for example, SNAC) and the solid composite medicament of wetted heparin, wherein:

(1) after solid composite medicament of the present invention is administered orally in the people about 120 minute, this people by administration shows the combination that is significantly higher than the same combination that do not comprise wetted heparin but comprise not wetted heparin blood plasma aPTT, anticoagulin IIa plasma concentration, anticoagulin Xa plasma concentration or above-mentioned any index of about 120 minutes level after by oral administration statistically

(2) after solid composite medicament of the present invention is administered orally in the people, this people by administration shows the combination of aPTT Emax, the aPTT EAUC (0-inf), anticoagulin IIa Emax, anticoagulin IIa EAUC (0-inf), anticoagulin Xa Emax, anticoagulin Xa EAUC (0-inf) or the above-mentioned any index that are significantly higher than the same combination that do not comprise wetted heparin but comprise the not wetted heparin level after by oral administration statistically, perhaps

(3) the two all is.

Another embodiment is the solid composite medicament of a kind of SNAC of comprising and wetted heparin, wherein:

(1) after solid composite medicament of the present invention is administered orally in the people about 120 minutes, this people by administration showed the situation below one or more:

(i) at least about 38 seconds blood plasma aPTT,

(ii) at least about the anticoagulin IIa plasma concentration of 0.11IU/ml, or

(iii) at least about the anticoagulin Xa plasma concentration of 0.1IU/ml,

(2) after solid composite medicament of the present invention is administered orally in the people, this people by administration shows the situation below one or more:

(i) at least about the aPTT Emax of 50IU/ml,

(ii) at least about 80IU ^*The aPTT EAUC (0-inf) of hr/ml,

(iii) at least about the anticoagulin IIa Emax of 0.35IU/ml,

(iv) at least about 0.7IU ^*The anticoagulin IIa EAUC (0-inf) of hr/ml,

(v) at least about the anticoagulin Xa Emax of 0.35IU/ml,

(vi) at least about 0.68IU ^*The anticoagulin Xa EAUC (0-inf) of hr/ml, or

(3) the two all is.

After administration about 120 minutes, people by administration preferably shows (i) at least about 39 or about 50 seconds blood plasma aPTT, (ii) at least about the anticoagulin IIa plasma concentration of 0.2IU/ml, (iii) at least about the anticoagulin Xa plasma concentration of 0.2IU/ml, or its any combination.After administration, preferably shown (i) at least about 100,150 or 180IU by the people of administration ^*The aPTTEAUC of hr/ml (0-inf) is (ii) at least about the anticoagulin IIa Emax of 0.4IU/ml, (iii) at least about 1.0IU ^*The anticoagulin IIa EAUC (0-inf) of hr/ml is (iv) at least about the anticoagulin Xa Emax of 0.4IU/ml, (v) at least about 1.0IU ^*The anticoagulin Xa EAUC (0-inf) of hr/ml, or its any combination.

Another embodiment be a kind of by orally give one or more solid composite medicaments that comprise SNAC and wetted heparin treat or need to prevent its people's the method for DVT, wherein

(1) after solid composite medicament of the present invention is administered orally in the people about 120 minutes, this people by administration showed the situation below one or more:

(i) at least 38 seconds blood plasma aPTT,

(ii) at least about the anticoagulin IIa plasma concentration of 0.11IU/ml, or

(iii) at least about the anticoagulin Xa plasma concentration of 0.1IU/ml

(2) after solid composite medicament of the present invention is administered orally in the people, this people by administration shows the situation below one or more:

(i) at least about the aPTT Emax of 50IU/ml,

(ii) at least about 80IU ^*The aPTT EAUC (0-inf) of hr/ml,

(iii) at least about the anticoagulin IIa Emax of 0.35IU/ml,

(iv) at least about 0.7IU ^*The anticoagulin IIa EAUC (0-inf) of hr/ml,

(v) at least about the anticoagulin Xa Emax of 0.35IU/ml,

(vi) at least about 0.68IU ^*The anticoagulin Xa EAUC (0-inf) of hr/ml, or

(3) the two all is.

After administration about 120 minutes, this people by administration preferably shows (i) at least about 39 or 50 seconds blood plasma aPTT, (ii) at least about the anticoagulin IIa plasma concentration of 0.2IU/ml, (iii) at least about the anticoagulin Xa plasma concentration of 0.2IU/ml, or its any combination.After administration, this people by administration preferably shows (i) at least about 100,150 or 180IU ^*The aPTTEAUC of hr/ml (0-inf) is (ii) at least about the anticoagulin IIa Emax of 0.4IU/ml, (iii) at least about 1.0IU ^*The anticoagulin IIa EAUC (0-inf) of hr/ml is (iv) at least about the anticoagulin Xa Emax of 0.4IU/ml, (v) at least about 1.0IU ^*The anticoagulin Xa EAUC (0-inf) of hr/ml, or its any combination.

Another embodiment of the invention is a kind of solid weight heparin medicament composition that comprises delivery agent and wetted heparin, wherein, with it after storing 15 days under the ambient condition, during with the said composition oral administration, the maximum anticoagulin Xa concentration that is reached be that said composition is up to the standard before the storage at least 66% or 75%.

The invention still further relates to a kind of solid composite medicament that comprises delivery agent and wetted heparin, wherein the granularity of not wetted heparin is lower than about 180 microns or be lower than about 120 microns or be lower than about 80 microns.A kind of method for preparing solid composite medicament also is provided, and it comprises particle mean size is lower than about 180 microns or be lower than about 120 microns or to be lower than about 80 microns heparin, wetting agent and delivery agent admixed together.

The invention still further relates to a kind of solid composite medicament that comprises the delivery agent that is arranged in suspension and wetted heparin, wherein the particulate particle mean size of suspension is lower than about 180 microns or be lower than about 120 microns or be lower than about 80 microns.A kind of method for preparing solid composite medicament also is provided, it comprises wetted heparin and delivery agent admixed together, form a kind of suspension that is arranged in solvent, then this suspension is ground, be lower than about 180 microns or be lower than about 120 microns or be lower than about 80 microns suspension thereby obtain a kind of particle mean size.

Brief Description Of Drawings

Fig. 1 is an anticoagulin xa activity (IU/ml) at the figure with the time behind each self administration of medication of pharmaceutical composition of embodiment 1 and comparing embodiment 1-4.

Fig. 2 is an anticoagulin IIa activity (IU/ml) at the figure with the time behind each self administration of medication of pharmaceutical composition of embodiment 1 and comparing embodiment 1-4.

To be anticoagulin xa activity (IU/ml) deliver medicine to the figure of the time behind the Rheses monkey (1 piece of capsule/monkey) to the capsule that will have table 15a (embodiment 3) or table 1 (embodiment) 1 described prescription to Fig. 3.

Fig. 4 is the figure of anticoagulin xa activity (IU/ml) to the time after embodiment 6 described capsules are delivered medicine to Cynos monkey (1 piece of capsule/monkey).

Fig. 5 is the figure of anticoagulin xa activity (IU/ml) to the time after embodiment 7 described capsules are delivered medicine to Rhesus monkey (1 piece of capsule/monkey).

Fig. 6 is the figure of anticoagulin xa activity (IU/ml) to the time after embodiment 8 described capsules are delivered medicine to Rhesus monkey (1 piece of capsule/monkey).

Fig. 7 is the overlay chart of Fig. 5 and 6.

Fig. 8 is the figure of anticoagulin xa activity (IU/ml) to the time after embodiment 9 described capsules are delivered medicine to Rhesus monkey (1 piece of capsule/monkey).

Fig. 9 is anticoagulin xa activity (IU/ml) and the aPTT figure to the time after embodiment 10 described capsules are delivered medicine to Rhesus monkey (1 piece of capsule/monkey).

Figure 10 is anticoagulin xa activity (IU/ml) and the aPTT figure to the time after embodiment 11 described capsules are delivered medicine to Rhesus monkey (1 piece of capsule/monkey).

Figure 11 is the figure of anticoagulin xa activity (IU/ml) to the time after embodiment 12 described capsules are delivered medicine to Rhesus monkey (1 piece of capsule/monkey).

The figure of the time of Figure 12 and 13 after to be anticoagulin xa activity (IU/ml) and aPTT to the embodiment 13 described capsules after will storing 15 days down at the relative humidity (Figure 13) of 40 ℃ and 75% relative humidity (Figure 12) or 25 ℃ and 60% deliver medicine to Rhesus monkey (1 piece of capsule/monkey).

Figure 14 and 15 is anticoagulin xa activities to before will storing under the relative humidity of 40 ℃ and 75% relative humidity or 25 ℃ and 60% and the figure of the time of the back 15 days embodiment 13 described capsules of storage after delivering medicine to Rhesus monkey (1 piece of capsule/monkey).

Figure 16,17,18,19 and 20 is that aPTT time, anticoagulin IIa, anticoagulin Xa and blood plasma SNAG concentration are to carrying out the figure of time of administration to healthy male according to embodiment 14 described therapeutic schemes.

Figure 21 and 22 is dissolubility figure of preparation described in the table 35a for preparing as described in the embodiment 15 and the 35b.

Figure 23 is the anticoagulin xa activity to the figure as making as described in the embodiment 15 and delivered medicine to the time behind the beasle dog (beagles) by preparation as described in the table 35a of administration and the 35b as described in the embodiment 17.

Figure 24 is the anticoagulin xa activity to the figure as making as described in the embodiment 15 and delivered medicine to the time behind the Rhesus monkey by preparation as described in the table 35a of administration and the 35b as described in the embodiment 18.

Figure 25 is the anticoagulin xa activity to the figure as making as described in the embodiment 15 and delivered medicine to the time behind the beasle dog by preparation as described in the table 35a of administration and the 35b as described in the embodiment 19.

Detailed description of the present invention

Definition

Unless stated otherwise, otherwise here with claims in used term " a kind of " comprise plural form. Therefore, for example, when relating to " a kind of molecule ", comprise one or more this quasi-molecules, " a kind of reagent " comprises one or more such different reagent, when relating to " the method ", comprise those skilled in the art known may be that method described here has been carried out the equal step and method that changes or replace.

Terminology used here " wetted heparin " refers to each heparin particle or molecule wholly or in part by solvent or the circumjacent heparin form of solvent mixture (being also referred to as " wetting agent "). Said heparin can be dissolved in the said wetting agent or can not be dissolved in the said wetting agent. Be not subjected to the constraint of any particular theory, think that said wetting agent is retained in the gap of the heparin polymer chain that is arranged in wetted heparin (not necessarily with the heparin dissolving), thereby so that heparin can faster dissolving when administration. Said delivery agent preferably with said solid composite medicament in wetted heparin intimate contact.

Terminology used here " heparin " refers to the heparin of form of ownership, comprise without limitation unassorted heparin, Hirudoid, dermatan class, chondroitin class, low molecular weight heparin (for example, TINZ (comprising tinzaparin sodium)), super low molecular heparin and ultra-low molecular weight heparin. Limiting examples comprises unassorted heparin, as liquaemin (for example, liquaemin USP,, derive from Scientific Protein Labs of Waunakee, WI). Heparin has about 1,000 or 5,000 to about 30,000 daltonian molecular weight usually. Term " low molecular weight heparin " is commonly referred to as wherein, and the heparin of at least 80% (weight) has about 3000 heparin to about 9000 daltonian molecular weight. The limiting examples of low molecular weight heparin comprises TINZ, Enoxaparin (enoxaprin) and DALT (daltiparin). TINZ is used for treating the acute symptomatic dvt that has or do not have pulmonary embolism with the warfarin sodium administering drug combinations by U.S.Food﹠Drug Administration approval and forms. The sodium salt of TINZ can be with InnohepA^TMTitle, derive from Pharmion Corporation of Boulder, CO. The heparin that term " super low molecular heparin " is commonly referred to as wherein at least about 80% (weight) has about 1500 heparin to about 5000 daltonian molecular weight. A limiting examples of super low molecular heparin is bemiparin. The heparin that term " ultra-low molecular weight heparin " is commonly referred to as wherein at least about 80% (weight) has about 1000 heparin to about 2000 daltonian molecular weight. A limiting examples of ultra-low molecular weight heparin is fondaparin.

Term " polymorphic " refers to the different crystal form of material.

Terminology used here " hydrate " comprises that without limitation (i) comprises with the material of the combined water of molecular forms and (ii) comprise the crystalline material of a part or the polymolecular crystallization water or comprise the crystalline material of free water.

Unless stated otherwise, otherwise terminology used here " SNAC " refer to N-(8-[2-hydroxy benzoyl]-amino) sad with and pharmaceutically useful salt, comprise its single sodium salt. It is sad that term " SNAC free acid " refers to N-(8-[2-hydroxy benzoyl]-amino). Unless stated otherwise, otherwise term " SNAC " refers to the form of ownership of SNAC, all amorphous and polymorphic forms that comprise SNAC, as be that the provisional application sequence number of submitting on May 6th, 2004 is 60/569,476 U. S. application and be these materials described in 60/619,418 the U.S. Patent application in the provisional application sequence number that on October 15th, 2004 submitted to.

Terminology used here " SNAD " refer to N-(8-[2-hydroxy benzoyl]-amino) capric acid with and pharmaceutically useful salt, comprise its single sodium salt. Unless stated otherwise, otherwise term " SNAD " refers to the SNAD of form of ownership, comprises all amorphous and polymorphic forms of SNAD.

Terminology used here " SNAC trihydrate " refers to per molecule SNAC wherein in conjunction with the crystal form of the single sodium of SNAC of trihyarol.

Terminology used here " solvate " comprises molecule or the ionic complex of solvent molecule or ion and delivery agent molecule or ion without limitation.

Term " delivery agent " refers to any delivery agent disclosed in the reference here or that introduce, comprises its pharmaceutically useful salt.

" effective dose of heparin " refers to and can effectively treat or prevent its amount that is delivered medicine to the heparin of individual illness within a period of time, and the quantity of the heparin of therapeutic action for example can be provided in required administration time interval. Such just as those skilled in the art are aware, the situation of other activating agent that effective dose will may be used simultaneously along with excipient operating position and the illness for the treatment of certainly and changing.

" effective dose of pharmaceutical composition " is effectively to treat or to prevent it to be delivered medicine to the quantity of the described pharmaceutical composition of individual illness (for example can provide therapeutic action in required administration time interval) within a period of time.

Term " treatment " refers to and preventatively prevents, cures, fully recovers, alleviates, alleviates, changes, compensates, improves, improves or affect the symptom of a kind of illness (for example, disease), this illness or the tendency of this illness occurs.

" effective dose of delivery agent " is the quantity of delivery agent that can promote the absorption of requirement heparin.

Term " individuality " comprises mammal, such as rodent, ox, pig, dog, cat, primate, and people particularly.

Terminology used here " AUC " referred in whole administration interval, area under the PC-time graph that calculates with trapezoidal rule in for example during 24 hours.

When being positioned at before a kind of pharmacokinetics value (for example, average peak), unless stated otherwise, otherwise term " on average " represents the arithmetic mean of instantaneous value of this pharmacokinetics value.

Terminology used here " pact " refers to set-point 10%, preferred 5% and more preferably 1% scope of being positioned at. Perhaps, term " about " refers to and falls into the value in the acceptable error range on this value science, and this value depends on how obtainable instrument provides qualitative value.

" indication " refers to the purposes that can prevent or treat with said medicine a kind of illness, and can with " treatment " Alternate.

" thrombus " refers to blood clot or by any trend that forms blood clot that causes in the body or in external many events.

" embolism " and " thromboembolia type complication " refers to the formation of thrombus.

" antilipemic " refers to the serum cholesterol that can reduce form of ownership and/or any medicine or the activating agent of triglycerides.

" contrast aPTT value " refers to those skilled in the art and is used for the aPTT value take second as unit that patient's serum aPTT value and the value for the treatment of are compared.

Delivery agent

The delivery agent that can be used in the pharmaceutical composition of the present invention comprises that these have the material of following formula:

Wherein

R ¹、R ²、R ³And R⁴Be independently hydrogen ,-OH ,-NR⁶R ⁷, halogen, C₁-C ₄Alkyl or C₁-C ₄Alkoxyl;

R ⁵Substituted or unsubstituted C₂-C ₁₆Alkylidene, substituted or unsubstituted C₂-C ₁₆Alkylene group, substituted or unsubstituted C₁-C ₁₂Alkyl (arlydene), substituted or unsubstituted aryl (C₁-C ₁₂Alkylidene); With

R ⁶And R⁷Hydrogen, oxygen or C independently₁-C ₄Alkyl.

Terminology used here " substituted " comprises the replacement with any or its any combination in the following substituting group without limitation: halogen, hydroxyl, C₁-C ₄Alkyl and C₁-C ₄Alkoxyl.

Term " alkyl ", " alkoxyl ", " alkylidene ", " alkylene group ", " alkyl (arlydene) " and " aryl (alkylidene) " comprise respectively straight chain and branched alkyl, alkoxyl, alkylidene, alkylene group, alkyl (arlydene), aryl (alkylidene) without limitation.

Preferred delivery agent comprises SNAC, SNAD, 8-(N-2-hydroxyl-5-chlorobenzene formacyl) aminocaprylic acid, 8-(N-2-hydroxyl-4-methoxybenzoyl base)-aminocaprylic acid, 4-[(4-chlorine-2-hydroxyl benzoyl without limitation) amino] butyric acid with and pharmaceutically useful salt.

In US patent 6,846,844,6,699,467,6,693,208,6,693,208,6,693,073,6,663,898,6,663,887,6,646,162,6,642,411,6,627,228,6,623,731,6,610,329,6,558,706,6,525,020,6,461,643,6,461,545,6,440,929,6,428,780,6,413,550,6,399,798,6,395,774,6,391,303,6,384,278,6,375,983,6,358,504,6,346,242,6,344,213,6,331,318,6,313,088,6,245,359,6,242,495,6,221,367,6,180,140,5,541,155,5,693,338,5,976,569,5,643,957,5,955,503,6,100,298,5,650,386,5,866,536,5,965,121,5,989,539,6, in 001,347,6,071,510 and 5,820,881 other suitable delivery agent of the present invention is described. In being 20050009748,20040110839,20040106825,20040068013,20040062773,20040022856,20030235612,20030232085,20030225300,20030198658,20030133953,20030078302,20030072740,20030045579,20030012817,20030008900,20020155993,20020127202,20020120009,20020119910,20020102286,20020065255,20020052422,20020040061,20020028250,20020013497,20020001591,20010039258 and 20010003001 U.S. Patent application, publication number also delivery agent of the present invention is described. In international publication WO 2005/020925, WO 2004/104018, WO 2004/080401, WO 2004/062587, WO 2003/057650, WO 2003/057170, WO 2003/045331, WO 2003/045306, WO 2003/026582, WO 2002/100338, WO 2002/070438, WO 2002/069937, WO 02/20466, WO02/19969, WO 02/16309, WO 02/15959, WO 02/02509, WO 01/92206, WO 01/70219, WO 01/51454, WO01/44199, WO01/34114, WO 01/32596, WO 01/32130, WO 00/07979, WO 00/59863, WO 00/50386, WO 00/47188, WO 00/40203 and WO 96/30036, also delivery agent of the present invention is described. US patent listed above and international open application here all are introduced into as a reference. These delivery agents can be prepared with method well known in the prior art, as being prepared with these methods described in above-mentioned patent and the disclosed patent application. For example, SNAC can be prepared with method well known in the prior art, as being prepared with these methods described in US patent 5,650,386 and 5,866,536 and the US patent application 2002/0065255.

Can separate to come by classification on the solid phase chromatography supporter of recrystallization or or series connection independent at one or more said delivery agent is carried out purifying. Suitable recrystallization solvent system comprises acetonitrile, methyl alcohol and oxolane without limitation. Classification separates and can carry out as mobile phase with methyl alcohol/just-propanol mixture at (i) suitable chromatography supporter such as aluminium oxide, (ii) carry out as mobile phase with trifluoracetic acid/acetonitrile mixture with reverse-phase chromatography, perhaps (iii) carries out as mobile phase with ion-exchange chromatography water or suitable buffer solution. When carrying out anion-exchange chromatography, preferably use 0-500mM sodium chloride gradient elution.

In addition, said delivery agent compound can also be the form of salt. The limiting examples of officinal salt comprises sodium, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, sulfate, phosphate, chloride, bromide, iodide, acetate, propionate, hydrobromic acid, NaOH, potassium hydroxide, ammonium hydroxide and potash. These salt can be prepared with method well known in the prior art. For example, can prepare sodium salt by being dissolved in delivery agent in the ethanol and adding sodium hydrate aqueous solution.

The quantity of delivery agent is the delivery agent effective dose and can determines effective amount for specific heparin component with method known to those skilled in the art in the solid composite medicament.

According to one embodiment of the invention, said pharmaceutical composition comprises about 50 to about 500mg SNAC. According to another embodiment, said pharmaceutical composition comprises about 215 to about 245mg SNAC.

The ratio of delivery agent and heparin in the said pharmaceutical composition (mg suitable with USP heparin unit) is generally about 1: 20 to about 1: 400. According to a preferred embodiment, this proportion is about 1: 65 to about 1: 150.

The weight ratio of heparin and delivery agent is generally about 1: 1 to about 1: 10 in the said pharmaceutical composition. According to a preferred embodiment, its weight ratio is about 1: 1 or 1: 2.5 to about 1: 5 or about 1: 7.5 or about 1: 2.5 to about 1: 10 or about 1: 5 to about 1: 10 heparin: delivery agent.

Heparin

Said pharmaceutical composition can comprise the heparin for the treatment of effective dose.Perhaps, when (i) uses when comprising the dosage form of many pharmaceutical compositions, or when (ii) the administrations simultaneously of many pharmaceutical compositions and its total being comprised the treatment effective dose, its quantity can be lower than effective dose.

Can determine the total amount of used heparin with method known to those skilled in the art.But, because compositions of the present invention can more effectively be transmitted heparin than other compositions or the compositions that only comprises heparin, so it can give dosage unit form or the lower heparin quantity of the used heparin quantity of transmission system than prior art in individuality, still can obtain identical blood levels and/or therapeutical effect simultaneously.

According to one embodiment of the invention, said pharmaceutical composition comprises about 10 to about 500mg heparin.According to another embodiment, said pharmaceutical composition comprises about 100 to about 115mg heparin.According to another embodiment, said pharmaceutical composition comprises about 2,000 to about 50,000 USP heparin units.According to another embodiment, said pharmaceutical composition comprises about 10,000 to about 20,000 USP heparin units.

According to another embodiment, said pharmaceutical composition comprises about 12,000 to about 18,000USP heparin unit.

Preferred heparin type is unassorted heparin.

Wetting agent

Said wetting agent can be can dissolve heparin and be present in liquid in the gap of heparin polymer chain.Because such wetting agent dissolving heparin is so it also is the solvent in the said pharmaceutical composition.According to an embodiment preferred, said pharmaceutical composition comprises the wetting agent that is enough to be partly dissolved said delivery agent quantity.According to another embodiment, said wetting agent can be different materials with solvent or solubilizing agent, and perhaps it can be identical material.

Suitable wetting agent comprises alcohols, polyalcohols, hydroxylating fatty acid ester (that is the fatty acid ester that, has one or more hydroxyls) and no hydroxylating fatty acid ester (that is the fatty acid ester that, does not have hydroxyl) without limitation.The example without limitation of suitable solvent comprises that ethanol, ethylene glycol, propylene glycol, glycerol, tetramethylolmethane, sorbitol, mannitol, transcutol, dimethyl isosorbide, polypropylene glycol, polyvinyl alcohol, hydroxypropyl emthylcellulose and other cellulose derivative, cyclodextrin and cyclodextrin derivative, PEG-40 castor oil hydrogenated are (with Cremophor ^RH 40 forms derive from the BASF Ag of Ludwigshafen, Germany), medium chain (C ₈-C ₁₀Fatty acid) triglyceride is (with Labrafac ^The form of CC derives from Gattefoss é Corporation of Paramus, NJ), oleoyl Polyethylene Glycol (macrogol)-6 monoglyceride (Labrafil ^M 1944 CS derive from Gattefoss é Corporation), inferior oleoyl (linoleoyl) Polyethylene Glycol-6 monoglyceride (Labrafil ^M 2125CS,, derive from Gattefoss é Corporation), PGML (Lauroglycol ^90, derive from Gattefoss é Corporation), caprylic/capric monoglyceride (Imwitor ^742, derive from Sasol Germarny GmbH of Witten, Germany), glyceryl cocoate (Imwitor ^928, derive from Sasol Germarny GmbH), caprylin (Imwitor ^988, derive from Sasol GermarnyGmbH), propylene glycol dicaprylate/dicaprate (Miglyol ^840, derive from Condea Vista Co.of Cranford, NJ), castor oil acid glyceride (Softigen ^701, derive from Sasol GermarnyGmbH), PEG-6 caprylic/capric monoglyceride (Softigen ^767, derive from Sasol GermarnyGmbH), two-two glyceryl polyamides base adipate ester (Softigen ^645, derive from Sasol GermarnyGmbH), PEG-25 trioleate (Tagat ^TO, derive from Goldschmidt Chemical Corp, Hopewell, Va.), polysorbate80 (Tween 80), mean molecule quantity are that about 200 to about 6000 Polyethylene Glycol ethers is (as tetrahydrofurfuryl alcohol PEG ether (glycofurol) (BASF of Ludwigshafen, Germany, trade mark is Tetraglycol ^)) or methoxyl group PEG (Union Carbide of Midland, Michigan)); amide-type or other nitrogen-containing compound are (as 2-Pyrrolidone; the 2-piperidones; ∑-caprolactam; the N-alkyl pyrrolidone; N-hydroxy alkyl-ketopyrrolidine; N-Alkylpiperidine ketone; N-alkyl caprolactam; dimethyl acetylamide and polyethylene-ketopyrrolidine); esters is (as ethyl propionate; tributyl citrate; CitroflexA-2; citroflex A-4; triethyl citrate; ethyl oleate; ethyl caprilate; ethyl n-butyrate.; glyceryl triacetate; the propylene glycol monoacetate; propylene-glycol diacetate; ∑-caprolactone with and isomer; Δ-valerolactone with and isomer and beta-butyrolactone with and isomer); other solubilizing agent well known in the prior art is (as dimethyl acetylamide; dimethyl isosorbide; N-Methyl pyrrolidone; monooctanoin and diethylene glycol monoethyl ether); with and composition thereof.Other suitable wetting agent is called as solubilizing agent in US patent 6,458,383, this patent here is introduced into as a reference.

Preferred wetting agent comprises that without limitation molecular weight is lower than about 800 daltonian Polyethylene Glycol (for example, Polyethylene Glycol-300), Capryol 90 (as Capmul ^PG8 (the fatty acid profile of GLC:＜1.0% C ₆,＞98.0% C ₈,＜2.0% C ₁₀And＜1.0% C ₁₂And higher), derive from Abitec Corporation of Columbus, Ohio; With Capryol 90 (comprising 90% monoesters), derive from Gttefosse Corp., Paramus, NJ) with and composition thereof.When using when contacting dissolved capsule with water, the pharmaceutical composition in the capsule not moisture substantially (for example, comprise be lower than about 8, about 5 or the water (based on 100% gross weight of pharmaceutical composition) of about 1% weight) or not moisture.

According to an embodiment, said pharmaceutical composition comprises Polyethylene Glycol-300.

According to another embodiment, said pharmaceutical composition comprises the mixture of Polyethylene Glycol-300 and Capryol 90.

In another embodiment, said pharmaceutical composition comprise about 100 to about 500mg Polyethylene Glycol-300 and about 20 to about 250mg Capryol 90.In another embodiment, said pharmaceutical composition comprise about 210 to about 240mg Polyethylene Glycol-300 and about 90 to about 110mg Capryol 90.

The ratio of wetting agent and heparin in the said pharmaceutical composition (mg and USP heparin unit) is generally about 1: 10 to about 1: 100.According to an embodiment preferred, this ratio is about 1: 25 to about 1: 60.

The weight ratio of heparin and delivery agent was generally about 1: 1 to about 1: 10 in the said pharmaceutical composition.According to an embodiment preferred, its weight ratio is about 1: 1 or 1: 2.5 to about 1: 5 or about 1: 2.5 to about 1: 10.

Above-mentioned wetting agent can with auxiliary wetting agent coupling, said auxiliary wetting agent such as water, caprylate/caprin are (with Capmul ^The form of MCM derives from Abitec Corporation ofColumbus, Ohio), polysorbate20, lauroyl Polyethylene Glycol-32 monoglyceride (Gelucire ^44/14, derive from Gattefosse Corp., Paramus, NJ), stearoyl ester Polyethylene Glycol-32 monoglyceride (Gelucire ^50/13, derive from Gattefosse Corp.), (form with Akomed E and Akomed R derives from Karlshamns AB of Karlshamn, Sweden to caprylic/capric triglyceride; With Captex ^355 form derives from Abitec Corporation of Columbus, Ohio; With Miglyol ^810 and 812 form derives from Condea Vista Co.of Cranford, NJ), with and composition thereof.

Other active component and additive

Other activating agent

Suitable other activating agent comprises warfarin sodium without limitation.Other suitable active component comprises aspirin (ASA or aspirin) or casing ASA, Ticlopidine, clopidogrel, pentoxifylline (pentoxifyline), cilostazol, dipyridamole, ER-dipyridamole, abciximab, cilostazol, eptifibatide or tirofiban without limitation, and it can use or unite use separately.Other suitable activating agent comprises separately or unites the thrombolytic agent of use without limitation, as alteplase, reteplase, streptokinase, tenecteplase and urokinase.Other suitable activating agent comprises separately or unites the antilipemic (antilipidemic drugs) of use without limitation, comprises that without limitation statins material such as Lip river cut down its spit of fland, its spit of fland of Ah cutting down and general its spit of fland of cutting down.Other biologic activity agent and chemical active agent comprise the pharmacology's agent and the therapeutic agent that can join in the solid dosage forms of the present invention without limitation.

Suitable biology and chemical active agent comprise protein-based without limitation; The polypeptide class; The peptide class; Hormones; Polysaccharide; The mixture of mucopolysaccharide and particularly mucopolysaccharide; Carbohydrate; Lipid; Little polarity organic molecule (being that molecular weight is 500 dalton or lower polarity organic molecule); Other organic compound; And particularly itself can not by (perhaps only by the part of dosage can by) gastrointestinal mucosa and/or be easy to by acid in the gastrointestinal tract and the cracked chemical compound of enzymology; Or its compositions.

The other example of suitable biologic activity agent comprises following material (comprising its synthetic, natural or recombinant sources) without limitation: growth hormone comprises human growth hormone (hGH), recombinant human somatropin (rhGH), bovine growth hormone (hGH), bovine growth hormone and pig growth hormone; Growth hormone releasing hormone; Somatotropin releasing factor (for example, GRF analog g); Interferon comprises α, β and γ; Il-1; Interleukin-2; Insulin comprises pig, cattle, people and biosynthetic human insulin, and it randomly has counter ion counterionsl gegenions, comprises zinc, sodium, calcium and ammonium; Insulin like growth factor comprises IGF-1; Heparin comprises unassorted heparin, Hirudoid, dermatan class, chrondroitin class, low molecular weight heparin, super low molecular heparin and ultra-low molecular weight heparin; Calcitonin comprises salmon, Anguillar japonica, pig and human calcitonin; Erythropoietin; Atrial natriuretic peptide; Antigen; Monoclonal antibody; Somatostatin; Protease inhibitor; Thyroliberin, gonadotropin releasing hormone; Oxytocin; Luteinising hormone-releasing hormo; Follicle stimulating hormone; Glucocerebrosidase; Thrombopoietin; Filgrastim; Prostaglandin; Cyclosporin; Vassopressin; Sodium cromoglicate (sodium cromoglicate or disodium (sodium ordisodium chromoglycate)); Vancomycin; (DFO) desferrioxamines; Diphosphate comprises fosamax, Tiludronate, etidronate, clodronate, pamldronate, olpadronate and Incadronate; Parathyroid hormone (PTH) comprises its fragment; Antimigraine such as BIBN-4096BS and other and calcitonin gene proteins associated antagonist; Antibacterial comprises antibiotic (comprise the antibiotic that acts on gram positive bacteria, Bactericidal, lipid peptide (lipopeptidal) and cyclic peptide (cyclic peptidal) antibiotic, comprise daptomycin), antibacterial agent and antifungal; Vitamin; The analog of these chemical compounds, fragment, plan are like the derivant of thing or Polyethylene Glycol (PEG)-modification; Or its any combination.

Other example comprises following material (comprising its synthetic, natural or recombinant sources) without limitation:

Amylin and amylin agonist;
	Thyroliberin;
Antigen;
	Antibacterial comprises antibiotic, antibacterial agent and antifungal; Antibiotic limiting examples comprises the antibiotic that acts on gram positive bacteria, Bactericidal, lipid peptide (lipopeptidal) and cyclic peptide (cyclic peptidal) antibiotic, as daptomycin with and analog;
Antimigraine such as BIBN-4096BS and other and calcitonin gene proteins associated antagonist, Sumatriptan Succinate;
	Antiviral agent comprises acyclovir, valaciclovir;
Atrial natriuretic peptide;
	Diphosphate, comprise fosamax, clodronate, etidronate, ibandronate,

Incadronate, YM 529, neridronic acid salt, olpadronate, pamldronate, Risedronate, Tiludronate, zoledronic acid salt, EB 1053 and YH529;
	Calcitonin comprises salmon, Anguillar japonica, pig and human calcitonin;
Cholecystokinin (CCK) and CCK agonist comprise CCK-8;
	Sodium cromoglicate (sodium cromoglicate or disodium);
Cyclosporin;
	(DFO) desferrioxamines;
Erythropoietin;
	Exedin and Exedin agonist comprise Exendin-3, Exendin-4;
Filgrastim
	Follicle stimulating hormone (reorganization and natural);
Glucagon-like peptide 1 (GLP-1), glucagon and glucagon-like peptide 2 (GLP-2);
	Glucocerebrosidase;
Gonadotropin releasing hormone;
	Somatotropin releasing factor;
Growth hormone releasing hormone;
	Growth hormone comprises human growth hormone (hGH), recombinant human somatropin (rhGH), bovine growth hormone (hGH) and pig growth hormone;
Hirudoid, dermatan class material, chrondroitin class material, low molecular weight heparin, super low molecular heparin, ultra-low molecular weight heparin and synthetic heparin comprise that sulphur reaches heparin;
	Immunoglobulin and immunoglobulins material
Insulin comprises pig, cattle, people and biosynthetic human insulin, and it randomly has counter ion counterionsl gegenions, comprises zinc, sodium, calcium and ammonium;
	Insulin like growth factor comprises IGF-1;
Interferon, (for example, Interferon alfacon-1 is (with Infergen to comprise α Form derive from InterMune, Inc.of Brisbane, CA)), α, β, ω and IFN-;
	Il-1; Interleukin-2; Il-1; Interleukin-21;
Alfasone and luteinising hormone-releasing hormo;

Leptin (OB albumen);
	Monoclonal antibody comprises Retuxin, the solvable receptor of TNF-α;
Oxytocin;
	Parathyroid hormone (PTH) comprises its fragment, comprises PTH 1-34 and PTH 1-38;
Peptide YY (PYY) comprises PYY agonist and PYY fragment 3-36;
	Prostaglandin;
Protease inhibitor;
	Somatostatin;
Thrombopoietin;
	Vancomycin;
Vassopressin;
	Vitamins;
Vaccine comprises that these resist the vaccine of anthraxs, Y.Pestis, influenza or herpes;

Comprise succagoga, its analog, fragment, plan derivant like Polyethylene Glycol (the PEG)-modification of thing or these chemical compounds; Or its any combination.

Said pharmaceutical composition can comprise any other activating agent for the treatment of effective dose.Perhaps, when (i) uses when comprising the dosage form of many pharmaceutical compositions, or when (ii) the administrations simultaneously of many pharmaceutical compositions and its total being comprised the treatment effective dose, its quantity can be lower than effective dose.

Can determine the total amount of used activating agent with method known to those skilled in the art.But, because compositions of the present invention can more effectively be transmitted heparin than other compositions or the compositions that only comprises heparin, so it can give individuality with dosage unit form or the lower heparin quantity of the used heparin quantity of transmission system than prior art, still can obtain identical blood levels and/or therapeutical effect simultaneously.

Additive

Solid composite medicament of the present invention and unit dosage forms can comprise other activating agent and pharmaceutically useful additive, as any compositions of excipient, carrier, diluent, stabilizing agent, plasticizer, binding agent, fluidizer, disintegrating agent, extender, lubricant, plasticizer, coloring agent, film former, correctives, odor mask, saccharide, sweeting agent, antiseptic, administration substrate, surfactant and any above-mentioned substance.The preferably pharmaceutically useful additive of these additives, as at Remington ' s, pharmaceutical science and put into practice (The Science and Practice of Pharmacy), (Gennaro, A.R. edit, the 20th edition, 1995, Mack Pub.Co.) these materials described in, it here is introduced into as a reference.

In one embodiment of the invention, said pharmaceutical composition or solid unit dosage form do not contain or do not contain fully carbomer substantially.According to another embodiment, said pharmaceutical composition or solid dosage forms do not contain or do not contain fully Carbopol substantially ^And/or carbomer Carbopol ^934P.

Suitable binding agent comprises that without limitation starch, gelatin, saccharide (as sucrose, molasses and lactose), Bibasic Calcium Phosphate dihydrate, natural and paragutta are (as arabic gum, sodium alginate, carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone, Polyethylene Glycol, ethyl cellulose and wax class.

Suitable fluidizer comprises Pulvis Talci and silicon dioxide (Silicon stone) (for example, pyrogenic silica and silica sol) without limitation.

Suitable disintegrating agent comprises starchy material, sodium starch glycolate, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, clay class, cellulose family (as refined cellulose, methylcellulose and sodium carboxymethyl cellulose), alginate, pregelatinized corn starch and gummy class (as agar, melon glue, carob gum, karaya, pectin and Tragacanth) without limitation.Preferred disintegrating agent is a sodium starch glycolate.

Suitable extender comprises starchy material (as rice fecula), microcrystalline Cellulose, lactose (for example, lactose monohydrate), sucrose, dextrose, mannitol, calcium sulfate, sulphuric acid dicalcium and sulphuric acid DFP without limitation.

Suitable lubricant comprises stearic acid, stearate (as calcium stearate and magnesium stearate), Pulvis Talci, boric acid, sodium benzoate, sodium acetate, Fumaric acid sodium, sodium chloride, Polyethylene Glycol, cotmar and castor oil without limitation.

Suitable surfactant comprises the block copolymer of sodium lauryl sulfate, hydroxylating soybean lecithin, polysorbate esters and propylene oxide and ethylene oxide without limitation.

In pharmaceutical compositions for use and dosage form, can be included in the US patent 6,458 that is introduced into as a reference here, hydrophilic non-ionic surfactant described in 383 and lipophilic surfactant.Suitable hydrophilic non-ionic surfactant comprises alkyl-glucoside without limitation; The alkyl maltoside; The alkyl thioglucoside; Lauryl polyethylene glycol glycerol acid esters; Polyoxyalkylene alkyl class such as polyethylene glycol alkyl ether class; Polyoxyalkylene alkylbenzene phenols such as polyalkylene glycol alkyl phenol; Polyoxyalkylene alkylphenol fatty acid ester such as polyethylene glycol fatty acid monoesters class and polyethylene glycol fatty acid two esters; The polyethylene glycol glycerol fatty acid ester; The polyglyceryl fatty acid ester class; Polyoxyalkylene fatty acid esters of sorbitan class such as Polyethylene Glycol fatty acid esters of sorbitan class; The hydrophilic ester exchange offspring of at least one member in polyhydric alcohol and monoglyceride, vegetable oil, hydrogenated vegetable oil, fatty acid and the sterols; Polyethylene glycol oxide sterols, its derivant and analog; Polyoxy ethylization vitamin with and derivant; Polyethylene glycol oxide-polyoxypropylene block copolymers; With and composition thereof.

More specifically, the operable hydrophilic surfactant active of the present invention comprises the PEG-10 laurate without limitation, the PEG-12 laurate, the PEG-20 laurate, the PEG-32 laurate, the PEG-32 dilaurate, the PEG-12 oleate, the PEG-15 oleate, the PEG-20 oleate, the PEG-20 dioleate, the PEG-32 oleate, the PEG-200 oleate, the PEG-400 oleate, the PEG-15 stearate, PEG-32 distearyl acid fat, the PEG-40 stearate, the PEG-100 stearate, the PEG-20 dilaurate, PEG-25 glyceryl trioleate, the PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm-kernel oil, the PEG-50 castor oil hydrogenated, the PEG-40 Oleum Ricini, the PEG-35 Oleum Ricini, the PEG-60 Oleum Ricini, the PEG-40 castor oil hydrogenated, the PEG-60 castor oil hydrogenated, the PEG-60 Semen Maydis oil, PEG-6 decanoin/caprylate monoglyceride, PEG-8 decanoin/caprylate monoglyceride, polyglycereol-10 laurate, the PEG-30 cholesterol, the PEG-25 plant sterol, the PEG-30 soyasterol, the PEG-20 trioleate, the PEG-40 sorbitan oleate, the PEG-80 sorbitan laurate, polysorbate20, polysorbate80, POE-9 Laurel ether, POE-23 Laurel ether, POE-10 oil ether, POE-20 oil ether, the POE-20 stearyl ether, tocopherol PEG-100 succinate, the PEG-24 cholesterol, polyglycereol-10 oleate, polysorbate40, polysorbate60, sucrose monostearate, sucrose monolaurate, sucrose palmitic acid ester, PEG10-100 nonyl phenol series, PEG15-100 octyl phenol series and poloxamer.

The lipophilic surfactant comprises aliphatic alcohols without limitation; The glycerine fatty acid esters; The acetylated glycerol fatty acid esters class; The fatty alcohol aliphatic ester class; The methyl glycol fatty acid ester class; The fatty acid esters of sorbitan class; Polyethylene Glycol fatty acid esters of sorbitan class; Sterols and sterol derivative; Polyoxy ethylization sterols and sterol derivative; The polyethylene glycol alkyl ether class; Sugar esters; Sugar ethers; Single-and the lactic acid derivative of two-monoglyceride; The hydrophobicity ester exchange offspring of at least one member in polyhydric alcohol and monoglyceride, vegetable oil, hydrogenated vegetable oil, fatty acid and the sterols; Fat soluble vitamin/vitamin derivative; With and composition thereof.For example, said lipophilic surfactant can be one or more glycerine fatty acid esters, methyl glycol fatty acid ester class or its mixture, or the ester exchange offspring of at least one member in one or more polyhydric alcohol and vegetable oil, hydrogenated vegetable oil and the triglyceride.

In said lipotropy ester exchange offspring, can use the ester exchange offspring of polyhydric alcohol such as ethylene glycol, glycerol, propylene glycol and sorbitol.Just as known in the art, can prepare many have different hydrophobicitys or hydrophilic surfactants by alcohols or polyalcohols are reacted with many natural and/or hydrogenated oils.Used oils is modal to be Oleum Ricini or castor oil hydrogenated or edible vegetable oil such as Semen Maydis oil, olive oil, Oleum Arachidis hypogaeae semen, palm-kernel oil, almond oil or almond oil.Alcohols comprises glycerol, propylene glycol, ethylene glycol, Polyethylene Glycol, maltol, sorbitol and tetramethylolmethane.In these alcohol-oily transesterification surfactant, hydrophobic surfactant comprises PEG-5 castor oil hydrogenated, PEG-7 castor oil hydrogenated, PEG-9 castor oil hydrogenated, PEG-6 Semen Maydis oil (Labrafil ^M 2125 CS derive from Gattefoss é Corporation of Paramus, NJ), PEG-6 almond oil (Labrafil ^M 1966 CS), PEG-6 almond oil (Labrafil ^M 1944CS), PEG-6 olive oil (Labrafil ^M 1980 CS), PEG-6 Oleum Arachidis hypogaeae semen (Labrafil ^M1969 CS), PEG-6 hydrogenated palm kernel oil (Labrafil ^M 2130 BS), PEG-6 palm-kernel oil (Labrafil ^M 2130 CS), PEG-6 triolein (Labrafil ^M 2735 CS), PEG-8 Semen Maydis oil (Labrafil ^M WL.2609 BS), PEG-20 corn monoglyceride (Crovol M40), PEG-20 almond monoglyceride (Crovol A40).

Said pharmaceutical composition and dosage form can comprise one or more enzyme inhibitors.Such enzyme inhibitor comprise without limitation such as unwrapping wire amide rhzomorph or the table unwrapping wire amide rhzomorph (epiactinonin) with and derivant chemical compound.Other enzyme inhibitor comprises aprotinin (Trasylol) and Bowman-Birk inhibitor without limitation.

Dosage form

The solid composite medicament of the present invention that comprises wetted heparin and delivery agent can be configured to solid unit dosage form.This dosage form can be for example tablet, sachet or capsule, for example hard or Perle.This dosage form can provide delivery agent, heparin and optional other activating agent immediately, continue or controlled release.

Solid composite medicament of the present invention and solid unit dosage form can followingly be prepared like that.Delivery agent to solid form is handled (as handling by grinding with 35 mesh sieves), obtains powder less relatively and that preferably have uniform grain sizes.Then, this delivery agent and heparin, optional filler and/or wetting agent is admixed together, for example mix, thereby obtain a kind of powder admixture with V-type blender or similar device.

Independently by preparing a kind of wetting agent mixture with wetting agent, heparin and delivery agent are admixed together.This mixture also can comprise for example water.Prescription to wet mix is selected, thereby makes that it can the moistening heparin when it is mixed with above-mentioned powder admixture.According to an embodiment preferred, this wetting agent also is configured to such wetting agent that can be partly dissolved said delivery agent when mixing with said powder admixture.

Under successive blended situation, the form of said powder admixture with the aliquot increment joined in the said wetting agent mixture.After adding all powder, continue to mix time enough (for example, 15 minutes), thereby obtain a kind of uniform compositions.The compositions of gained is generally semisolid, gel or liquid.

Then, can said composition be formulated as a kind of dosage form, for example capsule with method well known in the prior art.According to an embodiment preferred, said compositions is wrapped in Perle or the hard gelatin capsule (for example, No. 0 Licap Capsugel hard gelatin capsule).In US patent 6,605,298,6,458,383,6,261,601,5,714,477 and 3,510,561; US patent application 2003/0077303 and 2001/0024658; And among the international publication WO 88/10117 (it all here is introduced into as a reference) other suitable methods are described.

Use

The invention provides by solid composite medicament of the present invention being delivered medicine to the method that individuality carries out the animal transmission of heparin or promotes the transmission of heparin.Said individuality is the people preferably.Said people preferably needs the people of such transmission, or the people that can be benefited by the administration of heparin.

Another embodiment is to be administered orally in the thrombotic method that its individuality was treated or need to be prevented to individuality by the solid composite medicament of the present invention that antithrombotic is formed effective dose.Can comprise that without limitation dvt forms (DVT) and pulmonary infarction (PE) with the thrombosis of said medicine composite for curing or prevention any kind.

Another embodiment is a kind ofly to be administered orally in individuality by the solid composite medicament of the present invention that antithrombotic is formed effective dose and to treat or need to prevent its unstable angor of individuality and/or the method for the ischemia complication in the non-q wave myocardial infarction.

Another embodiment is a kind ofly to be administered orally in individuality by the solid composite medicament of the present invention that antithrombotic is formed effective dose and to treat or prevent the dvt of the individuality behind hip or knee reattachment surgery to form the method for (DVT).Another embodiment still is a kind ofly to be administered orally in the method for DVT that the patient treated or prevented the patient of thromboembolia type complication risk by the solid composite medicament of the present invention that antithrombotic is formed effective dose.Risky abdominal operation patient comprise without limitation these ages greater than 40 years old, fat, undergo surgery under 30 minutes the general anesthesia or have other risks and assumptions such as malignant tumor or the patient of DVT history or pulmonary infarction is arranged continuing to surpass.

Another embodiment is a kind ofly to be administered orally in the method that the DVT of the serious limited individuality of energy was treated or prevented to suffer to individuality by the solid composite medicament of the present invention that antithrombotic is formed effective dose.Other embodiments comprise treatment cardiac valve replacement (cardiac valve that comprises machinery and corpse source) without limitation; The treatment endocarditis; Carry out the patient's of neural operation prevention, said neural operation is for example excision of malignant brain tumor without limitation; Suffer from the patient's of acute spinal cord injury, the medical conditions relevant with thromboembolism prevention, said patient is without limitation for for example these suffer from ischemic stroke or energy is limited, the patient of cancer, myocardial infarction, cancer, congestive heart failure or serious lung disease; The secondary prevention of phenolics venous thromboembolism or have anemia of pregnant woman's the primary prevention of the thrombophilia (for example thrombin III, PROTEIN C, Protein S, labile factor deficiency, leiden mutation, thrombinogen (prothrombin) polymorphism, hyperhomocysteinemia) of genetic cause; Be used for the thromboembolism relevant or be used for the patient that these have artificial valve and atrial fibrillation simultaneously with atrial fibrillation; The cardioversion that is used for atrial fibrillation or atrial flutter; Be used for disseminated inravascular coagulation; Be used to reduce the complication risk of carrying out percutaneous coronary intervention, percutaneous tranluminal coronary angioplasty, arthrectomy, coronary artery or the transplanting of other blood vessel transplantation sheet fixed die, ischemic cerebrovascular events, hemodialysis, peripheral blood vessel intervention, Acute Myocardial Infarction Patients; Unstable angor and non--ST-section rising myocardial inyaretion; The cerebral thrombosis thromboembolism; Pregnancy complications, comprise without limitation with or without the gestation loss with anti-phospholipid antibody/antiphospholipid syndrome history women of fetus loss (fetal loss), foetal death or fetal abortion.At Drug Information, American Society of Health System Pharmacists can find other application of heparin in 2005, and it here is introduced into as a reference.

According to an embodiment, about 50,000 heparin to about 90,000 units (being contained in compositions of the present invention or the dosage form) administration every day one to five time (for example, one day three times) can be treated thrombosis.According to an embodiment preferred, each compositions comprises about 250mg to about 2.3g SNAC.

Another embodiment of the invention is that a kind of pharmaceutical composition of the application of the invention is treated or prevented the disease of animal or is used to obtain required physiological role, for example the method for the listed physiological role of following table.Said pharmaceutical composition comprises following listed suitable activating agent.Physicians ' Desk Reference (the 58th edition, 2004, Medical Economics Company, Inc., Montvale can find the specific adaptations of every kind of activating agent to levy in NJ), it here is introduced into as a reference.The listed activating agent of following table comprises that its analog, fragment, plan are like thing and poly ethyldiol modified derivant.

Activating agent	The limiting examples of disease and physiological role
		Amylin and amylin agonist;	Fat
Thyroliberin;	Hypercholesterolemia (with cholesterol reducing)
		Antigen;	Infect
Antibacterial comprises antibiotic, antibacterial agent and antifungal; Antibiotic limiting examples comprises the antibiotic that acts on gram positive bacteria, Bactericidal, lipid peptide and cyclic peptide antibiotic, as daptomycin with and analog;	Infect, comprise gram positive bacterial infection
		Antimigraine such as BIBN-4096BS and other and calcitonin gene proteins associated antagonist, Sumatriptan Succinate;	Migraine
Antiviral agent comprises acyclovir, valaciclovir;	Viral infection
		Atrial natriuretic peptide;	Vasodilation
Diphosphate comprises fosamax, clodronate, etidronate, ibandronate, Incadronate, YM 529, neridronic acid salt, olpadronate, pamldronate, Risedronate, Tiludronate, zoledronic acid salt, EB 1053 and YH529;	Cancer, atherosclerosis, osteoporosis and Paget; Suppress osteoclast
		Calcitonin comprises salmon, Anguillar japonica, pig and human calcitonin;	Osteoporosis; The disease of bone
Cholecystokinin (CCK) and CCK agonist comprise CCK-8;	Fat
		Sodium cromoglicate (sodium cromoglicate or disodium);	Asthma; Allergy
Cyclosporin;	Transplant rejection
		(DFO) desferrioxamines;	Iron overload
Erythropoietin;	Anemia
		Exedin and Exedin agonist comprise Exendin-3, Exendin-4;	Diabetes; Fat
Filgrastim	Reduce the infection of patients undergoing chemotherapy
		Follicle stimulating hormone (reorganization and natural);	Regulate reproductive function

Glucagon-like peptide 1 (GLP-1), glucagon and glucagon-like peptide 2 (GLP-2);	Diabetes; Fat
		Glucocerebrosidase;	Gaucher disease (with the metabolism lipoprotein)
Gonadotropin releasing hormone;	OD (with induction of ovulation)
		Somatotropin releasing factor;	The growth disease
Growth hormone releasing hormone;	The growth disease
		Growth hormone comprises human growth hormone (bGH), recombinant human somatropin (rhGH), bovine growth hormone (hGH) and pig growth hormone;	The growth disease
Heparin, comprise unassorted heparin, Hirudoid, dermatan class material, chrondroitin class material, low molecular weight heparin, super low molecular heparin, ultra-low molecular weight heparin and synthetic heparin, comprise that sulphur reaches heparin;	Thrombosis; Preclude blood is solidified
		Immunoglobulin	Infectious disease and blood abnormal development
Insulin comprises pig, cattle, people and biosynthetic human insulin, and it randomly has counter ion counterionsl gegenions, comprises zinc, sodium, calcium and ammonium;	Diabetes; The insulin resistance syndrome
		Insulin like growth factor comprises IGF-1;	Diabetes
Interferon, (for example, Interferon alfacon-1 is (with Infergen to comprise α Form derive from InterMune, Inc.of Brisbane, CA)), α, β, ω and IFN-;	Viral infection comprises chronic cancer and multiple sclerosis
		Il-1; Interleukin-2; Il-1; Interleukin-21;	Viral infection; Cancer
Alfasone and luteinising hormone-releasing hormo;	Regulate reproductive function
		Leptin (OB albumen);	Fat
Monoclonal antibody comprises Retuxin, the solvable receptor of TNF-α;	Prevention suppresses to repel; Cancer
		Oxytocin;	Production malfunction (shrinking) to stimulate
The other limit of first shape hormone (PTH) comprises its fragment, comprises PTH 1-34 and PTH 1-38;	Osteoporosis; The disease of bone
		Peptide YY (PYY) comprises PYY agonist and PYY fragment 3-36;	Fat; Diabetes; Eating disorders; The insulin resistance syndrome
Prostaglandin;	Hypertension
		Protease inhibitor;	AIDS
Somatostatin;	Hemorrhagic ulcer; Erosive gastritis
		Thrombopoietin;	Thrombocytopenia
Vancomycin;	Infect and disease prevention
		Vassopressin;	Wet the bed; Antidiuretic
Vitamins;	Vitamin deficiency

Vaccine comprises that these resist the vaccine of anthrax Or Y.Pestis, influenza and herpes;

Prevent disease and disease minimized

Come the present invention is carried out non-limitative illustration with the following examples.Unless stated otherwise, otherwise all used percentage ratios all are percentage by weights.

Embodiment 1

The capsular preparation of heparin/SNAC

Below in the table 1 the SNAC/ heparin preparations be prepared as follows described.

Table 1

Component	Destination number (mg/ capsule)	Acceptable scope (mg/ capsule)
			SNAC	229.59	218.0-241.1
Heparin sodium (USP)	(107.14 15,000 USP heparin unit)	101.14-112.5
			Polyethylene Glycol (PEG) 300	226.13	214.8-237.4
Sodium lauryl sulfate	6.70	6.4-7.0
			Capryol 90 (Capmul PG8)	100.44	95.4-105.5
Gross weight	670.0	635.7-703.5

Capryol 90 is with Capmul ^The form of PG8 derives from Abitec Corporation ofColumbus, Ohio.

With deriving from Quadro Engineering Inc.of Waterloo, the Quadro Comil that is furnished with 35 mesh sieve equivalents of Ontario ^TMGrinder grinds SNAC.Make this SNAC and heparin sodium (USP) of having carried out grinding pass through 35 mesh sieves.To wherein adding sodium lauryl sulfate, this mixture was mixed 15 minutes with 4-quart V-type agitator housing.With Liquid Macrogol and Capryol 90 at stainless-steel K itchen Aid ^TMThe independent mixing 15 minutes in the blender.This SNAC/ heparin sodium USP/ sodium lauryl sulfate admixture joined in this PEG 300/ Capryol 90 mixture with the aliquot increment and continue it is mixed.After adding all SNAC/ heparin sodium USP/ sodium lauryl sulfate admixtures that carried out grinding, it is continued to mix 15 minutes.

Preparation with gained (derives from Capsulgel ofMorris Plains, NJ) manually fills No. 0 Licap Capsugel-hard gelatin capsule.

Comparing embodiment 1

Be filled into 200 (± 3) mg microcrystalline Cellulose in No. 0 Capsugel hard gelatin capsule and with it as placebo.

Comparing embodiment 2

Cryodesiccated booth is pricked the heparin sheet

Following such tablet for preparing with prescription shown in the table 2.

SNAC is ground with the Quadro Comill that is furnished with 35 mesh sieves.The following heparin of like that booth being pricked (derives from VirTis of Gardiner, NY) lyophilization with the VirTis freeze dryer.Booth is pricked heparin be dissolved in and purify waste water, thereby obtain a kind of concentration solution for about 100mg/mL.This freeze dryer shelf is cooled to-40 ℃ in advance.Then, this booth is pricked heparin solution transfer in 3 pallets, each pallet has about 1.6kg solution.Transfer to this pallet in this freeze dryer and with its lyophilization, thereby obtain a kind of exsiccant powder.Then, this exsiccant powder being carried out booth pricks the heparin analysis and makes tablet with it.

Following such tablet for preparing.The cryodesiccated tinzaparin sodium of the requirement of weighing out (USP), SNAC, Bibasic Calcium Phosphate dehydrate (USP) and sodium lauryl sulfate also join them in 16 quarts of V-type agitator shells.These materials were mixed 15 minutes.The admixture of gained is divided into three granulates in small batches.With each transfer in small batches Key Instruments KG5 high speed shear granulator (KeyInstruments, Inc.of Englishtown, NJ) 5L the tube in and water as granulation liquid it is granulated.With this three all granulate in small batches after, the transfer of granules that this is moistening to pallet and with its in vacuum drying oven 50 ℃ and≤be dried to moisture under the 5.0Hg (vacuum) and be lower than 15%.With the grinder of being furnished with 35 mesh sieves this dried particles is ground.This particulate SNAC and booth bundle heparin content that has carried out grinding is analyzed.Prick the heparin analysis based on this particulate booth, the quantity of the outer excipient of count particles.

With said extra-granular excipient---Bibasic Calcium Phosphate dehydrate, pyrogenic silica and the magnesium stearate required quantity of sieving and weigh out with 35 mesh sieves.This has been carried out grinding and exsiccant SNAC/ booth is pricked the heparin granule and transferred in 8 quarts of V-type agitator shells with Bibasic Calcium Phosphate dehydrate and pyrogenic silica and with its mixing 15 minutes.After carrying out mixing uniformity test, add magnesium stearate and it was mixed 3 minutes.The admixture of gained is compressed into tablet with EK-O separate unit tablet machine (Korsch AG, Berlin, Germany).Target patch heavily is 1100mg, and acceptable scope is 1067-1133mg, and target patch is thick simultaneously is 15kP, and acceptable scope is 10-20kP.

Table 2

Component	Quantity (mg/ capsule)
		SNAC	693
Cryodesiccated booth is pricked heparin (15,000 USP heparin unit)	160.60 *
		The Bibasic Calcium Phosphate dihydrate	293.01
Sodium lauryl sulfate	222.19
		Pyrogenic silica	2.20
Magnesium stearate	11.00

^*-based on the effectiveness of 93.4U/mg,

Comparing embodiment 3

Not cryodesiccated heparin sheet

Prepare tablet with comparing embodiment 2 described methods, just heparin is not carried out lyophilization with prescription shown in the table 3.

Table 3

Component	Quantity (mg/ capsule)
		SNAC	460
Cryodesiccated booth is pricked heparin (30,000 USP heparin unit)	170.26 *
		The Bibasic Calcium Phosphate dihydrate	152.95
Sodium lauryl sulfate	8.0
		Pyrogenic silica	1.6
Magnesium stearate	8.00

Comparing embodiment 4

Cryodesiccated heparin tablet

Prepare tablet with prescription shown in the table 4 with comparing embodiment 2 described methods.

Table 4

Component	Quantity (mg/ capsule)
		SNAC	460
Cryodesiccated booth is pricked heparin	170.26

(30,000 USP heparin unit)
		The Bibasic Calcium Phosphate dihydrate	152.95
Sodium lauryl sulfate	8.0
		Pyrogenic silica	1.6
Magnesium stearate	8.00

Embodiment 2

Derive from the data of embodiment 1 and comparing embodiment 1-4

Give 15 individual embodiment 1 of use of human test and described each preparation of comparing embodiment 1-4 6 periods, separate during by 72 hours eluting each period.For each period, at the night before administration, individuality enters clinical, begins a kind of fasting in 8 hours that begin at 10p.m..In the morning, at fasting state these preparations are carried out administration.Table 5 pair said six periods and summarized by the preparation of administration.

Table 5

Period	Preparation	Unit dose number (tablet, capsule)	The total amount (U) of heparin (or booth bundle heparin)	The total amount of SNAC (mg)
					1	Comparing embodiment 1	1	0	0
2	Embodiment 1	4	60,000	920
					3	Comparing embodiment 2	3	45,000	2079
4	Embodiment 1	6	90,000	1380
					5	Comparing embodiment 3	2	60,000	920
6	Comparing embodiment 4 (n=13)	2	60,000	920

For each period, measured before administration 15 and 5 minutes and administration after the activity of anticoagulin Xa and anticoagulin IIa in 5,15,30,45,60,90 and 120 minutes institute's blood-sample withdrawals.Anticoagulin Xa and anticoagulin IIa activity and aPTT time are the indicators of heparin response, and provide a kind of basis for the bioavailability with each preparation compares.

The result of each sample 15 individualities in period is average, and its result is as shown in the table.

Table 6

Anticoagulin xa activity (IU/ml) (standard deviation is as shown in round parentheses)

Time (minute)	Period
							1	2	3	4	5	6
	-15	.003 (0.0046)	.007 (0.0110)	0.039 (0.024)	.011 (0.014)	.006 (0.012)							0 (0)
-5							.002 (0.0077)	.005 (0.0136)	.024 (0.021)	.003 (0.008)	.002 (0.006)	.002 (0.008)
	5	0 (0)	.012 (0.0224)	.042 (0.046)	.053 (0.055)	.026 (0.029)							.012 (0.019)
15							.004 (0.0155)	.051 (0.0685)	.081 (0.061)	.268 (0.166)	.055 (0.051)	.036 (0.048)
	30	.001 (0.0026)	.153 (0.0930)	.129 (0.054)	.355 (0.189)	.051 (0.053)							.025 (0.050)
45							0 (0)	.173 (0.1449)	.145 (0.052)	.313 (0.190)	.039 (0.042)	.023 (0.044)
	60	0 (0)	.139 (0.1522)	.116 (0.059)	.212 (0.151)	.009 (0.019)							.005 (0.019)
90							0 (0)	.075 (0.1041)	.083 (0.044)	.137 (0.132)	.002 (0.006)	0 (0)
	120	.001 (0.0026)	.041 (0.0508)	.061 (0.033)	.018 (0.022)	.003 (0.007)							.002 (0.006)

Table 7

Blood plasma anticoagulin Xa pharmacodynamic parameter

Period	Emax， IU/ml (CV，％)	TEmax，hr (CV，％)	EAUC (0-is last) (CV, %)	EAUC(0- inf) (CV，％)	EMRT，hr (CV，％)
						1	0.01 (160.30)	0.432 (174)	--	--	--
2	0.20 (69.42)	0.719 (54.0)	0.2082 (80.39)	0.3935 (62.31)	1.24 (28.1)
						3	0.16 (33.41)	0.723 (28.3)	0.1941 (39.77)	0.3241 (28.01)	1.42 (13.4)
4	0.36 (50.83)	0.707 (20.1)	0.4171 (58.08)	0.4528 (43.43)	1.25 (19.2)
						5	0.07 (70.74)	0.516 (35.5)	0.06632 (55.74)	0.1528 (45.58)	1.14 (45.3)
6	0.05 (93.81)	0.513 (48.5)	0.06261 (81.38)	--	--

Table 8

Anticoagulin IIa activity (IU/m1)

Time (minute)	Period
							1	2	3	4	5	6
	-15	.089 (0.254)	.025 (0.029)	.039 (0.027)	.035 (0.024)	.024 (0.024)							.015 (0.017)
-5							.026 (0.030)	.025 (0.028)	.062 (0.012)	.045 (0.019)	.028 (0.019)	.023 (0.018)
	5	.034 (0.036)	.029 (0.029)	.058 (0.013)	.074 ((0.039)	.039 (0.020)							.027 (0.020)
15							.030 (0.033)	.058 (0.057)	.067 (0.016)	.304 (0.135)	.073 (0.031)	.041 (0.025)
	30	.033 (0.034)	.137 (0.069)	.079 (0.025)	.383 (0.243)	.074 (0.035)							.038 (0.033)
45							.032 (0.033)	.160 (0.092)	.088 (0.037)	.382 (0.248)	.055 (0.032)	.035 (0.033)
	60	.027 (0.031)	.140 (0.090)	.071 (0.036)	.248 (0.211)	.042 (0.018)							.021 (0.030)
90							.024 (0.026)	.107 (0.061)	.083 (0.026)	.165 (0.153)	.048 (0.024)	.018 (0.018)
	120	.024 (0.031)	.069 (0.040)	.077 (0.016)	.044 (0.024)	.039 (0.021)							.009 (0.013)

Table 9

Blood plasma anticoagulin IIa pharmacodynamic parameter

Period	Emax， IU/ml (CV，％)	TEmax，hr (CV，％)	EAUC (0-is last) (CV, %)	EAUC(0- inf) (CV，％)	EMRT，hr (CV，％)
						1	0.05 66.44)	0.511 (119)	0.06896 (80.44)	--	--
2	0.18 (50.08)	0.706 (27.1)	0.2148 (49.14)	0.1702 (16.44)	1.00 (15.5)
						3	0.11 (24.65)	1.02 (48.9)	0.1543 (22.40)	--	--
4	0.42 (56.68)	0.773 (29.1)	0.5028 (63.54)	0.4131 (34.23)	1.18 (12.1)
						5	0.09 (35.40)	0.831 (79.8)	0.1011 (33.74)	--	--
6	0.06 (42.54)	0.612 (44.0)	0.06181 (60.62)	--	--

Table 10

Anticoagulin xa activity and the active ratio of anticoagulin IIa

Time (minute)	Period
							1	2	3	4	5	6
	-15	0.03	0.30	1.00	0.30	0.25							0.00
-5							0.08	0.18	0.39	0.06	0.07	0.10
	5	0.00	0.41	0.72	0.72	0.67							0.43
15							0.13	0.89	1.21	0.88	0.75	0.89
	30	0.02	1.12	1.64	0.93	0.69							0.66
45							0.00	1.08	1.65	0.82	0.70	0.67
	60	0.00	0.99	1.63	0.85	0.21							0.26
90							0.00	0.70	1.00	0.83	0.04	0.00
	120	0.03	0.60	0.79	0.41	0.08							0.25

Table 11

Blood plasma SNAC concentration (ng/mL) (standard deviation is as shown in round parentheses)

Time (minute)	Period
							1	2	3	4	5	6
	0	NA	0 (0)	2.36 (9.15)	0 (0)	0 (0)							0 (0)
5							NA	100.44 (276.47)	1394.87 (1630.58)	60.19 (67.57)	812.04 (648.93)	512.09 (322.79)
	15	NA	4731.95 (3900.82)	10139.4 (5481.83)	4168.13 (2515.09)	3612.24 (2286.80)							4339.32 (2010.81)
30							NA	4432.24 (2404.94)	8846.83 (4170.31)	5973.36 (2913.61)	2995.23 (1184.70)	3269.97 (1352.39)
	45	NA	1747.60 (1062.02)	4853.39 (3245.89)	4114.45 (23 59.29)	1399.63 (762.69)							871.15 (274.51)
60							NA	693.87 (352.40)	2095.89 (1205.31)	1637.34 (902.59)	682.07 (282.92)	513.43 (160.84)
	90	NA	535.45 (290.47)	1313.09 (571.42)	833.55 (400.36)	416.42 (218.59)							427.28 (210.71)
120							NA	373.32 (273.87)	1247.41 (861.34)	726.43 (529.29)	373.02 (305.72)	344.04 (432.82)

Table 12

Blood plasma SNAC pharmacokinetic parameters

Period	Cmax， ng/ml (CV，％)	Tmax，hr (CV，％)	AUC (0-is last), ng *hr/ml (CV，％)	AUC(0- inf)， ng *hr/ml (CV，％)	T 1/2，hr (CV，％)	CL/F， L/hr (CV，％)	Vd/F，L (CV，％)
								2	5907.10 (57.65)	0.436 (39.9)	3189.9 (35.630)	3194.0 (24.783)	0.522 (54.6)	301.62 (21.497)	229.13 (61.386)
3	11,874.21 (41.13)	0.392 (42.4)	7611.9 (33.044)	9141.8 (26.432)	0.618 (54.9)	239.91 (24.467)	215.66 (64.28)
								4	6,969.23 (39.77)	0.572 (26.1)	4632.7 (22.895)	4783.7 (10.429)	0.444 (39.6)	291.26 (11.009)	188.31 (43.187)
5	4456.64 (41.28)	0.348 (42.9)	2580.5 (30.130)	2833.4 (25.429)	0.454 (38.7)	339.51 (20.392)	226.25 (45.799)
								6	4637.60 (40.53)	0.331 (38.0)	2685.5 (26.388)	3016.5 (20.316)	0.730 (45.2)	317.07 (21.644)	326.35 (44.825)

Table 13

Blood plasma aPTT (second) (the mark standard deviation is as shown in round parentheses)

Time (minute)	Period
							1	2	3	4	5	6
	0	26 (2)	26 (2)	26 (2)	26 (2)	26 (2)							26 (2)
15							26 (2)	27 (2)	--	--	--	--
	30	26 (2)	35 (6)	31 (4)	47 (15)	29 (3)							29 (3)
45							27 (3)	38 (11)	31 (4)	49 (20)	28 (3)	28 (3)
	60	25 (4)	32 (6)	30 (3)	48 (23)	27 (2)							27 (2)
120							25 (2)	28 (2)	28 (2)	34 (13)	26 (2)	27 (2)
	480	26 (2)	26 (2)	26 (2)	26 (2)	26 (2)							26 (2)

Table 14

Blood plasma aPTT pharmacokinetic parameters

Period	Emax，sec (CV，％)	TEmax，hr (CV，％)	EAUC (0-is last) sec *hr (CV，％)
				1	27 (11)	0.305 (127)	52.795 (9.5374)
2	38 (28)	0.604 (25.6)	64.372 (17.531)
				3	32 (13)	0.583 (17.3)	58.736 (9.5973)
4	54 (41)	0.771 (49.8)	82.333 (32.203)
				5	29 (11)	0.408 (63.0)	54.809 (7.924)
6	29 (12)	0.469 (48.6)	67.017 (12.861)

As table 6 and 8 and Fig. 1 and 2 shown in, wetted heparin preparations (period 2 and 4) shows anticoagulin Xa and higher anticoagulin Xa and the IIa activity of IIa activity than placebo (period 1) and not wetted heparin/SNAC tablet ( period 3,5 and 6) usually.As shown in table 13, wetted heparin preparations shows the blood plasma aPTT time that the blood plasma aPTT time than placebo and not wetted heparin/SNAC tablet increases usually.

Embodiment 3

Preparation has the Perle of filling a prescription shown in table 15a, 15b and the 15c as described as follows.

Table 15a

Component	Mg/ capsule (3% weight)
		SNAC	230.00
Heparin sodium, USP (15,000 unit)	≤107.14
		Liquid Macrogol, NF (PEG 300)	265.00
Capmul PG8	107.00
		Purify waste water USP	54.00
Oleum Glycines, USP, super refining	QS(≥5.58)
		Gross weight	765.00

Table 15b

Component	The mg/ capsule	The % capsules weight	Acceptable scope (mg)
				SNAC	383.00	28.24	371.5-394.5
Heparin sodium, USP (25,000 unit)	≤178.57	≤13.17	≤173.2-184.0
				Liquid Macrogol, NF (PEG 300)	508.00	37.46	492.8-523.2
Capmul PG8	190.00	14.01	184.3-195.7
				Purify waste water USP	95.00	7.01	92.2-97.9
Oleum Glycines, USP, super refining	≥0.11	≥1.43	≥0.106-0.113
				Gross weight	1356.00	100.00	1315.3-1396.7

Table 15c

Component	The mg/ capsule	The % capsules weight	Acceptable scope (mg)
				SNAC	250.00	21.37	142.5-257.5
Heparin sodium, USP (37,500 unit)	≤267.86	≤22.89	≤259.8-275.9
				Liquid Macrogol, NF (PEG 300)	405.00	34.62	392.9-417.2
Capmul PG8	164.00	14.02	159.1-168.9

Purify waste water USP	81.99	7.00	79.5-84.4
				Oleum Glycines, USP, super refining	≥1.15	≥0.10	≥1.12-1.18
Gross weight	1170.00	100.00	1134.9-1205.1

The preparation of gelatinous mass

Be used for that said capsular gelatinous mass has the prescription shown in the following table 16 and it is prepared as follows described.The jar that holds gel is preheated to 55 ℃.The hot water overcoat heater of this gel melter is opened and its temperature controller is set at 90 ℃.This blender is opened in purifying waste water (USP) and it being joined in this gel melter of the required weight of weighing out.Independently prepare required the purifying waste water of about 3kg (USP) in the container at one and be used to carry out the color transfer.With the glycerol of requirement (99.7%, USP) join in the said gel melter, the said container of swiping then shifts fully to guarantee it.The liquid sorbitol (USP) of requirement dehydration (anhydrized) joined in this gel melter and this container swiped and shift fully guaranteeing.Then, close entrance door and all relief valve on this gel melter dome and be heated to the temperature that is greater than or equal to 80 ℃.Open the entrance door of this gel melter and relief valve and in this gel melter, add the gelatin (NF) of requirement, after adding fully, closing this blender.Close entrance door and pressure valve, open this blender and hot water jacket's heater controller is set at 85 ℃.After its temperature reaches at least 80 ℃, it was continued Hybrid Heating 75 ± 10 minutes.This gelatinous mass is checked (if can't see undissolved granule, then said gelatinous mass has formed and finished).The vacuum pump water pipe is linked to each other with outlet and open cold water and vacuum pump.This gelatinous mass is outgased, after can't see this gelatinous mass generation bubble, close this blender and vacuum pump.

White Opatint G-18000 fully mixed in its initial container with rustless steel oar and take by weighing out required quantity.Take by weighing FD﹠amp; C Green No.3 and D﹠amp; C YellowNo.10 also is dissolved in it in about 1/4th (1/4) the deposit water.

Open the entrance door of this gel melter and starting slow said Opatint of adding and dye mixture under the situation of blender.Then, close relief valve and entrance door, open vacuum pump.With this gelatinous mass that is colored degassing 10 ± 5 minutes, unclamp all valves then and turn off blender and vacuum pump.Its viscosity and moisture are measured in sampling.If its moisture is lower than 26%, then the moisture of this gelatinous mass is adjusted to about 26% by adding entry, if perhaps its moisture is higher than 25%, then its moisture is adjusted to 26% by further heating.With this gelatinous mass transfer to the gel that heats in advance and weighed hold in the jar and with its temperature maintenance at about 55 ℃.

Table 16

Component	Requirement	％w/w	Scope (mg)
				Gelatin, NF (150 Bloom Limed Bone, B type)	61.500	41.00	59.66-63.35
Glycerol, 99.7%, USP	21.000	14.00	20.37-21.63
				The dehydration liquid sorbitol, USP (Sorbitol Special, 76%)	13.500	9.00	13.10-13.91
Purify waste water USP	50.964	33.98	49.44-52.49
				White Opatint G-18000	3.000	2.00	2.91-3.09
FD&C Green NO.3	0.021	0.014	0.02-0.022
				D&C Yellow NO.10	0.015	0.010	0.0146-0.0155
Gross weight	149.996		145.50-154.50

The preparation of heparin/SNAC Perle

With the QuadroComil that is furnished with circular impeller and Comil Screen 2A006R04227587 (80 order) ^197 heparin sodiums with requirement (USP) are ground to its granularity and are not higher than 180 μ m.Take by weighing Liquid Macrogol (NF (PEG 300) Capmul of requirement ^PG8), purify waste water (USP) and Oleum Glycines (USP) and it is transferred in the rustless steel container of suitable size.An overhead stirrer is put in this mixture and this container is put on the electric hot plate.Then, begin to mix and heat.The temperature that continues to be heated to this mixture reaches 40 ± 10 ℃, with nitrogen this mixture is sheltered thereafter.

For 250mg/37, the 500IU preparation joins SNAC in this mixture under condition of stirring.Continuing to be mixed to SNAC fully distributes.Continuing in this mixture, to add heparin sodium (USP) under the condition of stirring.Continue to mix, fully disperseed until heparin.Then, turn off blender and pull down the blade of this blender and handle to clear up.

For 383mg/25,000 preparation mixes SNAC about 1 minute in a sack with the heparin that has carried out grinding.Join the admixture of gained in the said solvent system and continue to be mixed to this heparin/SNAC admixture and fully disperseed.Then, turn off this blender and pull down the blade of this blender and handle to clean.

For any in these two kinds of preparations, the suspension of gained is taken off and with the Vertical colloid mill with funnel it ground from said electric hot plate.Measure the aggregation size of grinding this suspension of front and back with the fineness of grinding gage.The granularity that always continues to be ground to its aggregation is lower than 180 μ m.After finishing grinding, measure the temperature of this suspension.If necessary, this suspension is preheated to 30-50 ℃.Then, this suspension is placed in the vacuum chamber and with its degassing to not observing bubble.Then, the heparin in the collection and treatment process/SNAC suspension sample.This heparin/SNAC suspension is covered and slowly under the condition of stirring it maintained under 30-50 ℃ continuously.

With Bochang capsule sealing machine, this heparin/SNAC soft-gelatin capsule formulation is sealed with the gelatinous mass that makes like that as mentioned above.Have the lubricant of Miglyol 812 (caprylic/capric triglyceride) soybean lecithin solution with 1%w/w as this capsule sealing machine.Said heparin/SNAC suspension is fed in the funnel of this capsule sealing machine and continuously it is stirred.It is 1267mg that this device is set at target capsule filling weight, acceptable scope is 1204 to 1330mg, and its trailing edge seam (trailing edge seam) acceptable limit of thickness is 0.81 ± 0.05mm for the thickness of 0.25mm and target ribbon (ribbon) at least.After sealing, to these capsules carry out dry until glue shell moisture for be less than or equal to 8% and the water content of whole material (heparin/SNAC suspension) for being less than or equal to 9%.After drying, sample presentation carries out release test.Then, these capsulations are served as a contrast (foillined), are suitable for introducing in the white HDPE wide mouthed bottle of seal cover and low moisture cotton balls to (Child Resistant), the paper tinsel that 100cc has the 38mm children unopenable.Each bottle is filled 30 (30) pieces of capsules.

Embodiment 4

Preparation comprises 15,000IU heparin, 250mg SNAC, 15% (w/w) Capmul as described as follows ^PG8 (Capryol 90) or Capmul ^MCM (glycerol caprylate/decanoin) (derives from Abitec Corp.of Columbus, OH), the hard gelatin capsule of 37 %PEG 300 and 1% sodium lauryl sulfate.Hard gelatin capsule also is prepared with above-mentioned preparation, and just it does not contain SNAC or contains 2%Carbopol ^934P (derives from Noveon of Cleveland, OH).

At first, with liquid excipient (for example, Capmul ^PG-8 or Capmul ^MCM and PEG-300) in mortar, mix, thus obtain a kind of uniform liquid mixture.Portioning is slowly sneaked into various solid constituents until the homogeneous mixture that obtains a kind of pastel (or suspension) denseness in this mixture.These solid materials comprise SNAC, heparin, sodium lauryl sulfate and optional Carbopol ^934P.In case determined the uniformity of this pastel (or suspension), then this mixture manually be filled in the hard gelatin capsule of suitable size.Junction point place between housing and medicated cap comes this capsule that has carried out filling is sealed by the edge with 50: 50 (%v/v) ethanol and the mixture moistening housing of purifying waste water.With these capsule stored frozen under-20 ℃ until being used.

Embodiment 5

Following like that will the Perle of preparation deliver medicine to 4 male Rhesus monkeys shown in the table 15a as having of making like that as described in the embodiment 3.Before experiment, be the Rhesus monkey fasting a whole night of 3.5-5.0kg with body weight and food put back in 2 hours after with this solid administration.Preceding 30 minutes of administration after administration 30 minutes, stop to supply water to it, be used to carry out except the water of administration quantity.With the pill rifle each dosage form is delivered to its rear, oral cavity.After discharging said dosage form, in the oral cavity, give the 5ml reverse osmosis water and swallow with promotion.After transmission, its oral cavity is checked to guarantee that this solid is swallowed.

The hard gelatin capsule that will have prescription shown in the table 1 as described above and make as described in the embodiment 1 delivers medicine to 7 male Rhesus monkeys.

In 400 minutes, the anticoagulin Xa in the blood sample is measured.The result of each group is average, and it as shown in Figure 3.

Embodiment 6

Preparation comprises or does not comprise 2%Carbopol ^934P have embodiment 4 described prescriptions (15,000IU heparin, 250mg SNAC, 15% (w/w) Capmul ^PG8,37 %PEG 300 and 1% sodium lauryl sulfate) hard gelatin capsule.Also preparation has embodiment 4 described prescriptions, but does not contain the hard gelatin capsule of SNAC.

The SNAC regulating liver-QI cellulose capsule that will contain or not contain Carbopol in the following method delivers medicine to 8 Cynos monkeys.Before administration, with these Cynomolgus monkey fasting at least 24 hours.One piece of capsule is inserted into the top of a pipe, to wherein blowing so that capsule is delivered medicine in the stomach.After administration, food was put back in 2 hours.It can obtain water at any time.Before administration and after administration in 400 minutes, will about 1.3ml whole blood collection in the Citrated test tube.Anticoagulin Xa in the blood sample is measured.

The capsule that will not contain SNAC as mentioned above like that delivers medicine to 4 Cynos monkeys.

The result of these three groups each groups is averaged, and its result as shown in Figure 4.

Embodiment 7

The hard gelatin capsule that preparation has prescription shown in the table 17 and is prepared as described in the embodiment 1.These capsules are delivered medicine to the group of 8 Rhesus monkeys (1 piece of capsule/monkey) with embodiment 5 described methods.

Table 17

Component	Quantity
		SNAC	250.0mg
Heparin sodium, USP	15,000IU
		Polyethylene Glycol (PEG) 300	37wt％
Sodium lauryl sulfate	1wt％
		Capmul PG8 (Capryol 90)	15wt％

Anticoagulin Xa in the blood sample in 6 hours is measured.The result is average, and it as shown in Figure 5.

Embodiment 8

As such hard gelatin capsule for preparing as described in the embodiment 1 with prescription shown in the table 18.These capsules are delivered medicine to the group of 8 Rhesus monkeys.

Table 18

Component	Quantity
		SNAC	250.0
Heparin sodium, USP	14,930IU
		Polyethylene Glycol (PEG) 300	37％
Sodium lauryl sulfate	1
		Capmul MCM (list of medium-chain fatty acid (mainly being sad and capric acid)-and two monoglycerides)	15％

Capmul ^MCM derives from Abitec Corporation of Columbus, Ohio.This preparation is equal to the preparation of embodiment 7, just uses Capmul ^MCM has replaced Capmul ^PG8.

Anticoagulin Xa in the blood sample during 6 hours is measured.The result is average, and it as shown in Figure 6.

To in Fig. 7, superpose by embodiment 7 and 8 results (Fig. 5 and 6) that obtain.

Embodiment 9

To have the hard gelatin capsule of filling a prescription shown in the table 1 and as described in the embodiment 1, making with embodiment 5 described methods and deliver medicine to 4 Rhesus monkeys (1 piece of capsule/monkey).The antagonism factor Xa is measured in about 400 minutes time after administration.

The result is average, and it as shown in Figure 8.

Embodiment 10

To have the group that the hard gelatin capsule of filling a prescription shown in the table 1 and making delivers medicine to 4 Rhesus monkeys (1 piece of capsule/monkey) with embodiment 5 described methods as described in the embodiment 1.

Antagonism thrombin xa activity and aPTT measure in 400 minutes.The result is average, and it as shown in Figure 9.

Embodiment 11

As such hard gelatin capsule for preparing as described in the embodiment 1 with prescription shown in the table 19.With embodiment 5 described methods these capsules are delivered medicine to 4 Rhesus monkeys (1 piece of capsule/monkey).

Table 19

Component	Destination number (mg/ capsule)
		SNAC	229.59
Heparin sodium, USP	107.14(15,000IU)
		Polyethylene Glycol (PEG) 300	226.13
Capryol 90 (Capmul PG8)	100.44

The preparation of table 19 is equal to the preparation of table 1, does not just contain sodium lauryl sulfate.Antagonism thrombin xa activity and APTT measure in 400 minutes.The result is average, and it as shown in figure 10.

Embodiment 12

These hard gelatin capsules have the prescription of embodiment 1, but have the SNAC of varying number, thereby make SNAC: the ratio of heparin is 0.5: 1, to 1: 1,2: 1 and 2.5: 1.(in embodiment 1, SNAC: the ratio of heparin is about 2.5: 1).With embodiment 5 described methods these capsules are delivered medicine to Rhesus monkey (1 piece of capsule/monkey).To comprise 0.5: 1,1: 1,2: 1,2.5: 1 SNAC: the preparation of heparin delivers medicine to 4,4,4 and 7 monkeys respectively.

In about 400 minutes period, measure the anticoagulin xa activity in the blood sample.This average of four groups as shown in figure 11.

Embodiment 13

Carry out stability test with embodiment 1 described hard gelatin capsule.With embodiment 5 described methods these capsules are delivered medicine to the Rhesus monkey.These capsules are stored 15 days under the relative humidity of 40 ℃ and 75% relative humidity or 25 ℃ and 60%.Then, these capsules are delivered medicine to two groups of Rhesus monkeys.For each administration, measure thrombin xa activity and aPTT in about 400 minutes.

These results are average, and they are shown in Figure 12 and 13.

Figure 14 to embodiment 1 described semi-solid capsule its preparation administration on the same day (t=0) and under 25 ℃/60%RH the average anticoagulin xa activity of 15 days (t=15) back during by administration compare.Figure 15 to embodiment 1 described semi-solid capsule its preparation administration on the same day (t=0) and under 25 ℃/75%RH the average anticoagulin xa activity of 15 days (t=15) back during by administration compare.With embodiment 5 described methods these capsules are delivered medicine to the Rhesus monkey.

Comparing embodiment 5

The preparation of tablet (not containing heparin)

Following such tablet for preparing with the described prescription of table 20.

Table 20

Component	Mg/ sheet (target)	The % tablet weight	Mg/ sheet (acceptable scope)
				SNAC	383.00	47.88	371.51-394.49
Propylene glycol, USP/EP/JP	40.0	5.00	38.80-41.2
				Capmul PG	80.0	10.00	77.6-82.40
Bibasic Calcium Phosphate, anhydride, USP/EP (Anhyrdous Emcompress)	≥268.75	≥33.59
				Silica sol, USP/NF/EP (Aerosil 200 VV Pharma)	16.00	2.00	15.52-16.48
30 POVIDONE K 30 BP/USP 90, USP/EP/JP (Kollidon 90F)	4.25	0.53	4.12-4.37
				Magnesium stearate, NF/EP/JP	8.00	1.00	7.76-8.24
Gross weight	800.00	100.00	776-824.00

Take by weighing Emcompress in SNAC and a part of granule ^TM(derive from JRS Pharma, Patterson NY), transfers to them in 16 quarts of rustless steel V-type agitator shells and it was mixed 15 minutes.Then, the admixture of gained being divided into 4 granulates in small batches.For each small quantities of granulation, this SNAC admixture is transferred to Key Instruments KG-5 high shear granulator, and (derive from Key Instruments, Trevose is PA) in the cylindrical shell of 5L.At first use requirement Capmul ^The mixture of PG8 and propylene glycol uses requirement Povidone K90 aqueous solution (deriving from BASF, Ludwigshafen, Germany) to granulate as granulation liquid as granulation liquid then.Finish granulation with the granulation liquid of purifying waste water as final.The transfer of granules of gained is carried out storage in the course of processing in the container with polyethylene liner.In a similar fashion other three is granulated in small batches and store.With these transfer of granules in the rustless steel pallet and with its under about 40 ℃ in vacuum drying oven drying at least 4 hours.These have been carried out dried granules transferred in the Polythene Bag, and its mixing was not less than 1 minute.(derive from Vector Corp., Marion IA) has carried out blended granule to these and has ground with the Vector Granul Mill Jr. grinder of being furnished with 35 mesh sieves.Come this particulate moisture of having carried out grinding is measured with Karl-Fisher Coulometer.If its moisture is lower than 10%w/w, think that then these granules are exsiccant.If its moisture is higher than 10%w/w, then continue it is carried out drying until obtaining acceptable moisture.Calculate with adjustment with particulate moisture and to be added into the outer anhydrous Emcompress of granule in this granule ^TMQuantity.To carry out dried granules and transfer to the storage of carrying out in the container of polyethylene liner in the course of processing.

Make the Aerosil of requirement ^200 VV Pharma (deriving from Degussa AG, Wolfgang, Germany) sieve by 35 mesh sieves.Also to the anhydrous Emconipress of remainder ^TMQuantity weigh.Then, this having been carried out dried granules transfers in one the 16 quarts rustless steel V-type agitator shells.With Aerosil ^200 VV Pharma and anhydrous Emcompress ^TMTransfer in the identical V-type agitator shell.This shell is installed in Yoke of a Patterson-Kelly V-type stirrer-driven unit, and (derive from Patterson-Kelly Co., East Stroudsburg PA) upward and with it mixed 15 minutes.After the mixing uniformity test shows that mixing is achieved success, take by weighing the magnesium stearate of requirement, it is sieved with 35 mesh sieves and it is transferred in the said V-type agitator shell.This material was mixed 3 minutes.With the Korsch EK-O that is furnished with the oval mould of 16.5mm/7.5mm (derive from Mori Machinery Co., Okayama, Japan) single operation platform tablet machine is pressed into tablet with the admixture of gained.In pressing process, carry out following inter process test: friability, tablet hardness, sheet weight, tablet thickness and disintegration.Target patch heavily is 800mg, and acceptable scope is 776-824mg, and the target tablet thickness is 8Kp, and acceptable scope is 5-11KP.After carrying out release test, these tablets are packaged in medicated cap with medicinal coil, children unopenable and the HDPE bottle of the introducing seal washer 30 every bottle.

Comparing embodiment 6

The preparation (25,000/383) of heparin/SNAC tablet

Preparation has the heparin/SNAC tablet of the described prescription of table 21 as described as follows.

Table 21

Component	Mg/ sheet (target)	The % tablet weight	Mg/ sheet (acceptable scope)
				SNAC	383.00	47.88	371.51-394.49
Heparin sodium, USP (25,000 unit)	≤178.57	≤22.32	173.21-183.93
				Propylene glycol, USP/EP/JP	40.00	5.00	38.80-41.2
Capmul PG	80.00	10.00	77.6-82.40
				Bibasic Calcium Phosphate, anhydride, USP/EP (Anhyrdous Emcompress TM)	≥90.18	≥1 1.27	87.47-92.89
Silica sol, USP/NF/EP (Aerosil 200 VV Pharma)	16.00	2.00	15.52-16.48
				30 POVIDONE K 30 BP/USP 90, USP/EP/JP (Kollidon 90F)	4.25	0.53	4.12-4.37
Magnesium stearate, NF/EP/JP	8.00	1.00	7.76-8.24
				Gross weight	800.00	100.00	776-824.00

Take by weighing the heparin sodium (USP) of requirement and carried out the SNAC that grinds, it is transferred in one the 16 quarts rustless steel V-type agitator shells and with it mixed 15 minutes.The admixture of gained is divided into four granulates in small batches.For each small quantities of granulation, said heparin/SNAC admixture is transferred in the cylindrical shell of Key Instruments KG-5 high shear granulator 5L.At first use requirement Capmul ^The mixture of PG8 and propylene glycol is granulated as granulation liquid with requirement PovidoneK90 aqueous solution then as granulation liquid.(USP) finishes granulation as final granulation liquid with purifying waste water.The transfer of granules of gained is carried out storage in the course of processing in the container with polyethylene liner.In a similar fashion other three is granulated in small batches and store.With these transfer of granules in the rustless steel pallet and with its under about 40 ℃ in vacuum drying oven drying at least 4 hours.These have been carried out dried granules transferred in the Polythene Bag, and its mixing was not less than 1 minute.(derive from Vector Corp., Marion IA) has carried out blended granule to these and has ground with the Vector Granul Mill Jr. grinder of being furnished with 35 mesh sieves.Come this particulate moisture of having carried out grinding is measured with Karl-Fisher Coulometer.If its moisture is lower than 10%w/w, think that then these granules are exsiccant.If its moisture is higher than 10%w/w, then continue it is carried out drying.Sampling is analyzed SNAC in this dried particles and heparin.Calculate with adjustment with the heparin analysis and to be added into the outer anhydrous Emcompress of granule in this granule ^TMQuantity.To carry out dried granules and transfer to the storage of carrying out in the container of polyethylene liner in the course of processing.

Make the Aerosil of requirement ^200 VV Pharma sieve by 35 mesh sieves.Also take by weighing the anhydrous Emcompress of requirement ^TMThis has been carried out dried granules transfers in one the 16 quarts rustless steel V-type agitator shells.With Aerosil ^200 VV Pharma transfer in the identical V-type agitator shell with anhydrous Emcompress.This shell is installed on the Yoke of aPatterson-Kelly V-type stirrer-driven unit and it was mixed 15 minutes.The mixing homogeneity test is carried out in sampling.After the mixing uniformity test shows that mixing is achieved success, take by weighing the magnesium stearate of requirement, it is sieved with 35 mesh sieves and it is transferred in the said V-type agitator shell.This material was mixed 3 minutes.With the Korsch EK-O single operation platform tablet machine of being furnished with the oval mould of 16.5mm/7.5mm it is pressed into tablet.In pressing process, carry out following inter process test: friability, tablet hardness, sheet weight, tablet thickness and disintegration.Target patch heavily is 780mg, and acceptable scope is 756.6-803.4mg, and the target tablet thickness is 8Kp, and acceptable scope is 5-11KP.After carrying out release test, these tablets are packaged in medicated cap with medicinal coil, children unopenable and the HDPE bottle of the introducing seal washer 30 every bottle.

Comparing embodiment 7

The preparation (37,500/250) of heparin/SNAC tablet

Heparin/SNAC the tablet that has the described prescription of table 22 with comparing embodiment 6 described method preparations.

Table 22

Component	Mg/ sheet (target)	% tablet weight (w/w)	Mg/ sheet (acceptable scope)
				SNAC	250	32.1	242.5-257.5
Heparin sodium, USP (37,500 unit)	≤267.9	≤34.3	≤259.8-275.9
				Propylene glycol, USP/EP/JP	39.0	5.00	37.8-40.2
Capmul PG	78.0	10.00	75.7-80.3
				Bibasic Calcium Phosphate, anhydride, USP/EP (Anhyrdous Emcompress)	≥117.8	≥15.1	≥114.3-121.3
Silica sol, USP/NF/EP (Aerosil 200 VV Pharma)	15.6	2.00	15.1-16.1
				30 POVIDONE K 30 BP/USP 90, USP/EP/JP (Kollidon 90F)	3.90	0.50	3.8-4.0
Magnesium stearate, NF/EP/JP	7.8	1.00	7.6-8.0
				Gross weight	780.00	100.00	756.6-803.4

Comparing embodiment 8

The preparation of liquid heparin/SNAC

Preparation 18mL is introduced into WO01/34114 embodiment 1 described SNAC/ heparin solution as a reference here.This solution comprises 90,000IU heparin and 2430mg SNAC.

Embodiment 14

Give 15 individual described preparations of following table that use of human test, it was separated during the eluting by 72 hours.For each period, the patient enters a kind of fasting that begins from 10p.m. of clinical beginning the evening before administration.In the morning, under fasting state, it is carried out administration with these preparations.Table 23 is summarized to these periods with by the preparation of administration.

Table 23

Period	Preparation	Unit dose number (tablet, capsule)	Heparin total amount (IU)	SNAC total amount (mg)
					A	Comparing embodiment 5 (" SNAC contrasts dosage ")	3	0	1149
B	Embodiment	3, table 15C (" 1: 1 ratio of capsule ")	2	75,000						500
					C	Comparing embodiment 6 (" 1: 2.5 ratio of tablet ")	3	75,000	1149
D	Comparing embodiment 7 (" 1: 1 ratio of tablet ")	2	75,000	500
					E	Embodiment	3, table 15B (" 1: 2.5 ratio of capsule ")	3	75,000	1149
F	Comparing embodiment 8 (" liquid reference dosage ")	18	90,000	2430

For each period, anticoagulin Xa and the IIa activity and the aPTT time of measurement 15,30,45,60,90,120 and 480 minutes institute's blood samplings when preceding 10 minutes of administration of beginning, administration and after the administration.Anticoagulin Xa and IIa activity and aPTT time are the corresponding indicators of heparin, and provide the foundation for the bioavailability to each preparation compares.

For each sample period, the APTT of 15 individualities and anticoagulin IIa and Xa result are averaged, its result is as follows.

Table 24

Blood plasma aPTT (second) (standard deviation is as shown in round parentheses)

Time (minute)	Therapeutic scheme
							A	B	C	D	E	F
	-10	29.7 (3.0)	29.4 (2.1)	30.1 (3.4)	30.0 (2.4)	29.8 (2.5)							29.2 (2.5)
0							29.1 (2.5)	29.1 (2.1)	29.4 (2.5)	29.4 (2.2)	28.9 (2.0)	29.1 (2.7)
	15	30.1 (2.9)	31.6 (2.4)	37.5 (6.7)	32.4 (2.7)	32.7 (6.9)							41.1 (14.8)
30							29.5 (2.70)	75.1 (54.8)	51.6 (25.6)	37.1 (8.4)	89.1 (63.8)	52.1 (42.8)
	45	29.3 (2.6)	78.4 (56.4)	60.2 (48.1)	38.1 (12.9)	102.6 (72.1)							53.7 (43.2)
60							29.6 (2.4)	73.0 (57.8)	51.7 (32.6)	35.9 (11.4)	97.0 (72.7)	51.7 (43.0)
	90	29.4 (2.4)	50.8 (31.7)	41.5 (18.8)	32.8 (7.5)	79.7 (66.8)							44.2 (36.7)
120							29.7 (2.3)	39.5 (16.1)	34.0 (7.9)	30.4 (2.6)	60.9 (50.4)	36.3 (19.0)
	480	29.36 (2.6)	29.2 (2.0)	29.4 (2.5)	29.4 (2.5)	29.3 (2.3)							29.3 (2.2)

These results as shown in figure 16.

Table 25

The aPTT pharmacodynamic parameter

Therapeutic scheme	Emax, IU/ml (standard deviation)	Tmax, hr (intermediate value) *	EAUC (0-is last), (IU *Hr/mL) (standard deviation)	EAUC(0- inf)，(IU *Hr/mL) (standard deviation)
					A	1.51 (2.30)	0.75 (0.25-8.00)	2.634 (3.925)	2.634 (3.925)
B	56.14 (57.39)	0,50 (0.50-1.00)	84.100 (109.584)	84.100 (109.584)
					C	31.76 (47.78)	0.75 (0.50-1.00)	42.865 (66.157)	42.865 (66.157)
D	9.31 (11.70)	0.50 (0.25-0.75)	12.088 (15.239)	12.088 (15.239)
					E	80.30 (77.38)	0.75 (0.25-1.50)	184.236 (240.894)	184.236 (240.894)
F	25.89 (42.59)	0.75 (0.25-8.00)	55.308 (120.021)	55.308 (120.021)

Table 26

The aPTT pharmacodynamic analysis

Variable	Relatively	Test (LS average)	With reference to (LS average)	Difference	90% confidence interval
						EAC(0- LAST) (IU * hr/mL)	B-F	84.100	55.308	28.793	-31.3，88.87
C-F	42.865	55.308	-12.44	-72.5，47.64
					D-F		12.088	55.308	-43.22	-103，16.86
E-F	184.236	55.308	128.93	68.85，189.0
					E-B		184.236	84.100	100.14	40.06，160.2
C-A	42.865	2.634	40.231	-19.8，100.3
					C-D		42.865	12.088	30.777	-29.3，90.85
B-D	84.100	12.088	72.012	11.93，132.1
					E-A		184.236	2.634	181.60	121.5，241.7
E-C	184.236	42.865	141.37	81.29，201.4
					Emax (IU/ml)		B-F	56.143	25.887	30.257	8.011，52.50
C-F	31.757	25.887	5.870	-16.4，28.12
						D-F	9.310	25.887	-16.58	-38.8，5.669
E-F	80.303	25.887	54.417	32.17，76.66
						E-B	80.303	56.143	24.160	1.915，46.41
C-A	31.757	1.513	30.243	7.998，52.49
						C-D	31.757	9.310	22.447	0.201，44.69
B-D	56.143	9.310	46.833	24.59，69.08
						E-A	80.303	1.513	78.790	56.54，101.0
E-C	80.303	31.757	48.547	26.30，70.79

As table 24 and shown in Figure 16, the aPTT of appearance arranges from growing to lacking with following descending: 1: 1 ratio (therapeutic scheme D) of 1: 2.5 ratio (therapeutic scheme C) of 1: 1 ratio (therapeutic scheme B) of 1: 2.5 ratio (therapeutic scheme E) of Perle, Perle, tablet, liquid SNAC/ heparin dosage (therapeutic scheme F), tablet and SNAC contrast dosage (therapeutic scheme A).The increase of the aPTT of 1: 2.5 ratio of Perle is than high about 2.4 times of the increase of the tablet of 1: 2.5 ratio, than high about 3 times of liquid SNAC/ heparin dosage.

Shown in table 26, in the method for least square average is analyzed, based on 90% confidence interval around the aPTT result difference, the preparation that EAUC (0-is last) shows remarkable significant difference relatively contrasts dosage (therapeutic scheme A) for Perle 1: 2.5 ratio (therapeutic scheme E) with SNAC, capsule 1: 2.5 ratio (therapeutic scheme E) and liquid are with reference to dosage (therapeutic scheme F), capsule 1: 2.5 ratio (therapeutic scheme E) and 1: 1 ratio (therapeutic scheme B) of capsule, 1: 1 ratio (therapeutic scheme B) of 1: 2.5 ratio (therapeutic scheme C) of capsule 1: 2.5 ratio (therapeutic scheme E) and tablet and capsule and 1: 1 ratio (therapeutic scheme D) of tablet.The preparation that Emax shows remarkable significant difference is compared as follows: capsule and tablet 1: 2.5 ratio (therapeutic scheme E and C) and SNAC contrast dosage (therapeutic scheme A), 1: 2.5 ratio of capsule and 1: 1 ratio (E and B) with liquid with reference to dosage (therapeutic scheme F), capsule 1: 2.5 ratio (E) and 1: 1 ratio (therapeutic scheme B) of capsule, capsule 1: 2.5 ratio (E) and 1: 2.5 ratio (therapeutic scheme C) of tablet, 1: 1 ratio (therapeutic scheme D) of capsule 1: 1 ratio (therapeutic scheme B) and tablet and tablet 1: 2.5 ratio (therapeutic scheme C) and 1: 1 ratio (therapeutic scheme D) of tablet.

Table 27

Anticoagulin IIa plasma concentration (IU/mL)

(standard deviation is as shown in round parentheses)

Time (minute)	Therapeutic scheme
							A	B	C	D	E	F
	-10	BLQ *	BLQ	BLQ	BLQ	BLQ							BLQ
0							BLQ	BLQ	BLQ	BLQ	BLQ	BLQ
	15	BLQ	0.07 (0.05)	0.12 (0.04)	0.08 (0.05)	0.07 (0.06)							0.11 (0.08)
30							BLQ	0.30 (0.20)	0.20 (0.11)	0.12 (0.08)	0.33 (0.23)	0.15 (0.16)
	45	BLQ	0.33 (0.22)	0.21 (0.13)	0.12 (0.10)	0.40 (0.33)							0.16 (0.17)
60							BLQ	0.29 (0.21)	0.20 (0.13)	0.10 (0.11)	0.39 (0.34)	0.15 (0.18)
	90	BLQ	0.20 (0.16)	0.14 (0.10)	BLQ	0.31 (0.31)							0.11 (0.15)
120							BLQ	0.14 (0.13)	0.10 (0.07)	BLQ	0.23 (0.24)	0.08 (0.11)
	480	BLQ	BLQ	BLQ	BLQ	BLQ							BLQ

^*The average that is lower than 0.05IU/mL is represented as and is lower than quantitative limit (BLQ).In order to add up, each value that is lower than quantitative limit (BLQ) is set to 0.025IU/ml.

The above results in 120 minutes as shown in figure 17.

Table 28

Blood plasma anticoagulin IIa pharmacodynamic parameter

Therapeutic scheme	Emax, IU/ml (standard deviation)	Tmax, hr (intermediate value) *	EAUC (0-is last), (IU *Hr/mL) (standard deviation)	EAUC(0-inf)， (IU *Hr/mL) (standard deviation)
					A	0.04 (0.04)	0.50 (0.25-8.00)	0.262 (0.261)	0.324 (0.236)
B	0.36 0.22	0.75 (0.50-1.00)	0.714 (0.771)	0.905 (0.786)
					C	0.22 0.13	0.75 (0.50-1.00)	0.566 (0.391)	0.715 (0.411)
D	0.13 0.10	0.50 (0.25-1.00)	0.369 (0.369)	0.418 (0.364)
					E	0.42 0.34	0.75 (0.50-1.00)	1.116 (1.167)	1.511 (1.214)
F	0.16 0.1 8	0.50 (0.25-1.00)	0.349 (0.301)	0.545 (0.636)

Table 29

Anticoagulin IIa pharmacodynamic analysis

Variable	Relatively	Test (LS average)	With reference to (LS average)	Difference	90% confidence interval
						EAC(0- LAST) (IU * hr/mL)	B-F	0.714	0.357	0.357	-0.029，0.744
C-F	0.571	0.357	0.214	-0.180，0.608
					D-F		0.363	0.357	0.006	-0.403.0.414
E-F	1.112	0.357	0.755	0.353，1.157
					E-B		1.112	0.714	0.398	0.011，0.784
C-A	0.571	0.447	0.124	-0.337，0.585
					C-D		0.571	0.363	0.208	-0.196，0.613
B-D	0.714	0.363	0.352	-0.045，0.748
					E-A		1.112	0.447	0.665	0.195，1.135
E-C	1.112	0.571	0.541	0.149，0.933
					Emax (IU/ml)		B-F	0.357	0.163	0.194	0.104，0.284
C-F	0.220	0.163	0.057	-0.033，0.146
						D-F	0.128	0.163	-0.035	-0.125，0.054
E-F	0.416	0.163	0.253	0.163，0.342
						E-B	0.416	0.357	0.059	-0.031，0.148
C-A	0.220	0.043	0.177	0.088，0.267
						C-D	0.220	0.128	0.092	0.002，0.182
B-D	0.357	0.128	0.229	0.140，0.319
						E-A	0.416	0.043	0.373	0.284，0.463
E-C	0.416	0.220	0.196	0.106，0.286

As table 27 and shown in Figure 17, the anticoagulin IIa mean concentration that occurs is arranged from high to low with following descending: 1: 2.5 ratio (therapeutic scheme C) of 1: 1 ratio (therapeutic scheme B) of 1: 2.5 ratio (therapeutic scheme E) of Perle, Perle, tablet, liquid SNAC/ heparin dosage (therapeutic scheme F), 1: 1 ratio (therapeutic scheme D) of tablet and SNAC contrast dosage (therapeutic scheme A).The increase of the anticoagulin IIa of Perle 1.2.5 ratio and anticoagulin Xa mean concentration all than 1: 2.5 tablet high about 2 times and than liquid with reference to high about 2.5 times of dosage.

Shown in table 29, in the method for least square average is analyzed, based on 90% confidence interval around the anticoagulin IIa result difference, the preparation that EAUC (0-is last) shows remarkable significant difference is capsule 1: 2.5 ratio (therapeutic scheme E) and SNAC contrasts dosage (therapeutic scheme A), liquid with reference to dosage (F) and tablet 1: 2. ratio (therapeutic scheme C).The preparation that Emax shows statistically-significant difference is compared as follows: capsule and tablet 1: 2.5 ratio (therapeutic scheme E and C) and SNAC contrast dosage (therapeutic scheme A), capsule 1: 2.5 and 1: 1 ratio (therapeutic scheme E and B) with liquid with reference to dosage (therapeutic scheme F), capsule 1: 2.5 ratio (therapeutic scheme E) and 1: 2.5 ratio (therapeutic scheme C) of tablet, 1: 1 ratio (therapeutic scheme D) of capsule 1: 1 ratio (therapeutic scheme B) and tablet and tablet 1: 2.5 ratio (therapeutic scheme C) and 1: 1 ratio (therapeutic scheme D) of tablet.

Table 30

Anticoagulin Xa plasma concentration (IU/mL)

(standard deviation is as shown in round parentheses)

Time (minute)	Therapeutic scheme
							A	B	C	D	E	F
	-10	BLQ *	BLQ	BLQ	BLQ	BLQ							BLQ
0							BLQ	BLQ	BLQ	BLQ	BLQ	BLQ
	15	BLQ	BLQ	0.11 (0.07)	0.06 (0.04)	0.07 (0.04)							0.11 (0.08)
30							BLQ	0.34 (0.28)	0.19 (0.14)	0.10 (0.07)	0.31 (0.22)	0.16 (0.16)
	45	BLQ	0.32 (0.22)	0.21 (0.18)	0.10 (0.10)	0.42 (0.33)							0.16 (0.17)
60							BLQ	0.28 (0.20)	0.21 (0.18)	BLQ	0.42 (0.36)	0.16 (0.19)
	90	BLQ	0.17 (0.14)	0.13 (0.12)	BLQ	0.31 (0.31)							0.12 (0.17)
120							BLQ	0.11 (0.11)	0.09 (0.08)	BLQ	0.23 (0.24)	0.09 (0.13)
	480	BLQ	BLQ	BLQ	BLQ	BLQ							BLQ

^*The average that is lower than 0.05IU/mL is represented as and is lower than quantitative limit (BLQ).In order to add up, each value that is lower than quantitative limit (BLQ) is set to 0.025IU/ml.

These results as shown in figure 18.

Table 31

Blood plasma anticoagulin Xa pharmacodynamic parameter

Therapeutic scheme	Emax, the IU/ml standard deviation)	Tmax, hr (intermediate value)	EAUC (0-is last), (IU *Hr/mL) (standard deviation)	EAUC(0- inf)，(IU *Hr/mL) (standard deviation)
					A	0.00 0.02	2.00 (2.00-2.00)	0.048	0.258
B	0.38 0.30	0.50 (0.50-1.00)	0.383 (0.295)	0.689 (0.626)
					C	0.22 0.18	0.75 (0.25-1.00)	0.296 (0.252)	0.552 (0.525)
D	0.11 0.10	0.50 (0.25-1.00)	1.162 (0.145)	0.297 (0.271)
					E	0.44 0.36	0.75 (0.50-1.00)	0.876 (0.729)	1.563 (1.198)
F	0.17 0.20	0.75 (0.25-1.00)	0.377 (0.394)	0.621 (0.758)

Table 32

Anticoagulin Xa pharmacodynamic analysis

Variable	Relatively	Test (LS average)	With reference to (LS average)	Difference	90% confidence interval
						EAC(0- LAST) (IU *hr/mL)	B-F	0.383	0.338	0.045	-0.148，0.238
C-F	0.274	0.338	-0.064	-0.261，0.133
					D-F		0.102	0.338	-0.236	-0.449，-0.024
E-F	0.877	0.338	0.538	0.334，0.743
					E-B		0.877	0.338	0.493	0.301，0.686
C-A	0.274	0.197	0.077	-0.469，0.623
					C-D		0.274	0.102	0.172	-0.029，0.373
B-D	0.383	0.102	0.281	0.083，0.480
					E-A		0.877	0.197	0.680	0.131，1.228
E-C	0.877	0.274	0.603	0.406，0.800
					Emax (IU/ml)		B-F	0.377	0.175	0.202	0.098，0.306
C-F	0.224	0.175	0.049	-0.055，0.153
						D-F	0.106	0.175	-0.069	-0.173，0.035
E-F	0.443	0.175	0.268	0.164，0.372
						E-B	0.443	0.377	0.066	-0.038，0.170
C-A	0.224	0.005	0.219	0.115，0.323
						C-D	0.224	0.106	0.118	0.014，0.222
B-D	0.377	0.106	0.271	0.167，0.375
						E-A	0.443	0.005	0.438	0.334，0.542
E-C	0.443	0.224	0.219	0.115，0.323

As table 30 and shown in Figure 180, the anticoagulin Xa mean concentration of appearance is arranged from high to low with following descending: 1: 1 ratio (therapeutic scheme D) of 1: 2.5 ratio (therapeutic scheme C) of 1: 1 ratio (therapeutic scheme B) of 1: 2.5 ratio (therapeutic scheme E) of Perle, Perle, tablet, liquid SNAC/ heparin dosage (therapeutic scheme F), tablet and SNAC contrast dosage (therapeutic scheme A).The increase of Perle 1.2.5 ratio anticoagulin Xa mean concentration than 1: 2.5 tablet high about 2 times and than liquid with reference to high about 2.5 times of dosage.

In the method for least square average is analyzed, based on 90% confidence interval around the anticoagulin Xa result difference, the preparation that EAUC (0-is last) shows remarkable significant difference be Perle 1: 2.5 ratio (E) with SNAC contrast dosage (A), capsule 1: 2.5 ratio (E) and liquid with reference to 1: 1 ratio (B) of 1: 2.5 ratio (C) of 1: 1 ratio (D) of 1: 1 ratio (B) of dosage (F), capsule 1: 2.5 ratio (E) and capsule, tablet 1: 2.5 ratio (C) and tablet, capsule 1: 2.5 ratio (E) and tablet and capsule and 1: 1 ratio (D) of tablet.The preparation that Emax shows statistically-significant difference is compared as follows: 1: 2.5 ratio (E) of Perle and tablet 1: 2.5 ratio (C) and SNAC contrast dosage (A), capsule 1: 2.5 and 1: 1 ratio (E and B) with liquid with reference to 1: 1 ratio (B) of 1: 2.5 ratio (C) of 1: 1 ratio (D) of dosage (F), tablet 1: 2.5 ratio (C) and tablet, capsule 1: 2.5 ratio (E) and tablet and capsule and 1: 1 ratio (D) of tablet.

Table 33

Blood plasma SNAC pharmacokinetic parameters

Therapeutic scheme	Cmax， ng/ml (SD)	Tmax， hr (SD)	AUC (0-is last), ng *hr/ml (SD)	AUC(0- inf)， ng *hr/ml (SD)	CL/F， L/hr (SD)	KeL (λz)(hr)	t 1/2， hr (SD)	VZ/F (L) (SD)
									A	5573.1 (2293.9)	0.50 (0.25- 2.00)	5239.74 (1615.83)	5448.01 (1604.81)	227.3 (61.2)	0.4903 (0.1395)	1.50 (0.33)	497.5 (207.0)
B	3041.7 (1105.7)	0.50 (0.25- 1.00)	2261.17 (563.76)	2293.28 (561.78)	230.0 (55.3)	0.8311 (0.7110)	1.21 (0.52)	417.0 (229.1)
									C	6463.3 (4252.6)	0.25 (0.25- 1.00)	5887.55 (2079.82)	5977.66 (2056.15)	206.4 (46.9)	0.4820 (0.1371)	1.55 (0.45)	475.2 (213.6)
D	2481.3 (1104.0)	0.25 (0.25- 0.50)	1967.73 (421.50)	2002.92 (418.81)	260.1 (55.6)	0.7755 (0.7636)	1.35 (0.61)	519.2 (311.4)
									E	6539.7 (3804.8)	0.50 (0.25- 1.00)	5913.98 (1641.69)	5954.53 (1633.97)	204.0 (44.6)	0.5953 (0.0861)	1.19 (0.17)	351.1 (95.1)
F	14254.0 (7153.3)	0.25 (0.25- 1.00)	13052.1 (4554.21)	13162.6 (4541.42)	205.5 (67.7)	0.6112 (0.1258)	1.19 (0.29)	361.1 (181.2)

Figure 19 and 20 has represented after administration high blood plasma SNAC concentration to 8 hours and 2 hours respectively.

In active each labelling of anticoagulant, the anticoagulation that these capsule preparations produced is higher than tablet formulation or liquid with reference to the (effect of 90,000 units/2430mg) produced of the similar dosage in the dosage.In capsule preparations, 0.38 with 0.44IU/mL under average maximum anticoagulin Xa concentration similar to 1: 1 respectively with 1: 2.5 ratio dosage group.But the EAUC value of same dose group is respectively 0.38 and 0.88IU ^*Hr/mL shows that the persistent period of viewed effect in 1: 2.5 ratio dosage group is longer.

The Emax value that this Perle produced is higher 2 to 3 times than tablet and liquid preparation.

Proof SNAC contrast dosage does not have inherent anticoagulating active.All treatments can be tolerated by individuality well.

Embodiment 15

Have the Perle of filling a prescription shown in table 35a and the 35b with embodiment 3 described methods (its exception is as follows) preparation:

Table 35a

Component	The mg/ capsule	The % capsules weight
			SNAC	250.00	21.37
Heparin sodium, USP (15,000 unit)	267.18	22.89
			Liquid Macrogol, NF (PEG 300)	402.70	34.42
Capmul PG8	164.00	14.02
			Purify waste water USP	81.99	7.00
Oleum Glycines, USP, super refining	1.17	0.10
			Polysorbate80	2.34	0.24
Gross weight	1,170.00	100

Table 35b

Component	The mg/ capsule	The % capsules weight
			SNAC	250.0	21.37
Heparin sodium, USP (25,000 unit)	267.86	22.89
			Liquid Macrogol, NF (PEG 300)	405.00	34.62
Capmul PG8	164.00	14.02
			Purify waste water USP	81.99	7.00
Oleum Glycines, USP, super refining	1.15	0.10
			Gross weight	1,170.00	100

For the described preparation of table 35a, with polysorbate80 with Capryol 90, purify waste water and Oleum Glycines is put in the rustless steel container, thereby carried out the grinding granularity with ball mill and be lower than 100 microns heparin to wherein adding with #140 mesh sieve.Aggregation suspension in the table 35a described preparation also is ground to granularity＜180 micron with MZ80/A Fryma colloid mill.

For the preparation of preparation of table 35b, not with polysorbate80 and Polyethylene Glycol (PEG) 300, Capryol 90 (Capmul ^PG8), purify waste water and Oleum Glycines adds together, also heparin is ground with the #80 mesh sieve, but this suspension is ground without colloid mill.Table 35a is described with the table 36 that the granularity of showing the 35b preparation is compared as follows face.

Table 36

The granularity data of preparation among table 35a and the 35b

Granule	Preparation among the table 35a	Preparation among the table 35b
			Carried out the heparin that grinds	＜100 microns	＜180 microns
Suspension (to grind number)	Target :≤180 microns 80 microns (initial aggregation)	Target≤180 micron 200 microns (initial aggregation) 160 microns (last aggregation)

Embodiment 16

Three kinds of different media (promptly purify waste water, 0.1N HCl (pH1.2 (simulated gastric fluid w/o pepsin)) and 6.8 phosphate buffer (simulated intestinal fluids, pH6.8 (w/o pancreatin)) under 37+/-0.5 ℃, is being furnished with the disintegrative of measuring the Perle that as described in the embodiment 15, makes in the #35-1000 type device (Cary, North Carolina) of 65-2000 type heater circulator in.The result is as follows.

Table 37

The disintegrate data

The disintegrate medium	Preparation among the table 35a	Preparation among the table 35b
			Mimic gastric juice, pH 1.2 (w/o pepsin)	6 minutes 15 seconds	4 minutes 31 seconds
Mimic intestinal juice, pH 6.8 (w/o pancreatin)	Do not survey	5 minutes 14 seconds
			Purify waste water	Do not survey	4 minutes 57 seconds

The stripping property of two kinds of preparations above in the phosphate buffer (simulated intestinal fluid) of 37 ± 0.5 ℃ pH6.8, under 75RPM, measuring in the superincumbent Vankel disintegrate device.The result of preparation shown in the table 35a as shown in figure 21.The result of preparation shown in the table 35b as shown in figure 22.

Embodiment 17

Will be as 4 beasle dogs that the Perle of filling a prescription shown in table 35a and the 35b delivers medicine to the about 8kg of body weight that have that make like that as described in the embodiment 15.Before administration,, food was put back in about 4 hours after with said solid administration these dog fasting at least 8 hours.Each dosage form is delivered to the rear portion in its oral cavity with hands.After placing this dosage form, in the oral cavity, use the 5ml reverse osmosis water and swallow with help.After transmission, check that its oral cavity is to guarantee that this solid is swallowed.Study with interleaved mode, the eluting phase is a week.

Time about 240 minutes after the measurement administration is interior by the anticoagulin Xa in the plasma sample of animal jugular vein, cephalic vein or saphena acquisition.From these dot cycle samplings.

The result is average, and it as shown in figure 23.

Embodiment 18

To deliver medicine to 4 Rhesus monkeys (1 piece of capsule/monkey) as the Perle of filling a prescription shown in table 35a and the 35b that has that makes like that as described in the embodiment 15 in the following method.

Before experiment, be Rhesus monkey fasting a whole night of 5.3 to 6.9kg with body weight and food put back in about 6 hours after with said solid administration.Each dosage form is delivered to the rear portion in animal oral cavity with delivery tube.After placing this dosage form, in the oral cavity, use the 5ml reverse osmosis water and swallow with help.After transmission, check that its oral cavity is to guarantee that this solid is swallowed.Study with interleaved mode, the eluting phase is a week.

The antagonism factor Xa is measured in about 400 minutes after administration.

The result is average, and it as shown in figure 24.

Embodiment 19

To deliver medicine to 4 beasle dogs as the Perle of filling a prescription shown in table 35a and the 35b that has that makes like that as described in the embodiment 15 in a kind of crossing research scheme, the eluting phase of this scheme is a week.Before administration,, after administration, food was put back in about 2 hours these Canis familiaris L. fasting a whole nights.With the pill rifle each dosage form is delivered to its rear portion, oral cavity.After placing this dosage form, in the oral cavity, use the 5ml reverse osmosis water and swallow with help.After transmission, check that its oral cavity is to guarantee that this solid is swallowed.

In about 360 minutes period, the thrombin xa activity is measured.The result is as described in following 38:

Table 38

Anticoagulin Xa pharmacokinetics result

Statistics	Preparation	Canis familiaris L.	C max(IU/mL)	T max(min)	AUC last
							Table 35a	A	1.03	50.0	104
	Table 35a	B	1.08	50.0	97.5

	Table 35a	C	0.340	40.0	20.8
							Table 35a	D	1.21	50.0	143
Average	Table 35a		0.915	47.5	31.2
						SD	Table 35a		0.391	5.00	51.0
％CV	Table 35a		42.7	10.5	56.0
							Table 35b	A	0.280	50.0	8.80
	Table 35b	B	0.490	50.0	32.8
							Table 35b	C	0.260	60.0	7.70
	Table 35b	D	0.370	30.0	28.9
						Average	Table 35b		0.350	47.5	19.5
SD	Table 35b		0.105	12.6	13.1
						％CV	Table 35b		30.0	26.5	67.2

Average anticoagulin Xa concentration in 240 minutes as shown in figure 25.

Embodiment 20

To deliver medicine to 4 Rhesus monkeys as the Perle of filling a prescription shown in table 35a and the 35b that has that makes like that as described in the embodiment 15 in a kind of crossing research scheme, the eluting phase of this scheme is a week.Before administration,, after administration, food was put back in about 2 hours these monkey fasting a whole nights.With the pill rifle each dosage form is delivered to its rear portion, oral cavity.After placing this dosage form, in the oral cavity, use the 5ml reverse osmosis water and swallow with help.After transmission, check that its oral cavity is to guarantee that this solid is swallowed.

Antagonism thrombin xa activity is measured in about 360 minutes.The result is as described in the following table 38.

Table 38

Anticoagulin Xa pharmacokinetics result

Statistics	Preparation	Canis familiaris L.	C max (IU/mL)	T max(min)	AUC last
							Table 35a	A	0.810	50.0	144
	Table 35a	B	0.810	90.0	182
							Table 35a	C	2.60	120	509
	Table 35a	D	0.790	50.0	152
						Average	Table 35a		1.25	77.5	247
SD	Table 35a		0.898	34.0	176
						％CV	Table 35a		71.7	43.9	71.3
	Table 35b	A	0.570	90.0	54.3

	Table 35b	B	0.520	90.0	53.1
							Table 35b	C	3.70	90.0	760
	Table 35b	D	0.930	90.0	152
						Average	Table 35b		1.43	90.0	255
SD	Table 35b		1.52	0	340
						％CV	Table 35b		107	0	133

Patent recited above, application, test method and publication here all are incorporated herein by reference.

According to top detailed description, those skilled in the art can easily recognize many modification of the present invention.All such tangible modification all drop in the claimed scope of claims fully.

Claims (129)

1. solid composite medicament, this solid composite medicament comprises:

(a) delivery agent; With

(b) wetted heparin.

2. solid composite medicament as claimed in claim 1, wherein said delivery agent is

Wherein

R ¹, R ², R ³And R ⁴Be independently hydrogen ,-OH ,-NR ⁶R ⁷, halogen, C ₁-C ₄Alkyl or C ₁-C ₄Alkoxyl;

R ⁵Be to be substituted or unsubstituted C ₂-C ₁₆Alkylidene, be substituted or unsubstituted C ₂-C ₁₆Alkylene group, be substituted or unsubstituted C ₁-C ₁₂Alkyl (arlydene) or be substituted or unsubstituted aryl (C ₁-C ₁₂Alkylidene); With

R ⁶And R ⁷Be hydrogen, oxygen or C independently ₁-C ₄Alkyl.

3. solid composite medicament as claimed in claim 2, wherein said delivery agent are selected from that N-(8-[2-hydroxy benzoyl]-amino) is sad, N-(10-[2-hydroxy benzoyl] amino) capric acid, 8-(N-2-hydroxyl-5-chlorobenzene formacyl) aminocaprylic acid, 8-(N-2-hydroxyl-4-anisoyl) aminocaprylic acid, 4-[(4-chloro-2-hydroxy benzoyl)-amino] butanoic acid, its pharmaceutically useful salt, with and composition thereof.

4. solid composite medicament as claimed in claim 3, wherein said delivery agent are N-[8-(2-hydroxy benzoyl) amino] sad or its pharmaceutically useful salt.

5. solid composite medicament as claimed in claim 4, wherein said delivery agent are N-[8-(2-hydroxy benzoyl) amino] sad single sodium.

6. solid composite medicament as claimed in claim 4, wherein said delivery agent are N-(10-[2-hydroxy benzoyl] amino) capric acid or its pharmaceutically useful salt.

7. as any described solid composite medicament among the claim 1-6, the heparin in the wherein said wetted heparin be selected from unassorted heparin, Hirudoid, dermatan class, chrondroitin class, low molecular weight heparin, super low molecular heparin, ultra-low molecular weight heparin, with and composition thereof.

8. as any described solid composite medicament among the claim 1-6, the heparin in the wherein said wetted heparin is unassorted heparin.

9. as any described solid composite medicament among the claim 1-6, the heparin in the wherein said wetted heparin is a low molecular weight heparin.

10. as any described solid dosage forms among the claim 1-6, the heparin in the wherein said wetted heparin is a super low molecular heparin.

11. as any described solid composite medicament among the claim 1-6, the heparin in the wherein said wetted heparin is a super low molecular heparin.

12. as any described solid composite medicament among the claim 1-11, the delivery agent in the wherein said wetted heparin and the proportion of heparin (the mg number suitable with USP unit) are about 1: 20 to about 1: 400.

13. as any described solid composite medicament among the claim 1-12, wherein said delivery agent and wetted heparin quilt gelling together.

14. as any described solid composite medicament among the claim 1-13, it also comprises gellant.

15. as any described solid composite medicament among the claim 1-13, wherein said solid composite medicament comprises the delivery agent of the agglomerative quantity that is enough to cause said delivery agent and wetted heparin.

16. as any described solid composite medicament in claim 1-13 and 15, wherein said wetted heparin comprises heparin and wetting agent.

17. solid composite medicament as claimed in claim 16, wherein said delivery agent is partly dissolved by said wetting agent.

18. solid dosage forms that comprises as any described solid composite medicament of claim in front.

19. solid dosage forms as claimed in claim 18, wherein said solid dosage forms is a tablet.

20. solid dosage forms as claimed in claim 18, wherein said solid dosage forms is a capsule.

21. solid dosage forms as claimed in claim 20, wherein said solid dosage forms is a Perle.

22. solid dosage forms as claimed in claim 20, wherein said solid dosage forms is a hard gelatin capsule.

23. as any described solid composite medicament of claim in front, wherein the dosage of said heparin is higher than about 150,000 IU.

24. solid composite medicament as claimed in claim 23, wherein the dosage of said heparin is that about 15,000 IU are to about 150,000 IU.

25. solid composite medicament as claimed in claim 24, wherein the dosage of said heparin is that about 25,000 IU are to about 90,000 IU.

26. solid composite medicament as claimed in claim 25, wherein the dosage of said heparin is about 30,000 IU to about 80,000IU.

27. solid composite medicament as claimed in claim 26, wherein the dosage of said heparin is that about 37,500 IU are to about 75,000 IU.

28. solid composite medicament as claimed in claim 27, wherein the dosage of said heparin is about 37,500 IU.

29. solid composite medicament as claimed in claim 27, wherein the dosage of said heparin is about 40,000 IU.

30. solid composite medicament as claimed in claim 27, wherein the dosage of said heparin is about 50,000 IU.

31. solid composite medicament as claimed in claim 27, wherein the dosage of said heparin is about 60,000 IU.

32. solid composite medicament as claimed in claim 27, wherein the dosage of said heparin is about 75,000 IU.

33. as the described solid composite medicament of claim 1-32, wherein the dosage of said SNAC is lower than about 2.4g.

34. solid composite medicament as claimed in claim 33, wherein the dosage of said SNAC is lower than about 2.2g.

35. solid composite medicament as claimed in claim 34, wherein the dosage of said SNAC is lower than about 1.8g.

36. solid composite medicament as claimed in claim 35, wherein the dosage of said SNAC is lower than about 1.2g.

37. 36 solid composite medicament as claimed in claim, wherein the dosage of said SNAC is lower than about 1g.

38. solid composite medicament as claimed in claim 37, wherein the dosage of said SNAC is lower than about 0.9g.

39. solid composite medicament as claimed in claim 38, wherein the dosage of said SNAC is lower than about 0.8g.

40. solid composite medicament as claimed in claim 39, wherein the dosage of said SNAC is lower than about 0.7g.

41. solid composite medicament as claimed in claim 40, wherein the dosage of said SNAC is lower than about 0.6g.

42. solid composite medicament as claimed in claim 41, wherein the dosage of said SNAC is less than or equal to about 0.5g.

43. as the described solid composite medicament of claim 1-32, wherein the dosage of said SNAC is that about 50mg is to about 2.4g.

44. solid composite medicament as claimed in claim 43, wherein the dosage of said SNAC is that about 100mg is to about 1.2g.

45. solid composite medicament as claimed in claim 44, wherein the dosage of said SNAC is that about 900mg is to about 1.2g.

46. solid composite medicament as claimed in claim 45, wherein the dosage of said SNAC is about 1.15g.

47. solid composite medicament as claimed in claim 46, wherein the dosage of said SNAC is that about 125mg is to about 1g.

48. solid composite medicament as claimed in claim 47, wherein the dosage of said SNAC is that about 250mg is to about 750mg.

49. solid composite medicament as claimed in claim 48, wherein the dosage of said SNAC is that about 400mg is to about 600mg.

50. solid composite medicament as claimed in claim 49, wherein the dosage of said SNAC is about 500mg.

51. heparin is delivered medicine to the method for animal, and it comprises the step of carrying out administration with as any described solid composite medicament of claim in front or dosage form.

52. treatment or prevention animal thrombotic method, it comprise orally use antithrombotic form effective dose as any described solid composite medicament or dosage form among the claim 1-50.

53. being dvts, method as claimed in claim 52, wherein said thrombosis form or pulmonary infarction.

54. as claim 51 or 52 described methods, wherein compare with the not therapeutic state of same individual, said effective dose is enough to aPTT is increased at least about 100%.

55. method as claimed in claim 54 is wherein compared with the not therapeutic state of same individual, said effective dose is enough to aPTT is increased at least about 150%.

56. method as claimed in claim 55 is wherein compared with the not therapeutic state of same individual, said effective dose is enough to aPTT is increased at least about 165%.

57. method as claimed in claim 56 is wherein compared with the not therapeutic state of same individual, said effective dose is enough to aPTT is increased at least about 200%.

58. as the described method of claim 51-57, wherein said effective dose is enough to anticoagulin Xa is increased to about 0.05 to about 0.4 IU/ml.

59. method as claimed in claim 58, wherein said effective dose are enough to anticoagulin Xa is increased to about 0.15 to about 0.35 IU/ml.

60. method as claimed in claim 59, wherein said effective dose are enough to anticoagulin Xa is increased to about 0.15 to about 0.20 IU/ml.

61. method as claimed in claim 60, wherein said effective dose are enough to anticoagulin Xa is increased to about 0.2 IU/ml.

62. as the described method of claim 51-57, wherein said effective dose is enough to anticoagulin Xa increased to and is higher than about 0.05 IU/ml.

63. being enough to anticoagulin Xa increased to, method as claimed in claim 62, wherein said effective dose be higher than about 0.1 IU/ml.

64. as the described method of claim 63, wherein said effective dose is enough to anticoagulin Xa increased to and is higher than about 0.15 IU/ml.

65. a method for preparing the solid dosage forms that comprises wetted heparin, its step that comprises has:

(a) delivery agent and heparin are mixed;

(b) thus this delivery agent and heparin joined obtain a kind of compositions that comprises wetted heparin in the wetting agent.

66. as the described method of claim 65, the heparin in the wherein said wetted heparin be selected from unassorted heparin, Hirudoid, dermatan class, chrondroitin class, low molecular weight heparin, super low molecular heparin, ultra-low molecular weight heparin, with and composition thereof.

67. as the described method of claim 65, the heparin in the wherein said wetted heparin is unassorted heparin.

68. as the described method of claim 65, the heparin in the wherein said wetted heparin is a low molecular weight heparin.

69. as the described solid dosage forms of claim 65, the heparin in the wherein said wetted heparin is a super low molecular heparin.

70. as the described method of claim 65, the heparin in the wherein said wetted heparin is a ultra-low molecular weight heparin.

71. an improvement comprises the method for bioavailability of the solid heparin dosage form of not wetted heparin, it step that comprises has:

(a) replace heparin not wetted in this dosage form with wetted heparin.

72. as the described method of claim 71, the heparin in the wherein said wetted heparin be selected from unassorted heparin, Hirudoid, dermatan class, chrondroitin class, low molecular weight heparin, super low molecular heparin, ultra-low molecular weight heparin, with and composition thereof.

73. as the described method of claim 71, the heparin in the wherein said wetted heparin is unassorted heparin.

74. as the described method of claim 71, the heparin in the wherein said wetted heparin is a low molecular weight heparin.

75. as the described method of claim 71, the heparin in the wherein said wetted heparin is a super low molecular heparin.

76. as the described method of claim 71, the heparin in the wherein said wetted heparin is a ultra-low molecular weight heparin.

77. a prevention animal thrombotic method, it comprise orally use antithrombotic form effective dose as any described solid composite medicament or dosage form among the claim 1-50.

78. as the described method of claim 77, wherein said thrombosis is that dvt forms or pulmonary infarction.

79. as claim 77 or 78 described methods, wherein compare with the not therapeutic state of same patient, said effective dose is enough to the aPTT increase is less than or equal to about 10%.

80. as the described method of claim 79, wherein said effective dose is enough to aPTT is increased about 10%.

81. as the described method of claim 80, wherein with do not treat the patient and compare and do not observe thrombosis or thrombosis quantity and reduce.

82. as claim 77 or 78 described methods, wherein compare with the not therapeutic state of same patient, said effective dose is enough to the aPTT increase is higher than about 10%.

83. as the described method of claim 77-82, wherein said effective dose is enough to anticoagulin Xa is increased to about 0.05 to about 0.4 IU/ml.

84. as the described method of claim 83, wherein said effective dose is enough to anticoagulin Xa is increased to about 0.15 to about 0.35 IU/ml.

85. as the described method of claim 84, wherein said effective dose is enough to anticoagulin Xa is increased to about 0.25 IU/ml.

86. as any thrombotic method of the described treatment of claim animal in front, wherein said animal is a mammal.

87. as the method that the described treatment of claim 86 mammal thrombosis forms, wherein said mammal is the people.

88. as any thrombotic method of the described prevention of claim animal in front, wherein said animal is a mammal.

89. as the method that the described prevention of claim 88 mammal thrombosis forms, wherein said mammal is the people.

90. a solid composite medicament, it comprises:

(a) SNAC and

(b) wetted heparin,

Wherein:

(1) solid composite medicament of the present invention is administered orally in behind the people 120 minutes, this people by administration shows and is significantly higher than the combination that will not comprise wetted heparin but comprise blood plasma aPTT, anticoagulin IIa plasma concentration, anticoagulin Xa plasma concentration or above-mentioned any index of the level that obtained in 120 minutes behind the same combination oral administration of not wetted heparin statistically, or

(2) after solid composite medicament of the present invention is administered orally in the people, this people by administration shows and is significantly higher than the combination that will not comprise wetted heparin but comprise aPTT Emax, aPTT EAUC (0-inf), anticoagulin IIa Emax, anticoagulin IIa EAUC (0-inf), anticoagulin Xa Emax, anticoagulin Xa EAUC (0-inf) or above-mentioned any index of the level that obtains behind the same combination oral administration of not wetted heparin statistically, or

(3) the two all is.

91. as the described solid composite medicament of claim 90, the heparin in the wherein said wetted heparin be selected from unassorted heparin, Hirudoid, dermatan class, chrondroitin class, low molecular weight heparin, super low molecular heparin, ultra-low molecular weight heparin, with and composition thereof.

92. as the described solid composite medicament of claim 90, the heparin in the wherein said wetted heparin is unassorted heparin.

93. as the described solid composite medicament of claim 90, the heparin in the wherein said wetted heparin is a low molecular weight heparin.

94. as the described solid composite medicament of claim 90, the heparin in the wherein said wetted heparin is a super low molecular heparin.

95. as the described solid composite medicament of claim 90, the heparin in the wherein said wetted heparin is a ultra-low molecular weight heparin.

96. a solid composite medicament, it comprises:

(a) SNAC and

(b) wetted heparin,

Wherein:

(1) after solid composite medicament of the present invention is administered orally in the people 120 minutes, this people by administration showed the situation below one or more:

(i) at least about 38 seconds blood plasma aPTT,

The (ii) anticoagulin IIa plasma concentration of 0.11IU/ml at least, or

The (iii) anticoagulin Xa plasma concentration of 0.1IU/ml at least,

(2) after solid composite medicament of the present invention is administered orally in the people, this people by administration shows the situation below one or more:

(i) at least about the aPTT Emax of 50 IU/ml,

(ii) at least about the aPTT EAUC (0-inf) of 80 IU*hr/ml,

(iii) at least about the anticoagulin IIa Emax of 0.35 IU/ml,

(iv) at least about the anticoagulin IIa EAUC (0-inf) of 0.7 IU*hr/ml,

(v) at least about the anticoagulin Xa Emax of 0.35IU/ml,

(vi) at least about the anticoagulin Xa EAUC (0-inf) of 0.68 IU*hr/ml, or

(3) the two all is.

97. as the described solid composite medicament of claim 96, wherein said people shows the blood plasma aPTT at least about 39 seconds.

98. as the described solid composite medicament of claim 96, wherein said people shows the blood plasma aPTT at least about 50 seconds.

99. as the described solid composite medicament of claim 96, wherein said people shows the anticoagulin IIa plasma concentration at least about 0.2IU/ml.

100. as the described solid composite medicament of claim 96, wherein said people shows the anticoagulin Xa plasma concentration at least about 0.2 IU/ml.

101. as the described solid composite medicament of claim 96, wherein said people shows the aPTT EAUC (0-inf) at least about 100 IU*hr/ml.

102. as the described solid composite medicament of claim 96, wherein said people shows the aPTT EAUC (0-inf) at least about 150 IU*hr/ml.

103. as the described solid composite medicament of claim 96, wherein said people shows the aPTT EAUC (0-inf) at least about 180 IU*hr/ml.

104. as the described solid composite medicament of claim 81, wherein said people shows the anticoagulin IIa Emax at least about 0.4 IU/ml.

105. as the described solid composite medicament of claim 96, wherein said people shows the anticoagulin IIa EAUC (0-inf) at least about 1.0 IU*hr/ml.

106. as the described solid composite medicament of claim 96, wherein said people shows the anticoagulin Xa Emax at least about 0.4IU/ml.

107. as the described solid composite medicament of claim 96, wherein said people shows the anticoagulin Xa EAUC (0-inf) at least about 1.0 IU*hr/ml.

108. as any described solid composite medicament among the claim 96-107, the heparin in the wherein said wetted heparin be selected from unassorted heparin, Hirudoid, dermatan class, chrondroitin class, low molecular weight heparin, super low molecular heparin, ultra-low molecular weight heparin, with and composition thereof.

109. as any described solid composite medicament among the claim 96-107, the heparin in the wherein said wetted heparin is unassorted heparin.

110. as any described solid composite medicament among the claim 96-107, the heparin in the wherein said wetted heparin is a low molecular weight heparin.

111. as any described solid dosage forms among the claim 96-107, the heparin in the wherein said wetted heparin is a super low molecular heparin.

112. as any described solid composite medicament among the claim 96-107, the heparin in the wherein said wetted heparin is a ultra-low molecular weight heparin.

113. treatment or prevention need its people's the method for DVT, this method comprises and orally uses the solid composite medicament that one or more comprise SNAC and wetted heparin, wherein

(1) after solid composite medicament of the present invention is administered orally in the people 120 minutes, this people by administration showed the situation below one or more:

(i) at least about 38 seconds blood plasma aPTT,

(ii) at least about the anticoagulin IIa plasma concentration of 0.11 IU/ml, or

(iii) at least about the anticoagulin Xa plasma concentration of 0.1IU/ml,

(2) after solid composite medicament of the present invention is administered orally in the people, this people by administration shows the situation below one or more:

(i) at least about the aPTT Emax of 50 IU/ml,

The (ii) aPTT EAUC (0-inf) of at least 80 IU*hr/ml,

(iii) at least about the anticoagulin IIa Emax of 0.35 IU/ml,

(iv) at least about the anticoagulin IIa EAUC (0-inf) of 0.7 IU*hr/ml,

(v) at least about the anticoagulin Xa Emax of 0.35 IU/ml,

(vi) at least about the anticoagulin Xa EAUC (0-inf) of 0.68 IU*hr/ml, or

(3) the two all is.

114. as the described method of claim 113, wherein said people shows the blood plasma aPTT at least about 39 seconds.

115. as the described method of claim 113, wherein said people shows the blood plasma aPTT at least about 50 seconds.

116. as the described method of claim 113, wherein said people shows the anticoagulin IIa plasma concentration at least about 0.2IU/ml.

117. as the described method of claim 113, wherein said people shows the anticoagulin Xa plasma concentration at least about 0.2IU/ml.

118. as the described method of claim 113, wherein said people shows the aPTT EAUC (0-inf) at least about 100IU*hr/ml.

119. as the described method of claim 113, wherein said people shows the aPTT EAUC (0-inf) at least about 150IU*hr/ml.

120. as the described method of claim 113, wherein said people shows the aPTT EAUC (0-inf) at least about 180IU*hr/ml.

121. as the described method of claim 113, wherein said people shows the anticoagulin IIa Emax at least about 0.4IU/ml.

122. as the described method of claim 113, wherein said people shows the anticoagulin IIa EAUC (0-inf) at least about 1.0IU*hr/ml.

123. as the described method of claim 113, wherein said people shows the anticoagulin Xa Emax at least about 0.4IU/ml.

124. as the described method of claim 113, wherein said people shows the anticoagulin Xa EAUC (0-inf) at least about 1.0IU*hr/ml.

125. as any described method among the claim 113-124, the heparin in the wherein said wetted heparin be selected from unassorted heparin, Hirudoid, dermatan class, chrondroitin class, low molecular weight heparin, super low molecular heparin, ultra-low molecular weight heparin, with and composition thereof.

126. as any described method among the claim 113-124, the heparin in the wherein said wetted heparin is unassorted heparin.

127. as any described method among the claim 113-124, the heparin in the wherein said wetted heparin is a low molecular weight heparin.

128. as any described method among the claim 113-124, the heparin in the wherein said wetted heparin is a super low molecular heparin.

129. as any described method among the claim 113-124, the heparin in the wherein said wetted heparin is a ultra-low molecular weight heparin.

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