CN1832758A - Pharmaceutical composition - Google Patents
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- CN1832758A CN1832758A CN 200480022544 CN200480022544A CN1832758A CN 1832758 A CN1832758 A CN 1832758A CN 200480022544 CN200480022544 CN 200480022544 CN 200480022544 A CN200480022544 A CN 200480022544A CN 1832758 A CN1832758 A CN 1832758A
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Abstract
A pharmaceutical composition comprising a 5HT1 receptor agonist or a pharmaceutically acceptable derivative thereof in combination with an NSAID or pharmaceutically acceptable derivative thereof wherein the 5HT1 receptor agonist and NSAID are located in discrete zones with respect to each other wherein each zone comprises the active ingredient and optionally a carrier.
Description
Invention field
The present invention relates to contain an above active component and be used for pharmaceutical composition for oral administration, it contains the 5HT with NASID (NSAID (non-steroidal anti-inflammatory drug)) combination
1Receptor stimulating agent is as active component, and specifically, compositions is easy-to-swallow solid dosage forms.
Background of invention
Chemical compound 5-hydroxy tryptamine (5HT or 5-HT), just known serotonin or intestinal amine are known vaso-active substance and endogenous neurotransmitter, act on inside and outside receptor of central nervous system and blood vessel.The medicine that acts on these receptors can be agonist or antagonist.These receptors have been divided into several receptor subclass, and itself also comprises subclass some subclass.
5HT
1Receptor stimulating agent can be used for various disease conditions, particularly for example migraine, cluster headache, chronic paroxysmal hemicrania, the headache relevant with angiopathy of treatment and the relevant disease of headache, and material or relevant headache, rebound headache and the tension headache of its withdrawal.5HT
1Receptor stimulating agent is well known in the art, and this term is interpreted as to comprise all types of 5HT widely
1Receptor stimulating agent, it includes but not limited to 5HT
1-sample receptor stimulating agent, 5HT
1BReceptor stimulating agent, 5HT
1DReceptor stimulating agent and 5HT
1FReceptor stimulating agent.The chemical compound that is particularly related to has sumatriptan (agent is as being recorded in the GB patent No. 2162522, and it incorporates this paper into by reference), naratriptan, rizatriptan, Zomitriptan, frovatriptan, eletriptan, Almogran, avitriptan, Donitriptan, Ah Buddhist nun Qu Tan, ALX-0646, LY334370, U109221, IS159 and PNY142633.The chemical compound that is particularly related to is a sumatriptan.
Project of world's clinical experiment widely is verified sumatriptan (with subcutaneous, oral, intranasal and rectal formulation listing) is as the effect and the toleration of migrainous acute treatment.
Though 5HT
1Agonist can be used in the migrainous treatment, but has been found that some patients after initial curative effect, occurs cephalagra once more in about 1-24 hour after alleviating in the early stage.In other words, after giving the therapeutic dose that the patient treats the migraine effective dose, observed decreased migraine potential, after alleviating first about 1-8 hour to after about 12-24 hour in cephalagra appears once more.We will be able to identify, and when treating with particular therapeutic agent, indivedual migraineurs can show mutually different symptom and lasting time of this phenomenon.
Though be not limited to any specific theory, sumatriptan and other 5-HT reagent are considered to by reducing specific nerve and circumvascular proinflammatory medium or both have brought into play its beneficial effect to the migraineur by the vasoconstriction of head selectivity blood vessel or by them.Yet they are considered to lack analgesic activity, it is believed that their pharmacological action depends on the specific blood drug level that institute reaches or keeps, and these concentration are ofer short duration.Recurrence in 24 hours has been proved well that recurrence has appearred in the patient who has 40-50% to be eased at first, but reason the unknown.
The headache that appears in the above-mentioned situation is various, is called " knock-on ", " recurrence ", " circulation " or " secondary " headache interchangeably.This term is not antagonistic, whether also do not know at present this after headache be exactly the continuation that causes physiology's chain of initial headache incident, or because other or repeatedly but the caused new headache of incoherent potential pathology.Also may be that the headache that continues is the reaction of successfully treating the therapeutic agent of initial cephalagra at first.Term " knock-on ", " recurrence " as used herein, " circulation " or " secondary " headache (the following definition) are considered to synonym, no matter the mechanism of above-mentioned headache or cause are how.
In some migraine forms, used analgesic for example acetaminophen and phenacetin and other non-steroidal non_narcotic analgesics, it is generally as anti-inflammatory agent, some patient had been found that all or part of alleviation.And when these reagent are taken in separately, they migrainous all symptoms are provided comprehensively and alleviation fast aspect seldom effective, especially when the symptom of outbreak had comprised nausea and vomiting, in therapeutic alliance of the present invention, its effectiveness was enhanced astoundingly.
NASID is known in the art; what be particularly related to has a diclofenac; nabumetone; naproxen; ketorolac; ibuprofen; flurbiprofen; ketoprofen; Ao Shaputai; etodolac; indometacin; mefenamic acid; tolfenamic acid and COX-2 selective depressant be Sai Laikaopu for example; Luo Feikaopu (VIOXX); valdecoxib; parecoxib; 4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzene sulfonamide (JTE-522); MK633 (etoricoxib); nimesulide; flosulide; DFP; 2-(4-ethyoxyl-phenyl)-3-(4-methane sulfonyl-phenyl)-pyrazolo [1; 5-b] pyridazine; Metro former times health; RS57067; piroxicam; NS 398; L-745,337 and COX-189.
NASID for example naproxen sodium is considered to alleviate migraine by its known analgesic effect, but also can by supervention behind its known antiinflammatory action reduction nerve and vascular inflammation or suppress such as but not limited to platelet or prostaglandin is synthetic suppresses to come relief of symptoms by other mechanism.In addition, naproxen and naproxen sodium have 12-15 hour half-life, and have produced long term effect.
U.S. Patent number 6,060499 discloses the migrainoid method of treatment people, and it comprises 5HT agonist for the treatment of effective dose simultaneously and the analgesic for the treatment of effective dose, especially long-acting NSAID.This administration expectation is the unit dosage forms administration with independent preparation or associating.U.S. Patent number 6060449 has been narrated, and is not limited to any theory, it is believed that associating 5HT agonist and long-acting NSAID can reach enhanced initial curative effect and lower recurrence headache sickness rate.
Though be not limited to any specific theory, but it is believed that, usually relevant with the 5-HT agonist " recurrence " headache is because the initial beneficial effect of 5-HT agonist is weakened gradually, because its action time is shorter, and a) the potential releaser of initial migraine still exists and/or b) and the source of disease body of pain and other symptom, possible blood vessel and/or neurogenic inflammation still exist.
Under this situation, NSAID is joined the appearance (or " knock-on relaxes ") that can prolong the effective antiinflammatory action time in the 5-HT agonist and prevent the recurrence headache, no matter what its reason is.
Oral administration has constituted the optimization approach of administration, since this approach is convenient especially and is that the patient is acceptable.For therapeutic alliance, a preparation that contains two or more active component also can be preferred.A preparation stability and effectiveness that important consideration is a composition when comprising more than a formulations of active ingredients, the reagent interaction to each other of suppose reagent itself or having an excipient can cause the effectiveness change of or all unstable active components or or all active component.
Present inventors it has surprisingly been found that when the granular preparation that mixes sumatriptan and naproxen sodium and when making a tablet, for example by directly suppressing, the preparation that obtains has unacceptable dissolution time.For example, the dissolving of two compositions than expection cause slow than slow trapping.This may be because naproxen sodium lost efficacy the dissolving that comprises particulate sumatriptan.
Surprisingly, with regard to each other, when active component was divided into independent discontinuity layer each other and makes solid oral dosage form, the preparation that obtains presented gratifying sumatriptan and naproxen sodium rate of dissolution.
Summary of the invention
Therefore, the invention provides and contain 5HT
1Receptor stimulating agent or its pharmaceutically acceptable derivates, the pharmaceutical composition of combination NSAID or its pharmaceutically acceptable derivates, wherein 5HT
1Receptor stimulating agent and NSAID are arranged in discontinuous layer with regard to each other, wherein each layer all contains active component and optional carrier.
Description of drawings
The solubility curve of naproxen sodium in Figure 1A naprox 550mg tablet.
Fig. 2 uses the solubility curve of the sumatriptan succinate of FDT granulation and naproxen sodium direct compression.
Fig. 3 comprises the solubility curve of the double-layer tablet of sumatriptan succinate FDT granule and naproxen sodium direct compression.
Fig. 4 comprises the solubility curve of sumatriptan succinate FDT granule and the particulate double-layer tablet of naproxen sodium.
Detailed Description Of The Invention
According to suitable 5HT used in the present invention1Receptor stimulating agent comprises sumatriptan, naratriptan, Zomitriptan, eletriptan, rizatriptan, frovatriptan, almotriptan, avitriptan, donitriptan, alniditan, ALX-0646, LY 334370, U1092291, IS159 (be 3-(2-amino-ethyl)-5-[acetamido-3-(4-hydroxy phenyl)-propionamido--acetylaminohydroxyphenylarsonic acid oxygen base]-indoles) and PNY142633 (i.e. (s)-3,4-dihydro-1-[2-[4-[4-amino carbonyl) phenyl]-the 1-piperazinyl] ethyl]-N-methyl isophthalic acid H-2-chromene-6-formamide). Naratriptan and sumatriptan are preferred, particularly preferably sumatriptan. The preferred form of sumatriptan is succinate, especially 1: 1 succinate. 5HT1Receptor stimulating agent can use separately or unite use with other material.
Suitable NSAID comprises diclofenac; nabumetone; naproxen; ketorolac; ibuprofen; flurbiprofen; ketoprofen; Ao Shaputai; etodolac; indometacin; mefenamic acid; tolfenamic acid and COX-2 selective depressant be celecoxib for example; Luo Feikaopu (VIOXX); valdecoxib; parecoxib; 4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzene sulfonamide (JTE-522); MK633 (etoricoxib); nimesulide; flosulide; DFP; 2-(4-ethyoxyl-phenyl)-3-(4-methane sulfonyl-phenyl)-pyrazolo [1; 5-b] pyridazine; Metro former times health; RS57067; piroxicam; NS398; L-745,337 and COX-189.Preferred COX-189 and naproxen.Preferred especially naproxen, the most preferably form of naproxen sodium.
" pharmaceutically acceptable derivates " refers to, any pharmaceutically acceptable salt, solvate, ester or the amide of active component or any other chemical compound or the salt or the solvate of this ester or amide, wherein other chemical compound is the chemical compound that energy (directly or indirectly) provides active component or its active metabolite or residue when giving the receiver.
Suitable pharmaceutically acceptable salt according to the present invention comprises and mineral acid for example hydrochloric acid, hydrobromic acid, phosphoric acid and sulphuric acid and the acid-addition salts that forms with organic acid, for example tartrate, maleate, fumarate, succinate and sulfonate.
In one aspect of the invention, the discontinuity layer district can be provided by adding excipient.Therefore the invention provides a kind of pharmaceutical composition, it contains 5HT
1Receptor stimulating agent or its pharmaceutically acceptable derivates and pharmaceutically acceptable carrier, and combination NSAID, wherein 5HT
1Receptor stimulating agent and NSAID are dispersed in its oneself the pharmaceutically acceptable carrier each other.
Suitable is 5HT in the compositions
1The carrier of receptor stimulating agent is different with the carrier of NSAID.
In one embodiment of the invention, 5HT
1Receptor stimulating agent and carrier thereof fully mix with NSAID and carrier thereof.
Suitable is 5HT
1Receptor stimulating agent and carrier thereof and NSAID and carrier thereof be uniform mixing fully.
Suitable is, when preparation compositions of the present invention, with the 5HT that forms
1Receptor stimulating agent/carrier mixture mixes with the NSAID/ carrier mixture of formation.For example, 5HT
1Receptor stimulating agent/carrier mixture and NSAID/ carrier mixture are mixed into capsular form.
More preferably, 5HT
1Receptor stimulating agent/carrier mixture mixes with the NSAID/ carrier mixture in mixture and compresses, and suitable is to form tablet.For example, with 5HT
1The mixture of receptor stimulating agent/carrier mixture and NSAID/ carrier mixture compresses the formation tablet.
5HT
1The appropriate carrier of receptor stimulating agent is that one or more are selected from following composition: binding agent, filler, lubricant and paired effervescent composition (effervescent couple), wicking agent (wicking agent), fluidizer, disintegrating agent and wetting agent.
The appropriate carrier of NSAID is that one or more are selected from following composition: binding agent, filler, paired effervescent composition, wicking agent, fluidizer, disintegrating agent and wetting agent.
Of the present invention one preferred aspect in, a floor provides the suitable floor district of activating agent, generally is neutralizing layer.Like this, preparation just can contain multilamellar, generally is the shaping layer of activating agent.
Suitable preparation is a tablet formulation.Like this, a special preparation is exactly a multilayer tablet, and wherein active component is in the layer that separates.Special preparation contains the pressed form of the activating agent that the powder type with other activating agent forms, for example tablet.Or tablet can prepare by overcompression, and it just comprises the label of an active component like this, and it is by another active component outer coatings parcel.
More preferably, the tablet that comprises the activating agent that is positioned at the discontinuity layer district with regard to each other can be a multilayer tablet.For example they can be double-layer tablet, and the layer form of one of them activating agent is downtrodden, add another activating agent form then and suppress on first active agent layer.They also can be the three-layer tablets with the similar approach preparation.If suitable active component can be used as granule and is produced.
The discontinuity layer district can separate by carrier layer, preferred inert carrier layer.Carrier layer generally comprises for example lactose and lubricant magnesium stearate for example of filler.
As indicated in, this compositions generally can be made into tablet or capsule.Tablet and capsule can be suppressed then by mixed active composition granule and prepare.
The granule of each activating agent can be by combined activity agent and suitable excipient, and for example hydroxypropyl emthylcellulose, microcrystalline Cellulose, primojel, lactose and magnesium stearate are used routine techniques to granulate then and obtained.
When preparing the granule of any activating agent, preferably use the high shear stress granulation technique.In a preferred embodiment, two active component are granulated.
Capsule can be by mixing encapsulated then preparation of activating agent of bead form or particle form.
The bead of each activating agent can be by combined activity agent and suitable excipient, and for example microcrystalline Cellulose and lactose use routine techniques to form bead then and obtain.Description according to this paper prepares granule.Tablet and capsular production can use technology known in the art to carry out.
In the context of the present invention, " being used for oral administration " refers to pharmaceutical composition and is being easy to whole solid dosage forms of swallowing, and do not dissolve substantially before administration or be suspended in the water; Yet compositions of the present invention can be in the particular that the dispersible tablet that meets according to the fineness of dispersion of European Pharmacopoeia and/or British Pharmacopoeia definition and dispersion rate requires.This dosage form can be tablet or capsular form and can prepare according to the routine techniques of the known preparation solid dosage forms of pharmaceutical field.Preferably, compositions of the present invention is the form of " swallowing " sheet.For fear of suspection, " swallowing " sheet is that (using for example water of a spot of liquid usually) is easy to the whole tablet of swallowing; It does not just dissolve basically before administration or is suspended in the water (for example, the tablet of WO92/11003 record, it also comprises the essence weight of two effervescent coupling compositions), neither " in mouth " be easy to basically dissolved (" mouthful molten " form).
By disclosing known pharmaceutical composition as solid dosage form, especially for the thin membrane coated tablet of the treatment disease relevant with headache with reference to the WO 92/15295 (Glaxo Group Ltd.) that incorporates this paper into.These preparations can form and comprise 5HT
1The floor district of receptor stimulating agent.
Regrettably, when treating the disease relevant, has some disadvantage with headache.For example this disease, especially migraine are accompanied by nauseating, vomiting and gastrointestinal dysfunction with the form that reduces the stomach activeness, and delay the mode of gastric emptying, and this causes potentially and delays and/or damaged drug absorption.
So just will expect active component especially 5HT
1Receptor stimulating agent is prepared to guarantee dissolving rapidly and to absorb.Like this of the present invention one preferred aspect in, provide and contained 5HT
1Receptor stimulating agent or its pharmaceutically acceptable derivates also make up NSAID or the pharmaceutical composition of its pharmaceutically acceptable derivates, wherein 5HT
1Receptor stimulating agent and NSAID are arranged in discontinuous floor district with regard to each other, wherein active component and optional carrier are all contained in each floor district, also have wherein to form at least to contain 5HT
1The floor district of receptor stimulating agent is to guarantee rapid absorption.
Be applied to 5HT
1" fast Absorption " of receptor stimulating agent refers to greater than about 70%, be preferably greater than approximately 80%, the active component more preferably greater than about 90% was dissolved in five minutes in the simulated gastric fluid (SGF) under the property the distinguished oar speed (discriminating paddle speed) of 10rpm in the USPII device.
One preferred aspect in, preparation is to contain 2 or more multi-layered tablet, wherein preparation contains 5HT
1The layer of receptor stimulating agent or its pharmaceutically acceptable derivates is to guarantee rapid absorption, and another layer contains NSAID or its pharmaceutically acceptable derivates and optional carrier.Most preferably, tablet is a double-layer tablet, and it contains through the comprise 5HT of preparation to guarantee to absorb rapidly
1The layer of receptor stimulating agent or its pharmaceutically acceptable derivates, and the layer that comprises NSAID or its pharmaceutically acceptable derivates and the carrier of choosing wantonly.
Like this one preferred aspect in, be used for fast Absorption through the preparation 5HT
1In the receptor stimulating agent layer, 5HT
1Receptor stimulating agent or its pharmaceutically acceptable derivates are with paired effervescent composition and make up disintegrating agent, filler (preferred insoluble bulking agent) and wicking agent and prepare.Concerning the patient who suffers from headache, this preparation has shown that effect takes place and/or higher efficient faster.
The layer that contains the pharmaceutical composition of NSAID or its pharmaceutically acceptable derivant can be prepared according to known NSAID preparation method.These are apparent to those skilled in the art.For example, following table has shown the several different compositionss of forming of naproxen sodium sheet.
| Compositions (mg/ sheet) | ||||||||
| | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| Naproxen sodium | 550 | 550 | 550 | 550 | 550 | 550 | 550 | 550 |
| Avicel PH 101 | 164 | 164 | 164 | 126 | 126 | 164 | 164 | 164 |
| PVP K-30，USP | - | 20 | - | 20 | - | 20 | 20 | 20 |
| PVP K-90，USP | - | - | 20 | - | 20 | - | - | - |
| Purify waste water USP | - | 110 | 110 | 110 | 110 | 125 | 150 | 175 |
| Ac-Di-Sol | - | - | - | 38 | 38 | - | - | - |
| Pulvis Talci, USP | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 |
| Magnesium stearate | 8 | 8 | 8 | 8 | 8 | 8 | 8 | 8 |
| Gross weight | 730 | 750 | 750 | 750 | 750 | 750 | 750 | 750 |
Bansal, P., Haribhakti, K., Subramanian, V., Plakogiannis, F., " prescription and processing variable are to the influence of naproxen sodium tablet dissolved curve ", DrugDevelopment and Industrial Pharmacy, 20 (13), 2151-2156,1994.
In another aspect of the present invention, also can prepare the NSAID layer that is used for fast Absorption, for example by comprising paired effervescent composition.
" fast Absorption " that is applied to NASID referred to greater than about 25%, is preferably greater than approximately 50%, and the active component more preferably greater than about 75% was dissolved in the simulated gastric fluid in five minutes under the property the distinguished oar speed of 30rpm in the USPII device.
So in another aspect of the present invention, in the NSAID layer, NSAID or its pharmaceutically acceptable derivates are with paired effervescent composition and make up disintegrating agent, insoluble bulking agent and wicking agent and prepare.
Therefore, in a preferred embodiment, the invention provides at the 5HT that is used for fast Absorption through preparation
15HT in the receptor stimulating agent layer
1Receptor stimulating agent or its pharmaceutically acceptable derivates, itself and the paired alkaline components of effervescent composition, disintegrating agent and insoluble bulking agent are prepared together, wherein alkaline components accounts for about 5 of this layer of dosage form dry weight and arrives about 50% weight, disintegrating agent accounts for about 0.5 to about 10% weight, insoluble bulking agent accounts for about 20 to about 99% weight, described insoluble bulking agent comprises wicking agent, it accounts for about 1 to about 99% weight, wherein greater than about 70%, preferred about 80%, more preferably from about 90% active component was dissolved in five minutes in the simulated gastric fluid (SGF) under the property the distinguished oar speed of 10rpm in the USPII device.
When NSAID also is formulated into when being used for fast Absorption, the invention provides the NSAID layer that is used for fast Absorption through preparation, it contains NSAID or its pharmaceutically acceptable derivates, itself and the paired alkaline components of effervescent composition, disintegrating agent and insoluble bulking agent are prepared together, wherein alkaline components accounts for about 5 of this layer of dosage form dry weight and arrives about 50% weight, disintegrating agent accounts for about 0.5 to about 20% weight, insoluble bulking agent accounts for about 30 to about 80% weight, described insoluble bulking agent comprises wicking agent, it accounts for about 1 to about 60% weight, wherein greater than about 25%, preferred about 50%, more preferably from about 75% active component was dissolved in the simulated gastric fluid in five minutes under the property the distinguished oar speed of 30rpm in the USPII device.
Suitable is, at the 5HT that is used for fast Absorption through preparation
1In the receptor stimulating agent layer, 5HT
1Receptor stimulating agent account for this layer dry weight about 0.001 to about 55% weight, preferred about 0.01 to about 45%, more preferably from about 0.01 to about 40%, especially about 1 to about 35%, more particularly about 20 to about 35%.
Suitable is, in the NSAID layer, NSAID account for this layer dry weight about 1 to about 90% weight, preferred about 2 to about 90%, more preferably from about 5 to about 85%, especially about 10 to about 75%, more particularly about 60 to about 75%.
In one embodiment of the invention, the preparation layer is to be used for fast Absorption, and pharmaceutical composition also contains the acid ingredient of paired effervescent composition.The effervescent composition is made up of acid ingredient and alkaline components basically in pairs, and there is reaction formation gas under the situation of water in this composition.
At the 5HT that is used for fast Absorption through preparation
1In the receptor stimulating agent layer, acid ingredient can comprise for example 5HT
1Receptor stimulating agent or its pharmaceutically acceptable derivates itself (wherein it has acidic character or the composition of acidic character can be provided in aqueous environment), or aliphatic carboxylic acid or its salt, for example citric acid or tartaric acid and salt thereof.Or acid ingredient can provide by acid in the NSAID layer or gastric acid, rather than forms 5HT in the pharmaceutical composition
1The part in receptor stimulating agent floor district.Preferably, acid ingredient is 5HT
1Receptor stimulating agent or its pharmaceutically acceptable derivates (form of sumatriptan or naratriptan, especially its salt for example, succinate for example is as sumatriptan succinate (1: 1)).Acid ingredient can use separately or with other combinations of substances.Suitable is that acid ingredient comprises 5HT
1Receptor stimulating agent or its pharmaceutically acceptable derivates, and aliphatic carboxylic acid or its salt, for example citric acid or tartaric acid and salt thereof.Suitable is that acid ingredient (comprises 5HT
1Receptor stimulating agent or its pharmaceutically acceptable derivates, when it works as acid ingredient) account for about 55% weight of this layer of dosage form dry weight, preferred about 5 to about 50%, and more preferably from about 10 to about 45%, especially about 15 to about 40%, more particularly about 20 to about 35%.Alkaline components can comprise for example alkali metal or alkaline earth metal carbonate or bicarbonate, for example sodium bicarbonate, potassium bicarbonate, magnesium carbonate or calcium carbonate.The preferred sodium bicarbonate of alkaline components.Alkaline components can use separately or use with other combinations of substances.Suitable is, alkaline components account for this layer of dosage form dry weight about 5 to about 50% weight, preferred about 7 to about 20%, more preferably from about 8 to about 15%, especially about 9 to about 12%.Acid can be monoacid or polyprotic acid, and similarly, alkali can be monoacidic base or polyacid base.Calculate according to acid/alkali equivalent (N), the ratio of acid ingredient and alkaline components generally can arrive in about 10: 1 scope at about 1: 10, and preferred about 1: 5 to about 5: 1, more preferably from about 1: 3 to about 3: 1, most preferably from about 1: 2 to about 2: 1.
At the NSAID layer that is used for fast Absorption through preparation, acid ingredient can comprise for example NSAID, as naproxen or its pharmaceutically acceptable derivates itself (wherein it has acidic character or can provide the composition with acidic character in aqueous environment), or aliphatic carboxylic acid or its salt, for example citric acid or tartaric acid and salt thereof.Or acid ingredient can pass through 5HT
1Acid or gastric acid in the receptor stimulating agent layer provide, rather than form the part of pharmaceutical composition NSAID layer, or as being included in 5HT
1The independent reagent of receptor stimulating agent layer and/or NSAID layer for example citric acid provides.Preferably, acid ingredient as independent reagent for example citric acid be provided.Acid ingredient can use separately or with other combinations of substances.Suitable is that acid ingredient comprises 5HT
1Receptor stimulating agent or its pharmaceutically acceptable derivates, and aliphatic carboxylic acid or its salt for example citric acid or tartaric acid and salt thereof.Suitable is, comprise as independent reagent for example the acid ingredient of citric acid account for this layer of dosage form dry weight until about 30% weight, preferred about 0.001 to about 20%, with preferred about 0.01 to about 15%, especially about 1 to about 15%, more particularly about 3 to about 10%.Alkaline components can comprise for example alkali metal or alkaline earth metal carbonate or bicarbonate, for example sodium bicarbonate, potassium bicarbonate, magnesium carbonate or calcium carbonate.The preferred sodium bicarbonate of alkaline components.Alkaline components can use separately or with other combinations of substances.Preferably, alkaline components account for this layer of dosage form dry weight about 5 to about 50% weight, preferred about 7 to about 20%, more preferably from about 8 to about 15%, especially about 9 to about 12%.Acid can be monoacid or polyprotic acid; Similarly, alkali can be monoacidic base or polyacid base.Calculate according to acid/alkali equivalent (N), the ratio of acid ingredient and alkaline components generally can arrive in about 10: 1 scope at about 1: 10, and preferred about 1: 5 to about 5: 1, more preferably from about 1: 3 to about 3: 1, most preferably from about 1: 2 to about 2: 1.
Disintegrating agent, in the time of in being used in compositions of the present invention, swelling when they contact with water.Suitable disintegrating agent will be well known by persons skilled in the art, and non-limiting instance comprises cross-linking sodium carboxymethyl cellulose, primojel, crospolyvinylpyrrolidone, polyvidone, starch (for example corn starch, pregelatinized Starch), low hydroxypropyl cellulose, alginic acid, sodium alginate, calcium phosphate,tribasic, calcium sulfate, carboxymethylcellulose calcium, microcrystalline Cellulose, Powderd cellulose, silicon dioxide colloid, docusate sodium, guar gum, hydroxypropyl cellulose, aluminium-magnesium silicate, methylcellulose, polacrilin potassium and the polyvinylpyrrolidone that replaces.Cross-linking sodium carboxymethyl cellulose is preferred.Disintegrating agent can use separately or with other combinations of substances.Suitable is, at 5HT
1In the receptor stimulating agent floor district, disintegrating agent account for this layer of dosage form dry weight about 0.5 to about 10% weight, preferred about 2 to about 8% weight, more preferably from about 3 to about 7%, especially about 4 to about 6%, more particularly about 5%.
In the NSAID layer, disintegrating agent account for this layer of dosage form dry weight about 0.5 to about 10% weight, preferred about 1 to about 8% weight, more preferably from about 1.5 to about 6%, especially about 2 to about 4%, more particularly about 3%.
Insoluble bulking agent is an inert substance, and in the time of in being used in compositions of the present invention, it can provide volume and stability.Some insoluble bulking agents also can serve as wicking agent.Wicking agent in the time of in being used in compositions of the present invention, having porous and also can absorb water and be applied in the solid dosage forms.Suitable wicking agent will be well known by persons skilled in the art, and limiting examples comprises that microcrystalline Cellulose is (for example as Avicel
TMAnd be provided), cross-linking sodium carboxymethyl cellulose, crospovidone, starch, carboxymethylcellulose calcium, silicified microcrystalline cellulose, magnesium oxide and tragakanta.Microcrystalline Cellulose is preferred.Wicking agent can use separately or with other combinations of substances.Suitable is, wicking agent account for this layer of dosage form dry weight about 1 to about 99% weight, preferred about 1 to about 80%, more preferably from about 5 to about 65%, especially about 12 to about 55%, more particularly about 18 to about 50%.Other suitable insoluble bulking agent comprises that dicalcium phosphate dihydrate, calcium phosphate dibasic anhydrous are (for example as Emcompress
TMAnd be provided), calcium phosphate,tribasic, calcium carbonate, magnesium carbonate, calcium sulfate, cellulose acetate, Powderd cellulose, Kaolin, polymethacrylates and Pulvis Talci.Calcium phosphate dibasic anhydrous is preferred.Insoluble bulking agent can use separately or with other combinations of substances.Suitable is, at 5HT
1In the receptor stimulating agent layer, insoluble bulking agent comprises wicking agent, account for this layer of dosage form dry weight about 30 to about 99% weight, preferred about 35 to about 80%, more preferably from about 40 to about 70%, especially about 45 to about 65%.In the NSAID layer, insoluble bulking agent comprises wicking agent, account for this layer of dosage form dry weight about 10 to about 99% weight, preferred about 15 to about 55%, more preferably from about 25 to about 45%, especially about 30 to about 40%.
Like this, in one embodiment of the invention, provide aforesaid pharmaceutical composition as solid dosage form, wherein 5HT
1The receptor stimulating agent layer contains 5HT
1Receptor stimulating agent or its pharmaceutically acceptable derivates, its account for this layer of dosage form dry weight about 0.001 to about 55% weight, preferred about 0.01 to about 45%, more preferably from about 0.1 to 40%, especially about 1 to about 35%, more particularly about 20 to about 35%, and the alkaline components of effervescent composition accounts for about 5 to about 50% weight in pairs, and preferred about 7 to about 20%, more preferably from about 8 to about 15%, especially about 9 to about 12%, and disintegrating agent accounts for about 0.5 to about 10% weight, and preferred about 2 to about 8%, more preferably from about 3 to about 7%, especially about 4 to about 6%, more particularly about 5%, insoluble bulking agent, comprise wicking agent, account for about 35 to about 80% weight, preferred about 40 to about 70%, and more preferably from about 45 to about 65%, wicking agent accounts for about 1 to about 80% weight, preferred about 5 to about 65%, and more preferably from about 12 to about 55%, especially about 18 to about 50%.
Like this, in one embodiment of the invention, aforesaid pharmaceutical composition as solid dosage form is provided, and wherein the NSAID layer contains its pharmaceutically acceptable derivates of NSAID, and it accounts for about 1 of this layer of dosage form dry weight and arrives about 90% weight, preferred about 2 to about 90%, more preferably from about 5 to 85%, especially about 10 to about 75%, more particularly about 60 to about 75%, the alkaline components of effervescent composition accounts for about 5 to about 50% weight in pairs, preferred about 7 to about 20%, and more preferably from about 8 to about 15%, especially about 9 to about 12%, disintegrating agent accounts for about 0.05 to about 10% weight, preferred about 1 to about 8%, and more preferably from about 1.5 to about 6%, especially about 2 to about 4%, more particularly about 3%, insoluble bulking agent comprises wicking agent, accounts for about 10 to about 99% weight, preferred about 15 to about 55%, and more preferably from about 25 to about 45%.
Like this, in one embodiment of the invention, provide aforesaid pharmaceutical composition as solid dosage form, wherein 5HT
1The receptor stimulating agent layer contains 5HT
1Receptor stimulating agent or its pharmaceutically acceptable derivates, it accounts for about 0.001 of this layer of dosage form dry weight and arrives about 55% weight, preferred about 0.01 to about 45%, more preferably from about 0.1 to 40%, especially about 1 to about 35%, more particularly about 20 to about 35%, the alkaline components of effervescent composition accounts for about 5 to about 50% weight in pairs, preferred about 7 to about 20%, more preferably from about 8 to about 15%, especially about 9 to about 12%, disintegrating agent accounts for about 0.5 to about 10% weight, preferred about 2 to about 8%, more preferably from about 3 to about 7%, especially about 4 to about 6%, more particularly about 5%, insoluble bulking agent, comprise wicking agent, account for about 35 to about 80% weight, preferred about 40 to about 70%, and more preferably from about 45 to about 65%, wicking agent accounts for about 1 to about 80% weight, preferred about 5 to about 65%, and more preferably from about 12 to about 55%, especially about 18 to about 50%, the NSAID layer contains its pharmaceutically acceptable derivates of NSAID, its account for this layer of dosage form dry weight about 1 to about 90% weight, preferred about 2 to about 90%, more preferably from about 5 to 85%, especially about 10 to about 75%, more particularly about 60 to about 75%, and the alkaline components of effervescent composition accounts for about 5 to about 50% weight in pairs, and preferred about 7 to about 20%, more preferably from about 8 to about 15%, especially about 9 to about 12%, and disintegrating agent accounts for about 0.05 to about 10% weight, and preferred about 1 to about 8%, more preferably from about 1.5 to about 6%, especially about 2 to about 4%, more particularly about 3%, insoluble bulking agent, comprise wicking agent, account for about 10 to about 99% weight, preferred about 15 to about 55%, and more preferably from about 25 to about 45%.
In another embodiment of the invention, provide aforesaid pharmaceutical composition, wherein 5HT
15HT is contained in receptor stimulating agent floor district
1Receptor stimulating agent or its pharmaceutically acceptable derivates, it comprises sumatriptan or naratriptan or its pharmaceutically acceptable derivates, preferred sumatriptan or its pharmaceutically acceptable derivates, the more preferably form of its succinate (1: 1), the alkaline components of effervescent composition comprises sodium bicarbonate in pairs, disintegrating agent comprises cross-linking sodium carboxymethyl cellulose, and insoluble bulking agent comprises microcrystalline Cellulose.
In another embodiment of the invention, provide aforesaid pharmaceutical composition, wherein 5HT
15HT is contained in receptor stimulating agent floor district
1Receptor stimulating agent or its pharmaceutically acceptable derivates, it comprises sumatriptan or naratriptan or its pharmaceutically acceptable derivates, preferred sumatriptan or its pharmaceutically acceptable derivates, the more preferably form of its succinate (1: 1), the alkaline components of effervescent composition comprises sodium bicarbonate in pairs, disintegrating agent comprises cross-linking sodium carboxymethyl cellulose, and insoluble bulking agent comprises calcium hydrogen phosphate, preferred anhydrous calcium hydrogen phosphate.
In another embodiment of the invention, provide aforesaid pharmaceutical composition, wherein 5HT
15HT is contained in receptor stimulating agent floor district
1Receptor stimulating agent or its pharmaceutically acceptable derivates, it comprises sumatriptan or its pharmaceutically acceptable derivates, the form (1: 1) of preferred its succinate, the alkaline components of effervescent composition comprises sodium bicarbonate in pairs, disintegrating agent comprises cross-linking sodium carboxymethyl cellulose, and insoluble bulking agent comprises calcium phosphate dibasic anhydrous or microcrystalline Cellulose or its mixture.
During preparation, compare (for example, the disclosed preparation of WO92/15295) with the conventional tablet preparation, comprising one or more insoluble bulking agents in compositions of the present invention also provides the compositions with improved operability.
Except mentioned component, pharmaceutical composition of the present invention can also contain pharmaceutically acceptable carrier and excipient for example binding agent (as pregelatinized Starch, polyvinylpyrrolidone, hydroxypropyl emthylcellulose) and lubricant (for example stearic acid, magnesium stearate, Pulvis Talci, sodium benzoate and hydrogenated vegetable oil).
Many drug substances all have inherent bitterness.Sometimes follow at orally give and comprise 5HT
1The tedious taste of in the compositions of receptor stimulating agent or its pharmaceutically acceptable derivates this can be eliminated basically by use film coating on the solid label.The solid label comprises 5HT
1Receptor stimulating agent or its pharmaceutically acceptable derivates.In addition, in the time of in being used in compositions of the present invention, film-coat has delayed the disintegrate of solid dosage forms, arrives in the stomach until it.Film-coat also can help to swallow, and can make solid dosage forms more satisfactory aesthetic, and make solid dosage forms more non-friable usually.
Therefore, in one embodiment, the invention provides the pharmaceutical composition of aforesaid film coating tablet form.
The peplos coating can comprise polymer aptly.Suitable polymer blend will be well known to a person skilled in the art, limiting examples comprises cellulose esters for example hydroxypropyl emthylcellulose, hydroxypropyl cellulose or methylcellulose and methacrylic acid and methylmethacrylate copolymer.Preferably, film coating will comprise hydroxypropyl emthylcellulose.
Whole film coating solid generally all is used on the solid dosage forms, label for example, and accounting for about 0.5 amount to about 10% weight of dosage form dry weight, preferred about 1 to about 4%, and more preferably from about 2 to about 3%.For example, about 8mg coating be used to heavily about 300 or the label of about 400mg on, the coating of about 4mg is used on the label of heavily about 175mg.
Film coating can also contain any pharmaceutically acceptable coloring agent or opacifier and comprise the aluminum color lake of water-soluble dye, water-soluble dye and inorganic pigment for example titanium dioxide and iron sesquioxide.
Film coating also can comprise one or more plasticizers that are used in usually in the polymer thin film coating, for example Polyethylene Glycol, propylene glycol, dibutyl sebecate, mineral oil, Oleum sesami, ethyl phthalate and triacetin.Can use patent thing film coating material, for example from Colorcon Ltd., Opaspray and Opadry that UK obtains.
The taste of Orally administered composition also can improve by using flavoring agent and/or sweeting agent.Suitable flavoring agent will be well known to a person skilled in the art, non-limiting instance comprises Fructus Citri Limoniae, Fructus Citri tangerinae, Fructus Citri grandis, Rhizoma et radix valerianae, caramel, butterscotch, Semen coryli heterophyllae or mint flavor.The suitable sweeting agent that is used in the present composition will be well known to a person skilled in the art, limiting examples comprises sucrose, glucide, cyclamic acid and alkali metal thereof or alkali salt, mannitol, acesulfame-K, stevioside, thaumatin and Aspartane.Flavoring agent and/or sweeting agent can use separately or with other combinations of substances.
In one aspect of the method, the invention provides the aforesaid pharmaceutical composition for oral administration that is used for, be used for the treatment of with for example cluster headache, chronic paroxysmal hemicrania, the headache relevant of the relevant disease of headache with angiopathy, and material or its give up relevant headache, rebound headache, tension headache, especially migraine.Suitable is 5HT
1Receptor stimulating agent is sumatriptan or naratriptan or its pharmaceutically acceptable derivates, preferred sumatriptan or its pharmaceutically acceptable derivates, more preferably sumatriptan succinate (1: 1).Suitable NSAID is naproxen or COX-189 or its pharmaceutically acceptable salt, more preferably naproxen sodium.
We will be able to identify, and treatment will be referred to comprise prevention and the alleviation to confirming symptom.
According to another aspect of the present invention, provide aforesaid be used for the pharmaceutical composition for oral administration solid dosage forms preparation be used for the treatment of with for example cluster headache, chronic paroxysmal hemicrania, the headache relevant of the relevant disease of headache with angiopathy, and material or its give up relevant headache, rebound headache, tension headache, the purposes in the especially migrainous medicine.Suitable is 5HT
1Receptor stimulating agent or its pharmaceutically acceptable derivates are sumatriptan or naratriptan or its pharmaceutically acceptable derivates, preferred sumatriptan or its pharmaceutically acceptable derivates, more preferably sumatriptan succinate (1: 1).Suitable is that NSAID is naproxen or COX-189 or its pharmaceutically acceptable salt, more preferably naproxen sodium.
The present invention provides on the other hand and has been used for the treatment of the method that the mammal that suffers from headache or be subjected to influence with the relevant disease of having a headache comprises the people, for example cluster headache, chronic paroxysmal hemicrania, the headache relevant, give up relevant headache, rebound headache, tension headache with material or its with angiopathy, especially migraine, it comprises the aforesaid pharmaceutical composition solid dosage forms of orally give.Suitable is 5HT
1Receptor stimulating agent or its pharmaceutically acceptable derivates are sumatriptan or naratriptan or its pharmaceutically acceptable derivates, preferred sumatriptan or its pharmaceutically acceptable derivates, more preferably sumatriptan succinate (1: 1).Suitable is that NSAID is naproxen or COX-189 or its pharmaceutically acceptable salt, more preferably naproxen sodium.
We will be able to identify, and the amount of the chemical compound that uses as active component in solid dosage forms compositions of the present invention will depend on used specific compound.In addition, used accurate treatment dosage will depend on patient's age and situation and the character of being controlled disease, judge by accompanying or follow the doctor the most at last.
Work as 5HT
1When receptor stimulating agent was sumatriptan or naratriptan, the consumption of chemical compound in the present composition will be 0.1 in the scope of 250mg.Compositions can give for example 1 to 4 time every day, preferably once or twice.Work as 5HT
1When receptor stimulating agent is sumatriptan, the amount of sumatriptan, the form of pharmaceutically acceptable salt preferably will be at 1mg in the scope of 200mg, and preferred 20mg is to 150mg, and for example 25,50,85 or 100mg, represent with the weight of free alkali.Work as 5HT
1When receptor stimulating agent is naratriptan, the amount of naratriptan, the form of pharmaceutically acceptable salt preferably will be at 0.1mg in the scope of 25mg, and preferred 1mg represents with the weight of free alkali to 2.5mg.When NSAID was naproxen or COX-189, the consumption of chemical compound in the present composition will be 25 in the scope of 100mg.When NSAID is naproxen, the amount of naproxen, the form of pharmaceutically acceptable salt preferably, will be in the scope of 1100mg at 100mg, preferred 250mg is to 800mg, and for example 454.5mg or 500mg represent with the weight of free acid, or 275,350,400,500 or 550mg, represent with the weight of sodium salt.
In an especially preferred embodiment, pharmaceutical composition of the present invention is a double-layer tablet, it comprises the 85mg sumatriptan, it is the form of 119mg sumatriptan succinate, with the 550mg naproxen sodium, be equivalent to the 500mg naproxen, wherein sumatriptan is used for rapid release through preparation at least.
In an especially preferred embodiment, pharmaceutical composition of the present invention is a double-layer tablet, it comprises the 85mg sumatriptan, it is the form of 119mg sumatriptan succinate, with the 500mg naproxen sodium, be equivalent to the 454.5mg naproxen, wherein sumatriptan is used for rapid release through preparation at least.
Typically, in the especially migrainous treatment of headache, compositions is given as single dose; If the patient is standing knock-on pain or recurrence, so then can be after the suitable time, give subsequently single dose according to the indication of accompanying or follow the doctor and providing.Like this, the especially migrainous treatment of the headache of imagining in the context of the invention is carried out with regard to acute, the single dose administration by active component basically.Compositions can give for example 1 to 4 time every day, preferably once or twice.
Now will the present invention will be described by following examples, embodiment should not be interpreted as the restriction to it.
The direct compression tablet of sumatriptan succinate granule and naproxen sodium
Tablet prepares by suppressing on hydraulic pressure Carver tablet machine by using routine techniques.Target is a kind of single of preparation, and it can provide the quick dissolving (being equivalent to 85mg sumatriptan free alkali) and the suitable rate of release (being equivalent to 500mg naproxen free acid) of 550mg naproxen sodium of 119mg sumatriptan succinate.The target solubility curve of sumatriptan succinate is under the dissolution test condition of formerly describing, and 95% dissolving in 5 minutes is arranged.As for naproxen sodium, aim curve be can and golden standard, promptly (the 550mg naproxen sodium, Roche), it discharged about 57% under same solubility test condition in 15 minutes Anaprox0DS, the curve of competition.Fig. 1 has shown the naproxen sodium solubility curve that obtains from Anaprox 550mg commercial tablets.
The first step of formulation development is to determine the feasibility of the associating direct compression of two medicines.With different filleies and binding agent (anhydrous Emcompress , Avicel PH 102 and Prosolv SMCC
TM90), and disintegrating agent, fluidizer and the lubricant selected, and available sumatriptan succinate and naproxen sodium USP from Montrose, from Albemarle Corporation, make preparation together.Provided representational preparation in the table 1.
Table 1
| |
1 amount (mg) | 2 amounts (mg) | 3 amounts (mg) |
| Naproxen sodium | 550 | 550 | 550 |
| The |
120 | 120 | 120 |
| Filler/binding agent | |||
| Anhydrous Emcompress | 327.7(29.79％) | - | - |
| Avicel PH 102 | - | 327.7(29.79％) | - |
| Prosolve 90 | - | - | 331.0(30.09％) |
| Disintegrating agent | |||
| Primojel | 55(5％) | 55(5％) | 55(5％) |
| Fluidizer | |||
| Colloidal silica | 3.3(0.3％) | 3.3(0.3％) | - |
| Pulvis Talci | 33(3％) | 33(3％) | 33(3％) |
| Lubricant | |||
| Magnesium stearate | 11(1％) | 11(1％) | 11(1％) |
| Every gross weight | 1100 | 1100 | 1100 |
The problem of these preparations has produced further research, even promote disintegrate together with dissimilar naproxen sodium with excellent physical properties and effervescent.Following table 2 has shown composition.
Table 2
| Composition | Weight range (mg)/sheet (%w/w) |
| Naproxen sodium (90 microns) | 550(50％) |
| The sumatriptan succinate | 120(10.9％) |
| Filler/binding agent | |
| Anhydrous Emcompress and/or microcrystalline Cellulose | 220-330(20-30％) |
| Disintegrating agent | |
| Cross-linking sodium carboxymethyl cellulose and/or | 55(5％) |
| Sodium bicarbonate 1 | 55-110(5-10％) |
| Fluidizer | |
| Colloidal silica | 3.3(0.3％) |
| Pulvis Talci | 0-33(0-3％) |
| Lubricant | |
| Magnesium stearate | 11(1％) |
| Every gross weight | 1000-1100 |
1Sodium bicarbonate, " finishing " Effersoda of USP or SPI
By combination carbonate bases (for example sodium bicarbonate) and acid, will spontaneously carry out the effervescent reaction under the situation of moisture content with formation water and carbon dioxide existing.Effer-soda
TM, SPIPharma, be " high stability, the sodium bicarbonate powder of surface modification, it has particle diameter in a big way, successively good mobility and lower viscosity ".
Yet we find that but the 90-micron naproxen sodium of good physical properties is arranged, and the combination direct compression work of two kinds of medicines all is unsuccessful.
The quick dispersible tablet of sumatriptan succinate (FDT) granule and naproxen sodium are direct
Tabletting
A preparation of the quick dispersible preparation of sumatriptan of research combination should have the quick disintegrate of sumatriptan succinate material in combination product.
Form and be shown in the table 3.
Table 3Sumatriptan succinate granule and naproxen sodium direct compression
| Composition | Amount (mg) | Amount/crowd (g) |
| Naproxen sodium (90 microns) | 550 | 25 |
| The sumatriptan succinate | 119 | Xxxxxxx |
| Sumatriptan succinate: anhydrous Emcompress | 10.8 | |
| Filler/binding agent | ||
| Anhydrous Emcompress | 133.1(12.1％) | 6.05 |
| Disintegrating agent | ||
| Cross-linking sodium carboxymethyl cellulose | 110(10％) | 5.0 |
| Sodium bicarbonate | 110(10％) | 5.0 |
| Fluidizer | ||
| Colloidal silica | 3.3(0.3％) | 0.15 |
| Lubricant | ||
| Magnesium stearate | 11(1％) | 0.5 |
| Every gross weight | 1100 | 50 |
Owing to used Suma FDT compound method, viewed surface viscosity problem has been lowered in the former preparation preparation, but does not eliminate.Fig. 2 has shown the solubility curve (left side) of sumatriptan succinate, shows that sumatriptan discharged in 5 minutes, discharges 95% with independent FDT granule in 5 minutes and compares.The dissolving of naproxen sodium (right side) was 67% in 15 minutes, can compare with Anaprox DS.
The dissolving of these two compositions is all than the FDT granule being joined expect in the preparation slow.This result has drawn conclusion, and when being mixed together, naproxen sodium has damaged the particulate dissolving of sumatriptan.
Ensuing method is a double-layer tablet.Introduce the FDT granular preparation and will reduce adhesion the sumatriptan side as the individual course that comprises the sumatriptan succinate.
The direct compression that the naproxen sodium material is carried out comprises disintegrating agent, lubricant and filler.Shown representational preparation compositions in the table 4.
Table 4 comprises the preparation compositions of the double-layer tablet of sumatriptan succinate FDT granule and naproxen sodium direct compression
| Composition | Amount (mg/ sheet) | (％w/w) |
| | ||
| Sumatriptan succinate: anhydrous Emcompress (1: 1 ratio) | 238 | 68.0 |
| Avicel PH 102 (microcrystalline Cellulose) | 52.75 | 15.1 |
| Cross-linking sodium carboxymethyl cellulose | 17.5 | 5.0 |
| | 40 | 11.4 |
| Magnesium stearate | 1.75 | 0.5 |
| Total layer is heavy | 350 | 100 |
| | ||
| Naproxen sodium (90 microns) | 550 | 68.75 |
| Citric acid | 56 | 7.0 |
| Cross-linking sodium carboxymethyl cellulose | 24 | 3.0 |
| Effersoda (sodium bicarbonate of finishing) | 1.20 | 15 |
| Colloidal silica | 2.4 | 0.3 |
| Avicel PH 102 (microcrystalline Cellulose) | 35.6 | 4.45 |
| Magnesium stearate | 12 | 1.5 |
| Total layer is heavy | 800 | 100 |
Slamp value=18.5
Hardness=15kp under the 15.7kN press power
In double-layer tablet combination as two preparations of individual course can be from tablet rapid release sumatriptan succinate, and not from a large amount of interference of naproxen sodium.Fig. 3 has shown the solubility curve of this two-tiered approach.
Shown that based on the sumatriptan succinate among the FDT of double-deck compounded plate and the solubility curve of naproxen sodium the sumatriptan succinate has dissolved 95% in 5 minutes.This result has confirmed the favourable part of double-layer tablet in the situation of energy rapid release sumatriptan succinate.In addition, it is about 59% that naproxen sodium discharged in 15 minutes, very near golden standard Anaprox DS.
Other bilayer preparations is listed in the table 5, and all these comprises by the method for granulation handles sumatriptan succinate FDT layer and naproxen sodium layer.
Table 5
| The |
4 amounts (mg) | 5 amounts (mg) | 6 amounts (mg) | |
| |
||||
| Intragranular | The sumatriptan succinate | 119 | 119 | 119 |
| Anhydrous Emcompress | 119 | 119 | 119 | |
| Outside the grain | Avicel PH 102 | 100 | 100 | 100 |
| Cross-linking |
20 | 20 | 20 | |
| |
40 | 40 | 40 | |
| |
2 | 2 | 2 | |
| Layer gross weight | 400 | 400 | 400 | |
| |
||||
| Intragranular | Naproxen sodium | 500 | 500 | 500 |
| Avicel PH 101 | 54 | 54 | 54 | |
| Polyvinylpyrrolidone, PVP | 27 | - | 20.25- 33.75 | |
| Hydroxypropyl cellulose | - | 13.5-33.75 | - | |
| Outside the grain | Avicel PH 102 | 40 | QS | QS |
| Cross-linking sodium carboxymethyl cellulose | 20.25 | 20.25 | 20.25 | |
| Colloidal silica | - | 0-4.73 | 0-4.73 | |
| Pulvis Talci | 27 | 21.5-53.75 | 21.5- 53.75 | |
| Magnesium stearate | 6.75 | 6.75 | 6.75 | |
| Layer gross weight | 675 | 675 | 675 | |
| The label gross weight | 1075 | 1075 | 1075 | |
The preparation of embodiment 4 to 6 comprises following standard preparation steps:
The naproxen sodium layer:
High-shear granulation
The fluid bed drying granule; Grind
The dry mixed of granule and other excipient
Sumatriptan succinic acid salt deposit:
High-shear granulation
The fluid bed drying granule; Grind
The dry mixed of granule and other excipient
Be pressed into double-layer tablet
Conventional aqueous film coating is for example used Opadry, Opaglos
The solubility curve of embodiment 4 tablet formulations is presented at (USPI device, pH6.8, phosphate buffer, 50rpm, n=6 sheet) among Fig. 4.This has shown that the sumatriptan succinate has dissolved 95% in 5 minutes.This result has further confirmed the favourable part of double-layer tablet under the situation of energy rapid release sumatriptan succinate.In addition, the release of naproxen sodium in 15 minutes is higher than golden standard Anaprox DS greater than 70%.
This description and claims form application partly can be as the basis for priority about any subsequent application.The claim of this subsequent application can be any new feature or the combination that this paper describes feature.This can form product, compositions, method or purposes claim and can comprise, the mode by embodiment but be not construed as limiting one or more following claim.
Claims (37)
1. one kind contains the 5HT that makes up with NSAID or its pharmaceutically acceptable derivates
1The pharmaceutical composition of receptor stimulating agent or its pharmaceutically acceptable derivates, wherein 5HT
1Receptor stimulating agent and NSAID are positioned at discontinuous floor district with regard to each other, wherein active component and optional carrier are all contained in each floor district.
2. according to the pharmaceutical composition of claim 1, it contains the 5HT that is selected from sumatriptan, naratriptan, Zomitriptan, eletriptan, rizatriptan, frovatriptan, Almogran, avitriptan, Donitriptan, Alniditan, ALX-0646, LY334370, U1092291, IS159 and PNY142633
1Receptor stimulating agent.
3. according to the pharmaceutical composition of claim 2,5HT wherein
1Receptor stimulating agent is sumatriptan or naratriptan.
4. according to the pharmaceutical composition of claim 3,5HT wherein
1Receptor stimulating agent is a sumatriptan.
5. according to the pharmaceutical composition of claim 4, it contains the sumatriptan succinate.
6. according to the pharmaceutical composition of claim 1; it contains and is selected from diclofenac; nabumetone; naproxen; ketorolac; ibuprofen; flurbiprofen; ketoprofen; Ao Shaputai; etodolac; indometacin; mefenamic acid; tolfenamic acid and COX-2 selective depressant be celecoxib for example; Luo Feikaopu (VIOXX); valdecoxib; parecoxib; 4-(4-cyclohexyl-2-methyl-5-oxazolyl)-2-fluorobenzene sulfonamide (JTE-522); MK633 (etoricoxib); nimesulide; flosulide; DFP; 2-(4-ethyoxyl-phenyl)-3-(4-methane sulfonyl-phenyl)-pyrazolo [1; 5-b] pyridazine; Metro former times health; RS57067; piroxicam; NS398; L-745,337 and the NSAID of COX-189.
7. according to the pharmaceutical composition of claim 6, wherein NSAID is COX-189 or naproxen.
8. according to the pharmaceutical composition of claim 7, wherein NSAID is a naproxen.
9. pharmaceutical composition according to Claim 8, wherein naproxen is a naproxen sodium.
10. contain 5HT with the NSAID combination
1The pharmaceutical composition of receptor stimulating agent or its pharmaceutically acceptable derivates and pharmaceutically acceptable carrier, wherein 5HT
1Receptor stimulating agent and NSAID are dispersed in pharmaceutical composition in its oneself the pharmaceutically acceptable carrier each other.
11. according to the pharmaceutical composition of claim 10,5HT in the compositions wherein
1The carrier of receptor stimulating agent is different with the carrier of NSAID.
12. according to the pharmaceutical composition of claim 10, wherein 5HT
1Receptor stimulating agent and carrier thereof and NSAID and carrier thereof are well-mixed.
13. according to the medication medication compositions of claim 10, it is a tablet form.
14. according to the pharmaceutical composition of claim 1, wherein 5HT
1The appropriate carrier of receptor stimulating agent comprises one or more and is selected from following composition: binding agent, filler, lubricant and paired effervescent composition, wicking agent, fluidizer, disintegrating agent and wetting agent.
15. according to the pharmaceutical composition of claim 1, wherein the appropriate carrier of NSAID comprises one or more and is selected from following composition: binding agent, filler, lubricant and effervescent composition, wicking agent, fluidizer, disintegrating agent and wetting agent in pairs.
16. according to the pharmaceutical composition of claim 1, it is a multilayer tablet, wherein active component is in isolating layer.
17. according to the pharmaceutical composition of claim 16, it is a double-layer tablet.
18. according to the pharmaceutical composition of claim 1, it contains the 5HT with NSAND or its pharmaceutically acceptable derivant combination
1Receptor stimulating agent or its pharmaceutically acceptable derivates, wherein 5HT
1Receptor stimulating agent and NSAID are positioned at discontinuous floor district with regard to each other, wherein active component and optional carrier are all contained in each floor district, wherein contain 5HT in addition at least
1The floor district of receptor stimulating agent be through the preparation to guarantee fast Absorption.
19. according to the pharmaceutical composition of claim 18, it is to contain two-layer or multiwalled tablet, wherein contains 5HT
1A layer of receptor stimulating agent or its pharmaceutically acceptable derivant be through the preparation to guarantee fast Absorption, another layer contains NSAID or its pharmaceutically acceptable derivates and optional carrier.
20. according to the pharmaceutical composition of claim 19, it is a double-layer tablet, contains and comprises 5HT
1The layer of receptor stimulating agent or its pharmaceutically acceptable derivant, its be through preparation guaranteeing fast Absorption, and the layer that contains NSAID or its pharmaceutically acceptable derivates and optional carrier.
21. according to the pharmaceutical composition of claim 18, wherein 5HT
1Receptor stimulating agent or its pharmaceutically acceptable derivates are with paired effervescent composition and make up disintegrating agent, insoluble bulking agent and wicking agent and prepare.
22. according to the pharmaceutical composition of claim 18, wherein 5HT
1Receptor stimulating agent or its pharmaceutically acceptable derivates are prepared with alkaline components, disintegrating agent and the insoluble bulking agent of paired effervescent composition, wherein alkaline components accounts for about 5 of this layer of dosage form dry weight and arrives about 50% weight, disintegrating agent accounts for about 0.5 to about 10% weight, insoluble bulking agent accounts for about 20 to about 99% weight, described insoluble bulking agent comprises wicking agent, it accounts for about 1 to about 99% weight, and the active component dissolving in five minutes in simulated gastric fluid (SGF) under the property the distinguished oar speed of 10rpm in the USPII device greater than about 70% is wherein arranged.
23. according to the pharmaceutical composition of claim 1, wherein 5HT
1The receptor stimulating agent layer contains 5HT
1Receptor stimulating agent or its pharmaceutically acceptable derivates, it accounts for about 0.001 of this layer of dosage form dry weight and arrives about 55% weight, the alkaline components of effervescent composition accounts for about 5 to about 50% weight in pairs, disintegrating agent accounts for about 0.5 to about 10% weight, insoluble bulking agent, comprise wicking agent, account for about 35 to about 80% weight, wicking agent accounts for about 1 to about 80% weight.
24. according to the pharmaceutical composition of claim 18, wherein in the NSAID layer, NSAID or its pharmaceutically acceptable derivates be through preparation to be used for fast Absorption.
25. according to the pharmaceutical composition of claim 18, wherein in the NSAID layer, NSAID or its pharmaceutically acceptable derivates are with paired effervescent composition and make up disintegrating agent, insoluble bulking agent and wicking agent and prepare.
26. pharmaceutical composition according to claim 18, wherein NSAID or its pharmaceutically acceptable derivates and the alkaline components of effervescent composition in pairs, disintegrating agent and insoluble bulking agent are prepared together, wherein alkaline components accounts for about 5 of this layer of dosage form dry weight and arrives about 50% weight, disintegrating agent accounts for about 0.5 to about 20% weight, insoluble bulking agent accounts for about 30 to about 80% weight, described insoluble bulking agent comprises wicking agent, it accounts for about 1 to about 60% weight, and the active component dissolving in five minutes in simulated gastric fluid under the property the distinguished oar speed of 30rpm in the USPII device greater than about 25% is wherein arranged.
27. pharmaceutical composition according to claim 1, wherein the NSAID layer contains NSAID or its pharmaceutically acceptable derivates, it accounts for about 1 of this layer of dosage form dry weight and arrives about 90% weight, the alkaline components of effervescent composition accounts for about 5 to about 50% weight in pairs, disintegrating agent accounts for about 0.05 to about 10% weight, insoluble bulking agent comprises wicking agent, accounts for about 10 to about 99% weight.
28. according to the pharmaceutical composition of claim 1, it is a double-layer tablet, wherein 5HT
1The receptor stimulating agent layer contains 5HT
1Receptor stimulating agent or its pharmaceutically acceptable derivates, it accounts for about 0.001 of this layer of dosage form dry weight and arrives about 55% weight, the alkaline components of effervescent composition accounts for about 5 to about 50% weight in pairs, disintegrating agent accounts for about 0.5 to about 10% weight, insoluble bulking agent, comprise wicking agent, account for about 35 to about 80% weight, wicking agent accounts for about 1 to about 80% weight, the NSAID layer contains NSAID or its pharmaceutically acceptable derivates, it accounts for about 1 of this layer of dosage form dry weight and arrives about 90% weight, the alkaline components of effervescent composition accounts for about 5 to about 50% weight in pairs, and disintegrating agent accounts for about 0.05 to about 10% weight, insoluble bulking agent, comprise wicking agent, account for about 10 to about 99% weight.
29. according to the pharmaceutical composition of claim 1, wherein 5HT
15HT is contained in receptor stimulating agent floor district
1Receptor stimulating agent or its pharmaceutically acceptable derivates, it contains sumatriptan or naratriptan or its pharmaceutically acceptable derivates, the alkaline components of effervescent composition comprises sodium bicarbonate in pairs, and disintegrating agent comprises cross-linking sodium carboxymethyl cellulose, and insoluble bulking agent comprises microcrystalline Cellulose.
30. according to the pharmaceutical composition of claim 1, wherein 5HT
15HT is contained in receptor stimulating agent floor district
1Receptor stimulating agent or its pharmaceutically acceptable derivates, it contains sumatriptan or naratriptan or its pharmaceutically acceptable derivates, the alkaline components of effervescent composition comprises sodium bicarbonate in pairs, disintegrating agent comprises cross-linking sodium carboxymethyl cellulose, insoluble bulking agent comprises calcium hydrogen phosphate, preferred calcium phosphate dibasic anhydrous.
31. according to the pharmaceutical composition of claim 1, wherein 5HT
15HT is contained in receptor stimulating agent floor district
1Receptor stimulating agent or its pharmaceutically acceptable derivates, it contains sumatriptan or its pharmaceutically acceptable derivates, the alkaline components of effervescent composition comprises sodium bicarbonate in pairs, disintegrating agent comprises cross-linking sodium carboxymethyl cellulose, and insoluble bulking agent comprises calcium hydrogen phosphate or microcrystalline Cellulose or its mixture.
32. according to the pharmaceutical composition of claim 20, the 550mg naproxen sodium that it contains the 85mg sumatriptan of promising 119mg sumatriptan succinate form and is equivalent to the 500mg naproxen.
33. according to the pharmaceutical composition of claim 20, the 500mg naproxen sodium that it contains the 85mg sumatriptan of promising 119mg sumatriptan succinate form and is equivalent to the 454.5mg naproxen.
34. be used for the treatment of the pharmaceutical composition with the relevant disease of headache according to claim 1, described disease be selected from cluster headache, chronic paroxysmal hemicrania, the headache relevant with angiopathy, and material or its give up relevant headache, rebound headache, tension headache and migraine.
35. treatment suffers from or the mammiferous method of susceptible and headache diseases related, headache be selected from cluster headache, chronic paroxysmal hemicrania, the headache relevant with angiopathy, and material or its give up relevant headache, rebound headache, tension headache and migraine, it comprises the pharmaceutical composition of orally give according to the solid dosage forms of claim 1.
36. according to the method for claim 36, wherein mammal is the people.
37. according to the method for claim 36, wherein said disease is a migraine.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US47648403P | 2003-06-06 | 2003-06-06 | |
| US60/476,484 | 2003-06-06 | ||
| US60/487,413 | 2003-07-15 | ||
| US60/490,385 | 2003-07-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1832758A true CN1832758A (en) | 2006-09-13 |
Family
ID=36994618
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200480022544 Pending CN1832758A (en) | 2003-06-06 | 2004-06-02 | Pharmaceutical composition |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1832758A (en) |
| ZA (1) | ZA200509860B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102088966B (en) * | 2008-06-20 | 2015-06-10 | 阿尔法制药有限公司 | Pharmaceutical formulation |
-
2004
- 2004-06-02 CN CN 200480022544 patent/CN1832758A/en active Pending
-
2005
- 2005-12-05 ZA ZA200509860A patent/ZA200509860B/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102088966B (en) * | 2008-06-20 | 2015-06-10 | 阿尔法制药有限公司 | Pharmaceutical formulation |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200509860B (en) | 2007-03-28 |
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