CN102755310A - Composition drug preparation containing levodopa - Google Patents
Composition drug preparation containing levodopa Download PDFInfo
- Publication number
- CN102755310A CN102755310A CN2012102605781A CN201210260578A CN102755310A CN 102755310 A CN102755310 A CN 102755310A CN 2012102605781 A CN2012102605781 A CN 2012102605781A CN 201210260578 A CN201210260578 A CN 201210260578A CN 102755310 A CN102755310 A CN 102755310A
- Authority
- CN
- China
- Prior art keywords
- levodopa
- preparation
- amantadine
- salt
- release
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 title claims abstract description 168
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 title claims abstract description 153
- 229960004502 levodopa Drugs 0.000 title claims abstract description 144
- 238000002360 preparation method Methods 0.000 title claims abstract description 105
- 239000003814 drug Substances 0.000 title claims abstract description 84
- 239000000203 mixture Substances 0.000 title claims description 61
- 229940079593 drug Drugs 0.000 title abstract description 35
- 201000010099 disease Diseases 0.000 claims abstract description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 24
- 239000002775 capsule Substances 0.000 claims abstract description 23
- 230000033001 locomotion Effects 0.000 claims abstract description 9
- 208000011580 syndromic disease Diseases 0.000 claims abstract description 9
- 230000002496 gastric effect Effects 0.000 claims abstract description 8
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 claims description 78
- 229960003805 amantadine Drugs 0.000 claims description 56
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 35
- 239000000463 material Substances 0.000 claims description 32
- 239000003826 tablet Substances 0.000 claims description 29
- 238000000576 coating method Methods 0.000 claims description 28
- 239000011248 coating agent Substances 0.000 claims description 25
- 238000009501 film coating Methods 0.000 claims description 19
- 239000007888 film coating Substances 0.000 claims description 18
- 208000018737 Parkinson disease Diseases 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 11
- 239000004925 Acrylic resin Substances 0.000 claims description 10
- 229920000178 Acrylic resin Polymers 0.000 claims description 10
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 10
- 239000001856 Ethyl cellulose Substances 0.000 claims description 10
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 10
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 10
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 10
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- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 10
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 5
- 229930006000 Sucrose Natural products 0.000 claims description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 5
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 5
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- 150000001875 compounds Chemical class 0.000 claims description 5
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 5
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- 239000005720 sucrose Substances 0.000 claims description 5
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
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- 235000011132 calcium sulphate Nutrition 0.000 claims 1
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- 208000027089 Parkinsonian disease Diseases 0.000 abstract description 8
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- 238000013265 extended release Methods 0.000 abstract description 7
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- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 19
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- IVTMXOXVAHXCHI-YXLMWLKOSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid;(2s)-3-(3,4-dihydroxyphenyl)-2-hydrazinyl-2-methylpropanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1.NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 IVTMXOXVAHXCHI-YXLMWLKOSA-N 0.000 description 10
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- 229960004205 carbidopa Drugs 0.000 description 7
- TZFNLOMSOLWIDK-JTQLQIEISA-N carbidopa (anhydrous) Chemical compound NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 TZFNLOMSOLWIDK-JTQLQIEISA-N 0.000 description 7
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
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- BNQDCRGUHNALGH-UHFFFAOYSA-N benserazide Chemical compound OCC(N)C(=O)NNCC1=CC=C(O)C(O)=C1O BNQDCRGUHNALGH-UHFFFAOYSA-N 0.000 description 3
- 230000006866 deterioration Effects 0.000 description 3
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- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical compound C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 2
- YVPUUUDAZYFFQT-UHFFFAOYSA-N 7-(4-methylpiperazin-1-yl)-3h-1,3-benzoxazol-2-one Chemical compound C1CN(C)CCN1C1=CC=CC2=C1OC(=O)N2 YVPUUUDAZYFFQT-UHFFFAOYSA-N 0.000 description 2
- 102000015554 Dopamine receptor Human genes 0.000 description 2
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- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 description 2
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- WOLHOYHSEKDWQH-UHFFFAOYSA-N amantadine hydrochloride Chemical compound [Cl-].C1C(C2)CC3CC2CC1([NH3+])C3 WOLHOYHSEKDWQH-UHFFFAOYSA-N 0.000 description 2
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- JRURYQJSLYLRLN-BJMVGYQFSA-N entacapone Chemical compound CCN(CC)C(=O)C(\C#N)=C\C1=CC(O)=C(O)C([N+]([O-])=O)=C1 JRURYQJSLYLRLN-BJMVGYQFSA-N 0.000 description 2
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a solid oral extended-release preparation which provides extended-release levodopa and admantadine and can be tablets, capsules and micropills, and belongs to the technical field of drug extended-release preparations. The tablets, capsules and micropills can be ordinary gastric soluble or enteric soluble preparations; and the drug release form can be extended release or double release. The drug extended-release preparation which is composed of levodopa (levodopa salt) and admantadine (admantadine salt) is used for treating parkinsonism and other movement-related symptoms, diseases or syndrom.
Description
Technical field
The present invention relates to a kind of solid-state oral slow-releasing preparation that slow release (extended release) levodopa and amantadine are provided, be tablet, capsule, pellet, belong to the medicament slow release preparation technical field.Described tablet, capsule, pellet can be common gastric solubility or enteric solubility preparation, and its drug release form can be slow release or rapid release or two releasing.The medicament slow release preparation that this levodopa or levodopa salt and amantadine or amantadine salt are formed is used to treat parkinson disease and relevant disease, disease or the syndrome of other motions.
Background technology
The cause of disease of parkinson (PD) also is not very clear now.Generally acknowledge that at present its cause of disease is the degeneration of neurocyte, a kind of gradual disease causes that mainly due to ganglion basal dopamine receptor functional deterioration the major lesions position is at black substance and striatum.A kind of neurocyte that is nigral cell is arranged here, and the progressively forfeiture of minimizing, function gradually of nigral cell quantity causes a kind of material of dopamine that cries to reduce, thereby causes above-mentioned symptom.
Drug therapy PD is main with Drug therapy still at present, recovers striatum DA and Ach mediator system balancing, uses anticholinergic and improves DA mediator function medicament, improves symptom.Principle of medication: 1. begin, slowly increase progressively, obtain satisfactory effect with smaller dose as far as possible from low dose; 2. the therapeutic scheme individuation is selected medicine according to patient age, symptom type and degree employment status, drug price and ability to shoulder economically etc.; 3. should blindly not add medicament, unsuitable drug withdrawal suddenly need be taken throughout one's life; 4. the PD Drug therapy is complicated; The ancillary drug DR excitomotor of releasing in recent years, MAO-B inhibitor, catechol-oxygen position-transmethylase etc.; Share the mitigation symptoms fluctuation that to heighten the effect of a treatment with Carbidopa and reduce Carbidopa dosage; Use curative effect undesirable separately, should weigh the advantages and disadvantages, suitably select drug combination.
The parkinson disease curative that has gone on the market at present still can not satisfy clinical demand.In whole therapeutic process, there is not a kind of single Therapeutic Method in full force and effect; Therefore should carry out the specific aim treatment according to the order of severity of the disease different phase and the state of an illness.
In the main seven big medical markets of the whole world (U.S., Japan, France, Germany, Italy, Spain and Britain), there are more than 150 ten thousand people to suffer the puzzlement of parkinsonism (PD).
PD is a kind of gradual disease, causes mainly due to ganglion basal dopamine receptor functional deterioration.The related clinical symptoms of PD is more.Wherein in unstable these 4 main clinic symptoms of bradykinesia, tetanic, static tremor and posture, 2 symptoms to occur as diagnostic characteristic.Up to now, still do not have effective ways treatment PD clinically, present medicine mainly is the clinical symptoms that alleviates PD.
Guangdong Pharmaceutical University has applied for " a kind of compositions and application thereof that contains levodopa and Borneolum Syntheticum " in 2010.03.23, and application number is: 201010132986.X the invention discloses a kind of compositions and application thereof that contains levodopa and Borneolum Syntheticum.When the present composition was used to prepare the medicine of treatment parkinson disease or restless legs syndrome, toxic and side effects is little, and was evident in efficacy, was fit to clinical being widely used.
The Beijing DeZhong Wanquan Drug Technology Development Co., Ltd has applied for " a kind of pharmaceutical composition that contains levodopa and benserazide hydrochloride " in 2008.07.09, and application number is: 200810116328.4.The invention discloses a kind of pharmaceutical composition that contains levodopa and benserazide hydrochloride, mix with levodopa and pharmaceutically acceptable carrier again after Ro-4-4602. is dispersed in the specific carrier.Having good stability of this compositions is used to treat parkinson disease, symptomatic parkinsonism (after the encephalitis, arteriosclerotic or toxic).
Hanoverian, Germany Solvay Pharma GmbH has applied for " combination preparation that comprises SLV308 and levodopa " in 2007.06.15; Application number is: 200780022520.0 the present invention relates to SLV308 or its N-oxide; Or those chemical compounds (I), the last acceptable salt of pharmacology of (II) and the combination preparation of levodopa are used for being used to simultaneously, respectively or in turn treat the obstacle, particularly parkinson disease of needs recovery dopaminergic function and the purposes of restless legs syndrome.2007.05.31; " long-term 24 hour intestinal administration of levodopa/carbidopa " have been applied for; Application number is: the Parkinsonian method of 200780019726.8 treatments; It is included in greater than in during 16 hours continuously pharmaceutically the compositions of effective dose through intestinal this patient who needs is arranged, said compositions comprises levodopa and the optional carbidopa that comprises.
The benefactor has applied for " levodopa/carbidopa/entacapone pharmaceutical preparation " in 2000.06.29 in the Espoo, Finland Europe, and application number is: 00809586.8.The present invention relates to oral administration solid fixed dosage compositions, said composition comprises entacapone, levodopa and carbidopa or its pharmaceutically acceptable salt or the hydrate that the pharmacology goes up effective dose, and comprises at least a pharmaceutically acceptable excipient.Compositions of the present invention for example can be used for parkinsonian treatment.
Dublin, Ireland Unelhatt Corp. has applied for " pharmaceutical composition that contains levodopa and carbidopa " in 2004.04.06, and application number is: 200480010282.8.The present invention relates to oral solid drug composition, be used for the constant of levodopa/carbidopa combination and discharge with prolonging, said compositions is used to treat parkinson disease.
Massachusetts, USA Transform Pharmaceuticals Inc. has applied for " pharmaceutical composition and the method for using levodopa and carbidopa " in 2004.08.26, and application number is: 200480024879.8.The present invention relates to the stable composition of levodopa and carbidopa, use these combination treatments patient's method, and prepare these method for compositions.
Virgin Islands Tortola Island Osmotica Corp. has applied for " extended release solid pharmaceutical composition that contains Carbidopa " in 2006.08.04, and application number is: 200680029229.1.The invention provides a kind of compressed tablets of slow releasing tablet of the levodopa that the carbidopa that contains the slow release form and slow release form be provided.Said tablet randomly further comprises the release immediately or the rapid release composition of carbidopa and/or levodopa.A kind of tablet can contain with the slow release form with discharge rapidly or the levodopa that exists of releasing pattern immediately, and with the slow release form with discharge rapidly or the carbidopa that exists of releasing pattern immediately.Said tablet is used to treat parkinson disease and relevant disease, disease or the syndrome of other motions.
Nimeguen, Holland Synthon B. V. has applied for " montelukast amantadine salt " in 2007.03.15, and application number is: 200780009429.5.The present invention relates to the method for the amantadine salt of montelukast, the method for preparing montelukast amantadine salt, the pharmaceutical composition that comprises this salt and purification of montelukast or its salt.
Levodopa (L-DOPA) is used to treat the history in existing more than 40 year of PD.Be still at present and alleviate the efficacious therapy method of PD clinical symptoms.Dopamine can not pass blood brain barrier, and levodopa then can pass blood brain barrier and get into intracranial, and is metabolized to dopamine at intracranial.
Yet levodopa has significant disadvantages.One of which, medication is frequent: on average need take 5 every day.Its two, early treatment's effect is obvious, but this effect generally can only be kept 1～5 year.Along with the state of an illness further worsens, the therapeutic effect of levodopa will weaken gradually, so that be difficult to control the symptom that the patient occurs again.And then the state of an illness is further development of the motor complication obstacle.These dyskinesia comprise the fluctuation of PD symptom, unusual fluctuation disease, tremble and fall etc.So in PD treatment guide, stress when using the levodopa treatment parkinson, will note 2 points: first postpones the use (young patient that especially those is needed long-term treatment) of exogenous levodopa; Second delays the deterioration of PD symptom.
Except that L-DOPA, quite a few kinds of different classes of medicines also can be used for treating PD.But these medicines only play the effect of regulating the endogenous dopamine level.Present most typical therapeutic scheme is to adopt the method for different medicines to postpone the use of levodopa in the course of disease stage by stage.
Thereby another kind of therapeutic strategy then is the symptom fluctuation that reduces PD patient through the L-DOPA slow releasing preparation.The compound slow release preparation IPX066 that is in III phase clinical stage (carbidopa levodopa) by IMPAX pharmacy/GlaxoSmithKline PLC research and development then is the most promising a kind of medicine.Compare with the L-DOPA quick releasing formulation that need take 5 those every days, IPX066 only need take 3 times every day.
The levodopa pharmacological action: levodopa amine is synthetic dopamine precursor in the body; Itself is parmacodynamics-less activity also; Get into maincenter through blood brain barrier; Change into dopamine and play a role through the DOP Adecarboxylase effect, improve the adjusting that random neural impulse conducts to motor cortex, make the sx of primary disease.
Amantadine (amantadine) pharmacological action: promoting DA to discharge at teleneuron, stop reuptake also anticholinergic effect to be arranged, is that glutamic acid antagonistic strive forward has neuroprotective, can improve less moving, tetanic and trembles etc.
Simultaneously, bibliographical information is arranged, clinical application levodopa and amantadine drug combination treatment PD have good potentiation.In amantadine sheet (capsule) preparation description, mention, initial amantadine has merged with levodopa to be used, and then the dosage of amantadine should maintain 100mg, every day 1 or 2 times, and levodopa should increase to till the righttest curative effect gradually.When share, potentiation can be arranged, if can reduce single levodopa consumption with cholinolytic type antiparkinsonian drug or levodopa; Make the symptom that is occurred or side effect makes moderate progress or curative effect is not undulatory property; When curative effect is lost, use amantadine if add, then curative effect can be recovered again.
Therefore, the present invention forms compound recipe with amantadine and levodopa, on the one hand can potentiation, and can reduce the levodopa consumption on the other hand, thereby reduce the side effect of levodopa itself.According to amantadine day maintenance dose, and with reference to the two controlled release tablet specifications (50mg/200mg) of clinging in the card left side of drugs approved by FDA.
Amantadine is rapid and complete in gastrointestinal absorption, is distributed in after the absorption in saliva, the nasal secretions.Content in animal tissue especially lung is higher than the content of serum.These article can pass through Placenta Hominis and blood brain barrier.Normal person's half-life of renal function is 11～15 hours, and the renal failure person is 24 hours.The patient Ke Da of long-term dialysis 7～10 days.2～4 hours blood drug level peakings in oral back are about 0.3 μ g/ml; Every day, the pill taker can reach Css in 2～3 days, and steady plasma-drug concentration is 0.2～0.9 μ g/ml.Mainly by RE.Discharge with urine through glomerular filtration with original shape more than 90%, part can passively absorb again; Excretion rate can advance to add rapidly in aciduria; Also have on a small quantity and drain by milk.Do the patient of hemodialysis, have only a small amount of (about 4%) to remove in the blood without leave.
The oral back of levodopa is by little intestinal absorption.1～2 hour blood drug level peaking behind the (medicine) being taken before meal is distributed widely in each tissue in the body, and 1% entering maincenter changes into dopamine and plays a role, all the other major parts all outside brain the metabolism decarboxylation become dopamine, so onset is slow.Half-life (t1/2) is 1～3 hour, as uses the periphery dopa decarboxylase inhibitor, can reduce the consumption of levodopa, and the amount that makes it to get in the brain increases, and can reduce the untoward reaction that the periphery dopamine causes.Oral back 80% was degraded into the dopamine metabolite in 24 hours, be mainly 4-hydroxy-3-methoxy-.alpha.-toluic acid. and dihydroxyphenyl acetic acid, and by RE, some metabolite can make urinates the color that reddens.It is about 5% that prototype excretes, and can pass through galactopoiesis.
Can know from the pharmacokinetics of amantadine, levodopa; Be suitable for levodopa is developed into the slow release release; Amantadine is developed into general rapid release release, thereby the two drug half-life and the relatively stable coordination of blood drug level are got up, reduced the fluctuation of blood drug level; And prolonged administration time, reduced administration number of times.
Levodopa (L-DOPA) is used to treat the history in existing more than 40 year of parkinsonism (PD).Be still at present and alleviate the efficacious therapy method of PD clinical symptoms.Yet the symptom fluctuation can appear in the PD patient of nearly all employing L-DOPA treatment to a certain extent, thus the drug development merchant recognize reduce the patient because of the dyskinesia that uses the L-DOPA treatment and occurs and symptom fluctuate important.
It is that slow release, amantadine (100mg) are the enteric coatel tablets of common quick release that the present invention adopts levodopa (t1/2: be 1～3 hour) and amantadine (t1/2: be 11～15 hours) to be developed into levodopa (200mg) according to the different half-life of medicine.Its innovative point is: 1, levodopa and amantadine are formed new compound preparation, all do not go public both at home and abroad, belong to chemical medicine 1.5 kind new medicines by " medicine registration management way "; 2, the modern medicines novel form, the new technique that adopt slow release to combine with rapid release; 3, be developed into enteric coatel tablets, reduced gastrointestinal side effect, this medicine and prescription enteric coatel tablets thereof are not all gone public both at home and abroad at present.
At present, the modern novel form of the medicine that the present invention adopted, new technique belong to initiative both at home and abroad.Has following advantage: one, levodopa is developed into the slow release release pharmaceutical formulations, has reduced the untoward reaction of levodopa, kept the stable state of blood drug level better, thereby effectively reduce PD patient's symptom fluctuation; Two, amantadine and levodopa drug combination have increased the dose of levodopa through blood brain barrier, have reduced the consumption of levodopa, thereby have further reduced the untoward reaction of levodopa; Three, according to all absorbing good characteristics in little intestinal absorption and amantadine at gastrointestinal tract in levodopa; The two drug development is become enteric coatel tablets; Significantly reduced untoward reaction such as gastrointestinal tract is felt sick, vomiting, inappetence, thereby improved greatly parkinsonism (PD) patient's quality of life and the compliance that makes medicament.
Technical scheme
The invention discloses a kind of slow releasing preparation that contains the composition medicine of levodopa, be tablet, capsule, pellet.Described tablet, capsule, pellet can be common gastric solubility or enteric solubility preparation, and its drug release form can be slow release or rapid release or two releasing (slow release and rapid release) combination.The medicament slow release preparation that this levodopa and amantadine are formed is used to treat parkinson disease and relevant disease, disease or the syndrome of other motions.
Technical scheme of the present invention is achieved in that
(1) the present invention with levodopa or levodopa salt and amantadine or amantadine salt be active ingredient in addition pharmaceutically acceptable pharmaceutic adjuvant process the matrix type pair release tablet formulations that are used to treat relevant disease, disease or syndromes of parkinson disease and other motions; Wherein the weight of levodopa every single dose (a slice) in tablet is 10mg～500mg, preferred 200mg; The weight of every single dose (a slice) is 5mg～300mg in amantadine or the amantadine salt tablets, preferred 100mg; The weight of the every single dose of pharmaceutic adjuvant (a slice) is 15mg～2200mg, and preferred 300mg～1000mg is specific as follows:
Concrete preparation process is:
Method one: the 1. preparation of matrix sustained release tablet core: with levodopa or levodopa salt and a certain amount of pharmaceutic adjuvant, cross 80 mesh standard sieves behind the pulverize separately, take by weighing by recipe quantity; Fully mix together; Add a certain amount of 50%～95% alcoholic solution again as binding agent, the preparation soft material is crossed 20 mesh standard sieves; Cross 16～30 mesh standard sieve granulate, tabletting after 3 hours in 60 ℃ of dryings;
2. rapid release film coating solution preparation: amantadine or amantadine salt are added in film-coat type material (as: Opadry) or sugar-coat type material or the enteric coating type material (as: acrylic resin II number, III number, cellulose acetate-phthalate); Fully stir dissolving, temperature is controlled at 37～40 ℃;
3. coating: spray coating, 40 ℃～65 ℃ of intake air temperatures, 35 ℃～55 ℃ of air outlet temperature, atomizing pressure 15-50psi, rotating speed 8～16rpm, fluid transfer rate 20-54g/min;
4. the quality of controlling every is 30～3000mg.
Method two: the 1. two preparations of releasing the sheet slow-releasing granules of matrix type: with levodopa or levodopa salt and a certain amount of pharmaceutic adjuvant; Cross 80 mesh standard sieves behind the pulverize separately, take by weighing, fully mix together by recipe quantity; Add a certain amount of 50%～95%～95% alcoholic solution again as binding agent; The preparation soft material is crossed 20 mesh standard sieves, crosses 16～30 mesh standard sieve granulate after 3 hours in 60 ℃ of dryings.
2. the two preparations of releasing the sheet immediate-release granules of matrix type: with amantadine or amantadine salt and a certain amount of pharmaceutic adjuvant; Cross 80 mesh standard sieves behind the pulverize separately, take by weighing, fully mix together by recipe quantity; Add a certain amount of 50%～95% alcoholic solution again as binding agent; The preparation soft material is crossed 20 mesh standard sieves, crosses 16～30 mesh standard sieve granulate after 3 hours in 60 ℃ of dryings.
3. tabletting: in the prescription ratio with slow-releasing granules and immediate-release granules mix homogeneously after tabletting, the quality of controlling every is 30～3000mg.
4. coating: adopt in film-coat type material (as: Opadry) or sugar-coat type material or the enteric coating type material (as: acrylic resin II number, III number, cellulose acetate-phthalate); Fully stir dissolving, spray coating, 40 ℃～65 ℃ of intake air temperatures; 35 ℃～55 ℃ of air outlet temperature; Atomizing pressure 15-50psi, rotating speed 8～16rpm, fluid transfer rate 20-54g/min.
Said pharmaceutic adjuvant is microcrystalline cellulose (MCC), Polyethylene Glycol (PEG), hydroxypropyl methylcellulose (HPMC), hydroxyethyl-cellulose (HEC), polyvinylpyrrolidone (PVP), Brazil wax, medical starch, lactose, glucose, sucrose, ethyl cellulose (EC), crosslinked Carboxymethyl cellulose sodium, calcium phosphate, calcium sulfate is a kind of or combination in any;
Described lubricant is one or more combination of magnesium stearate, Pulvis Talci, silicon dioxide;
Described coating material is one or more combination of film-coat type material (as: Opadry), sugar-coat type material, enteric coating type material (as: acrylic resin II number, III number, cellulose acetate-phthalate).
Advantage of the present invention:
1. levodopa is developed into the slow release release pharmaceutical formulations, has reduced the untoward reaction of levodopa, kept the stable state of blood drug level better, thereby effectively reduce PD patient's symptom fluctuation;
2. amantadine and levodopa drug combination have increased the dose of levodopa through blood brain barrier, have reduced the consumption of levodopa, thereby have further reduced the untoward reaction of levodopa;
3. according to all absorbing good characteristics in little intestinal absorption and amantadine at gastrointestinal tract in levodopa; The two drug development is become enteric coatel tablets; Significantly reduced untoward reaction such as gastrointestinal tract is felt sick, vomiting, inappetence, thereby improved greatly parkinsonism (PD) patient's quality of life and the compliance that makes medicament.
4. the present invention adopts the coatings immediate release drug, makes that immediate release drug discharges more rapidly, drug level is more even.
5. the present invention adopts the matrix sustained release tablet core, makes slow releasing pharmaceutical discharge more speed stabilizing, and tablet can half-and-half be mixed to open and take, and does not influence drug release.
(2) the present invention with levodopa or levodopa salt and amantadine or amantadine salt be active ingredient in addition pharmaceutically acceptable pharmaceutic adjuvant process the film controlling type pair release tablet formulations that are used to treat relevant disease, disease or syndromes of parkinson disease and other motions; Wherein the weight of levodopa every single dose (a slice) in tablet is 10mg～500mg, preferred 200mg; The weight of every single dose (a slice) is 5mg～300mg in amantadine or the amantadine salt tablets, preferred 100mg; The weight of the every single dose of pharmaceutic adjuvant (a slice) is 15mg～2200mg, and preferred 300mg～1000mg is specific as follows:
Concrete preparation process is:
Method one: the 1. preparation of slow release label: with levodopa or levodopa salt and a certain amount of pharmaceutic adjuvant, cross 80 mesh standard sieves behind the pulverize separately, take by weighing by recipe quantity; Fully mix together; Add a certain amount of 50%～95% alcoholic solution again as binding agent, the preparation soft material is crossed 20 mesh standard sieves; Cross 16～30 mesh standard sieve granulate, tabletting after 3 hours in 60 ℃ of dryings;
2. film control coatings: sustained release coating material preparation coating solution is arranged, carry out spray coating, 40 ℃～65 ℃ of intake air temperatures, 35 ℃～55 ℃ of air outlet temperature, atomizing pressure 15-50psi, rotating speed 8～16rpm, fluid transfer rate 20-54g/min;
3. rapid release film coating solution preparation and coating: amantadine or amantadine salt are added in film-coat type material (as: Opadry) or sugar-coat type material or the enteric coating type material (as: acrylic resin II number, III number, cellulose acetate-phthalate); Fully stir dissolving; Carry out spray coating at film control layer again, coating conditions and parameter are the same;
4. the quality of controlling every is 30～3000mg.
Said pharmaceutic adjuvant is microcrystalline cellulose (MCC), Polyethylene Glycol (PEG), hydroxypropyl methylcellulose (HPMC), hydroxyethyl-cellulose (HEC), polyvinylpyrrolidone (PVP), Brazil wax, medical starch, lactose, glucose, sucrose, ethyl cellulose (EC), carboxymethyl starch sodium (CMS), low-substituted hydroxypropyl cellulose (L-HPC), crosslinked Carboxymethyl cellulose sodium, calcium phosphate, calcium sulfate is a kind of or combination in any;
Described lubricant is one or more combination of magnesium stearate, Pulvis Talci, silicon dioxide;
Described coating material is the enteric coating type material like the combination of one or more of acrylic resin II number, III number, cellulose acetate-phthalate.
Advantage of the present invention:
1. levodopa is developed into the slow release release pharmaceutical formulations, has reduced the untoward reaction of levodopa, kept the stable state of blood drug level better, thereby effectively reduce PD patient's symptom fluctuation;
2. amantadine and levodopa drug combination have increased the dose of levodopa through blood brain barrier, have reduced the consumption of levodopa, thereby have further reduced the untoward reaction of levodopa;
3. according to all absorbing good characteristics in little intestinal absorption and amantadine at gastrointestinal tract in levodopa; The two drug development is become enteric coatel tablets; Significantly reduced untoward reaction such as gastrointestinal tract is felt sick, vomiting, inappetence, thereby improved greatly parkinsonism (PD) patient's quality of life and the compliance that makes medicament.
4. the present invention adopts film coating double speed to discharge medicine, makes that drug release is more constant, drug level is more even.
(3) the present invention with levodopa or levodopa salt and amantadine or amantadine salt be active ingredient in addition pharmaceutically acceptable pharmaceutic adjuvant process the film controlling type that is used to treat parkinson disease and other motions relevant disease, disease or syndromes and pair release capsules; Wherein the weight of levodopa every single dose () in tablet is 10mg～500mg, preferred 200mg; The weight of every single dose (a slice) is 5mg～300mg in amantadine or the amantadine salt tablets, preferred 100mg; The weight of the every single dose of pharmaceutic adjuvant () is 15mg～2200mg, and preferred 300mg～1000mg is specific as follows:
Concrete preparation process is:
1. the preparation of slow release capsule-core: with a certain amount of pharmaceutic adjuvant; Cross 80 mesh standard sieves behind the pulverize separately, take by weighing, fully mix together by recipe quantity; Add a certain amount of 50%～95% alcoholic solution again as binding agent; The preparation soft material is crossed 20 mesh standard sieves, crosses 32 mesh standard sieve granulate after 3 hours in 60 ℃ of dryings;
2. the preparation one of rapid release capsule-core: with a certain amount of pharmaceutic adjuvant; Cross 80 mesh standard sieves behind the pulverize separately, take by weighing, fully mix together by recipe quantity; Add a certain amount of 50%～95% alcoholic solution again as binding agent; The preparation soft material is crossed 20 mesh standard sieves, crosses 16～30 mesh standard sieve granulate after 3 hours in 60 ℃ of dryings;
3. the preparation two of rapid release capsule-core: amantadine or amantadine salt are dissolved in the film coating liquid, carry out spray coating, 40 ℃～65 ℃ of intake air temperatures; 35 ℃～55 ℃ of air outlet temperature; Atomizing pressure 15-50psi, rotating speed 8～16rpm, fluid transfer rate 20-54g/min;
4. adopt the enteric capsule shell packing, the quality of controlling every is 30～3000mg.
Said pharmaceutic adjuvant is microcrystalline cellulose (MCC), Polyethylene Glycol (PEG), hydroxypropyl methylcellulose (HPMC), hydroxyethyl-cellulose (HEC), polyvinylpyrrolidone (PVP), Brazil wax, medical starch, lactose, glucose, sucrose, ethyl cellulose (EC), carboxymethyl starch sodium (CMS), low-substituted hydroxypropyl cellulose (L-HPC), crosslinked Carboxymethyl cellulose sodium, calcium phosphate, calcium sulfate is a kind of or combination in any;
Described lubricant is one or more combination of magnesium stearate, Pulvis Talci, silicon dioxide;
Described coating material is one or more combination of Opadry, standard thin film coating solution.
Advantage of the present invention:
1. levodopa is developed into the slow release release pharmaceutical formulations, has reduced the untoward reaction of levodopa, kept the stable state of blood drug level better, thereby effectively reduce PD patient's symptom fluctuation;
2. amantadine and levodopa drug combination have increased the dose of levodopa through blood brain barrier, have reduced the consumption of levodopa, thereby have further reduced the untoward reaction of levodopa;
3. according to all absorbing good characteristics in little intestinal absorption and amantadine at gastrointestinal tract in levodopa; The two drug development is become enteric coated capsule; Significantly reduced untoward reaction such as gastrointestinal tract is felt sick, vomiting, inappetence, thereby improved greatly parkinsonism (PD) patient's quality of life and the compliance that makes medicament;
4. big at the gastrointestinal tract distribution area, bioavailability is high, and zest is little;
4, the present invention with levodopa or levodopa salt and amantadine or amantadine salt be active ingredient in addition pharmaceutically acceptable pharmaceutic adjuvant process the pellets of pair releasing that are used to treat parkinson disease and other motions relevant disease, disease or syndromes; Wherein the weight of levodopa every single dose (20) in tablet is 10mg～500mg, preferred 200mg; The weight of every single dose in amantadine or the amantadine salt tablets (20) is 5mg～300mg, preferred 100mg; The weight of the every single dose of pharmaceutic adjuvant (20) is 15mg～2200mg, and preferred 300mg～1000mg is specific as follows:
Concrete preparation process is:
1. two preparations of releasing the ball core: with a certain amount of pharmaceutic adjuvant; Cross 80 mesh standard sieves behind the pulverize separately, take by weighing, fully mix together by recipe quantity; Add a certain amount of 50%～95% alcoholic solution again as binding agent; The preparation soft material, can through centrifugal impelling method or boiling granulating method or spray granulation method or coating pan method extrude spheronization or liquid in method such as granulation prepare micropill, preferably extrude spheronization.
2. film coating solution preparation: amantadine or amantadine salt are added in film-coat type material (as: Opadry) or sugar-coat type material or the enteric coating type material (as: acrylic resin II number, III number, cellulose acetate-phthalate); Fully stir dissolving, temperature is controlled at 37～40 ℃;
3. coating: spray coating or fluidized bed coating, 40 ℃～65 ℃ of intake air temperatures, 35 ℃～55 ℃ of air outlet temperature, atomizing pressure 15-50psi, rotating speed 8～16rpm, fluid transfer rate 20-54g/min;
4. controlling per 20 quality is 30～3000mg.
5. adopt common gastric-dissolved capsule or enteric capsule shell packing.
Said pharmaceutic adjuvant is microcrystalline cellulose (MCC), Polyethylene Glycol (PEG), hydroxypropyl methylcellulose (HPMC), hydroxyethyl-cellulose (HEC), polyvinylpyrrolidone (PVP), Brazil wax, medical starch, lactose, glucose, sucrose, ethyl cellulose (EC), carboxymethyl starch sodium (CMS), low-substituted hydroxypropyl cellulose (L-HPC), crosslinked Carboxymethyl cellulose sodium, calcium phosphate, calcium sulfate is a kind of or combination in any;
Described lubricant is one or more combination of magnesium stearate, Pulvis Talci, silicon dioxide;
Described coating material is the enteric coating type material like the combination of one or more of acrylic resin II number, III number, cellulose acetate-phthalate.
Advantage of the present invention:
1. levodopa is developed into the slow release release pharmaceutical formulations, has reduced the untoward reaction of levodopa, kept the stable state of blood drug level better, thereby effectively reduce PD patient's symptom fluctuation;
2. amantadine and levodopa drug combination have increased the dose of levodopa through blood brain barrier, have reduced the consumption of levodopa, thereby have further reduced the untoward reaction of levodopa;
3. according to all absorbing good characteristics in little intestinal absorption and amantadine at gastrointestinal tract in levodopa; The two drug development is become enteric coated micropill; Significantly reduced untoward reaction such as gastrointestinal tract is felt sick, vomiting, inappetence, thereby improved greatly parkinsonism (PD) patient's quality of life and the compliance that makes medicament.
4. big at the gastrointestinal tract distribution area, bioavailability is high, and zest is little;
5. because particle diameter is little, receive digestive tract to carry the food rhythm and pace of moving things to influence little (close like pylorus etc.).
The specific embodiment
Various details embodiment, but content of the present invention is not limited thereto fully.
Embodiment 1: the two enteric coatel tablets of releasing of Buddha's warrior attendant levodopa (L-dopa)
Preparation process is:
1. the preparation of slow release label: with levodopa and a certain amount of pharmaceutic adjuvant, cross 80 mesh standard sieves behind the pulverize separately, take by weighing by recipe quantity; Fully mix together; Add a certain amount of 65% alcoholic solution again as binding agent, the preparation soft material is crossed 20 mesh standard sieves; Cross 20 mesh standard sieve granulate, tabletting after 3 hours in 60 ℃ of dryings;
2. film coating solution preparation (intestinal rapid release): amantadine is added in the enteric coating type material (as: acrylic resin II number, III number, cellulose acetate-phthalate), fully stir dissolving, temperature is controlled at 37～40 ℃;
3. coating: earlier with release membranes control coatings on the slow release label coating, again with intestinal rapid release coating solution spray coating, 40 ℃～65 ℃ of intake air temperatures; 35 ℃～55 ℃ of air outlet temperature; Atomizing pressure 15-50psi, rotating speed 8～16rpm, fluid transfer rate 20-54g/min;
4. the quality of controlling every is 30～3000mg.
Embodiment 2: the two gastric soluble tablets of releasing of Buddha's warrior attendant levodopa (L-dopa)
Preparation process is:
1. the preparation of slow release label: with levodopa and a certain amount of pharmaceutic adjuvant, cross 80 mesh standard sieves behind the pulverize separately, take by weighing by recipe quantity; Fully mix together; Add a certain amount of 65% alcoholic solution again as binding agent, the preparation soft material is crossed 20 mesh standard sieves; Cross 20 mesh standard sieve granulate, tabletting after 3 hours in 60 ℃ of dryings;
2. film coating solution preparation (stomach rapid release): amantadine is added film-coat type material (as: Opadry) or sugar-coat type material, fully stir dissolving, temperature is controlled at 37～40 ℃;
3. coating: spray coating, 40 ℃～65 ℃ of intake air temperatures, 35 ℃～55 ℃ of air outlet temperature, atomizing pressure 15-50psi, rotating speed 8～16rpm, fluid transfer rate 20-54g/min;
4. the quality of controlling every is 30～3000mg.
Embodiment 3: the two enteric coated capsulees of releasing of Buddha's warrior attendant levodopa (L-dopa)
1. the preparation of slow release capsule-core: with levodopa and a certain amount of pharmaceutic adjuvant; Cross 80 mesh standard sieves behind the pulverize separately, take by weighing, fully mix together by recipe quantity; Add a certain amount of 65% alcoholic solution again as binding agent; The preparation soft material is crossed 20 mesh standard sieves, crosses 32 mesh standard sieve granulate after 3 hours in 60 ℃ of dryings;
2. the preparation of rapid release capsule-core: amantadine is dissolved in the film coating liquid, the slow release capsule-core is carried out spray coating, 40 ℃～65 ℃ of intake air temperatures; 35 ℃～55 ℃ of air outlet temperature; Atomizing pressure 15-50psi, rotating speed 8～16rpm, fluid transfer rate 20-54g/min;
4. adopt the enteric capsule shell packing, the quality of controlling every is 30～3000mg.
Embodiment 4: the two capsules of releasing of Buddha's warrior attendant levodopa (L-dopa)
1. the preparation of slow release capsule-core: with levodopa and a certain amount of pharmaceutic adjuvant; Cross 80 mesh standard sieves behind the pulverize separately, take by weighing, fully mix together by recipe quantity; Add a certain amount of 65% alcoholic solution again as binding agent; The preparation soft material is crossed 20 mesh standard sieves, crosses 32 mesh standard sieve granulate after 3 hours in 60 ℃ of dryings;
2. the preparation of rapid release capsule-core: amantadine is dissolved in the film coating liquid, carries out spray coating, 40 ℃～65 ℃ of intake air temperatures, 35 ℃～55 ℃ of air outlet temperature, atomizing pressure 15-50psi, rotating speed 8～16rpm, fluid transfer rate 20-54g/min;
3. adopt the packing of conventional capsule shell, the quality of controlling every is 30～3000mg.
Embodiment 5: the two enteric-coated microcapsules of releasing of Buddha's warrior attendant levodopa (L-dopa)
Preparation process is:
1. the preparation of slow release ball core: with levodopa and a certain amount of pharmaceutic adjuvant, cross 80 mesh standard sieves behind the pulverize separately, take by weighing by recipe quantity; Fully mix together; Add a certain amount of 80% alcoholic solution again as binding agent, the preparation soft material is through extruding spheronizator; Cross 60 mesh standard sieves, cross 60 mesh standard sieve granulate after 3 hours in 60 ℃ of dryings;
2. film coating solution preparation (intestinal rapid release): amantadine is added in the enteric coating type material (as: acrylic resin II number, III number, cellulose acetate-phthalate), fully stir dissolving, temperature is controlled at 37～40 ℃;
3. coating: spray coating or fluidized bed coating, 40 ℃～65 ℃ of intake air temperatures, 35 ℃～55 ℃ of air outlet temperature, atomizing pressure 15-50psi, rotating speed 8～16rpm, fluid transfer rate 20-54g/min;
4. controlling per 20 quality is 30～3000mg.
Embodiment 6: the two gastric solubleness microcapsules of releasing of Buddha's warrior attendant levodopa (L-dopa)
Preparation process is:
1. the preparation of slow release ball core: with levodopa and a certain amount of pharmaceutic adjuvant, cross 80 mesh standard sieves behind the pulverize separately, take by weighing by recipe quantity; Fully mix together; Add a certain amount of 80% alcoholic solution again as binding agent, the preparation soft material is through extruding spheronizator; Cross 60 mesh standard sieves, cross 60 mesh standard sieve granulate after 3 hours in 60 ℃ of dryings;
2. film coating solution preparation (stomach rapid release): amantadine is added film-coat type material (as: Opadry) or sugar-coat type material, fully stir dissolving, temperature is controlled at 37～40 ℃;
3. coating: spray coating or fluidized bed coating, 40 ℃～65 ℃ of intake air temperatures, 35 ℃～55 ℃ of air outlet temperature, atomizing pressure 15-50psi, rotating speed 8～16rpm, fluid transfer rate 20-54g/min;
4. controlling per 20 quality is 30～3000mg.
Embodiment 7: the two enteric coated capsulees of releasing of Buddha's warrior attendant levodopa (L-dopa)
1. the preparation of slow release capsule-core: with hydrochloric acid levodopa and a certain amount of pharmaceutic adjuvant; Cross 80 mesh standard sieves behind the pulverize separately, take by weighing, fully mix together by recipe quantity; Add a certain amount of 65% alcoholic solution again as binding agent; The preparation soft material is crossed 20 mesh standard sieves, crosses 32 mesh standard sieve granulate after 3 hours in 60 ℃ of dryings;
2. the preparation of rapid release capsule-core: with amantadine hydrochloride and a certain amount of pharmaceutic adjuvant; Cross 80 mesh standard sieves behind the pulverize separately, take by weighing, fully mix together by recipe quantity; Add a certain amount of 65% alcoholic solution again as binding agent; The preparation soft material is crossed 20 mesh standard sieves, crosses 32 mesh standard sieve granulate after 3 hours in 60 ℃ of dryings;
3. mix coating: with above two kinds of capsule-cores, use film coating liquid, carry out spray coating, 40 ℃～65 ℃ of intake air temperatures, 35 ℃～55 ℃ of air outlet temperature, atomizing pressure 15-50psi, rotating speed 8～16rpm, fluid transfer rate 20-54g/min:
4. adopt the enteric capsule shell packing, the quality of controlling every is 30～3000mg.
Embodiment 8: the two gastric-dissolved capsules of releasing of Buddha's warrior attendant levodopa (L-dopa)
1. the preparation of slow release capsule-core: with hydrochloric acid levodopa and a certain amount of pharmaceutic adjuvant; Cross 80 mesh standard sieves behind the pulverize separately, take by weighing, fully mix together by recipe quantity; Add a certain amount of 65% alcoholic solution again as binding agent; The preparation soft material is crossed 20 mesh standard sieves, crosses 32 mesh standard sieve granulate after 3 hours in 60 ℃ of dryings;
2. the preparation of rapid release capsule-core: with amantadine hydrochloride and a certain amount of pharmaceutic adjuvant; Cross 80 mesh standard sieves behind the pulverize separately, take by weighing, fully mix together by recipe quantity; Add a certain amount of 65% alcoholic solution again as binding agent; The preparation soft material is crossed 20 mesh standard sieves, crosses 32 mesh standard sieve granulate after 3 hours in 60 ℃ of dryings;
3. mix coating: with above two kinds of capsule-cores, use film coating liquid, carry out spray coating, 40 ℃～65 ℃ of intake air temperatures, 35 ℃～55 ℃ of air outlet temperature, atomizing pressure 15-50psi, rotating speed 8～16rpm, fluid transfer rate 20-54g/min;
4. adopt the packing of common gastric-dissolved capsule shell, the quality of controlling every is 30～3000mg.
Embodiment 9: the two enteric coated capsulees of releasing of Buddha's warrior attendant levodopa (L-dopa)
1. the preparation of slow release capsule-core: with levodopa and a certain amount of pharmaceutic adjuvant; Cross 80 mesh standard sieves behind the pulverize separately, take by weighing, fully mix together by recipe quantity; Add a certain amount of 65% alcoholic solution again as binding agent; The preparation soft material is crossed 20 mesh standard sieves, crosses 32 mesh standard sieve granulate after 3 hours in 60 ℃ of dryings;
2. the preparation of rapid release capsule-core: with amantadine and a certain amount of pharmaceutic adjuvant; Cross 80 mesh standard sieves behind the pulverize separately, take by weighing, fully mix together by recipe quantity; Add a certain amount of 65% alcoholic solution again as binding agent; The preparation soft material is crossed 20 mesh standard sieves, crosses 32 mesh standard sieve granulate after 3 hours in 60 ℃ of dryings;
3. mix coating: with above two kinds of capsule-cores, use film coating liquid, carry out spray coating, 40 ℃～65 ℃ of intake air temperatures, 35 ℃～55 ℃ of air outlet temperature, atomizing pressure 15-50psi, rotating speed 8～16rpm, fluid transfer rate 20-54g/min;
4. adopt the enteric capsule shell packing, the quality of controlling every is 30～3000mg.
Claims (18)
1. a composition medicine slow releasing preparation that contains levodopa is characterized in that: slow releasing tablet or capsule or pellet that this preparation is made up of levodopa, amantadine and pharmaceutic adjuvant.
2. by the described a kind of composition medicine preparation that contains levodopa of claim 1, it is characterized in that: described slow releasing preparation is for slow release or is two (slow release and rapid release) combined pharmaceutical formulations of releasing.
3. by the described a kind of composition medicine preparation that contains levodopa of claim 1, it is characterized in that: in the said preparation by levodopa or levodopa salt and amantadine or the compound recipe combination slow releasing preparation formed by amantadine salt.
4. by the described a kind of composition medicine preparation that contains levodopa of claim 1; It is characterized in that: said pharmaceutic adjuvant label is by one or more combination of microcrystalline cellulose (MCC), Polyethylene Glycol (PEG), hydroxypropyl methylcellulose (HPMC), hydroxyethyl-cellulose (HEC), polyvinylpyrrolidone (PVP), carboxymethyl starch sodium (CMS), low-substituted hydroxypropyl cellulose (L-HPC), Brazil wax, medical starch, lactose, glucose, sucrose, ethyl cellulose (EC), crosslinked Carboxymethyl cellulose sodium, calcium phosphate, calcium sulfate, magnesium stearate, Pulvis Talci, silicon dioxide, and coating solution is by one or more combination of film-coat material (as: Opadry), sugar coating material, enteric coating material (as: acrylic resin II number, III number, cellulose acetate-phthalate).
5. by claim 1 or 2 or 3 or 4 described a kind of composition medicine preparations that contain levodopa, it is characterized in that: described pharmaceutical preparation is applied to treat parkinson disease and relevant disease, disease or the syndrome of other motions.
6. by claim 1 or 2 or 3 or 4 described a kind of composition medicine preparations that contain levodopa; It is characterized in that: the every single dose specification of levodopa or levodopa salt is 10mg～500mg, amantadine or is 5mg～300mg by the every single dose specification of amantadine salt in the described pharmaceutical preparation, and every single dose specification of pharmaceutic adjuvant is 30mg～3000mg.
7. by claim 1 or 2 or 3 or 4 described a kind of composition medicine preparations that contain levodopa, it is characterized in that: levodopa or levodopa salt are natural extract in the described pharmaceutical preparation.
8. by claim 1 or 2 or 3 or 4 described a kind of composition medicine preparations that contain levodopa, it is characterized in that: levodopa or levodopa salt are synthetic in the described pharmaceutical preparation.
9. by claim 1 or 2 or 3 or 4 described a kind of composition medicine preparations that contain levodopa, it is characterized in that: levodopa or levodopa salt are slow release, amantadine or are rapid release by amantadine salt in the described pharmaceutical preparation.
10. by the described a kind of composition medicine preparation that contains levodopa of claim 9, it is characterized in that: levodopa or levodopa salt are matrix type slow release, amantadine or are film coating type rapid release by amantadine salt in the described pharmaceutical preparation.
11. by the described a kind of composition medicine preparation that contains levodopa of claim 9, it is characterized in that: levodopa or levodopa salt are slow release and amantadine or by the two release formulations of the film coating type of amantadine salt rapid release combination in the described pharmaceutical preparation.
12. by claim 1 or 2 or 3 or 4 described a kind of composition medicine preparations that contain levodopa, it is characterized in that: described medicament slow release preparation tablet, capsule, pellet are gastric solubleness pharmaceutical preparation.
13. by claim 1 or 2 or 3 or 4 described a kind of composition medicine preparations that contain levodopa, it is characterized in that: described medicament slow release preparation tablet, capsule, pellet are enteric pharmaceutical preparation.
14. by claim 1 or 2 or 3 or 4 described a kind of composition medicine preparations that contain levodopa, it is characterized in that: described medicament slow release preparation tablet, capsule, pellet are the showy pharmaceutical preparation of stomach.
15. by claim 1 or 2 or 3 or 4 described a kind of composition medicine preparations that contain levodopa; It is characterized in that: levodopa or 6～22 hours release time of levodopa salt in the described medicament slow release preparation, amantadine or amantadine salt release time are 2～12 hours.
16. by claim 1 or 2 or 3 or 4 described a kind of composition medicine preparations that contain levodopa, it is characterized in that: figure of tablet is circular piece or ellipse slice in the described medicament slow release preparation.
17. by claim 1 or 2 or 3 or 4 described a kind of composition medicine preparations that contain levodopa, it is characterized in that: levodopa or levodopa salt are matrix type or film coating type in the described medicament slow release preparation.
18. by claim 1 or 2 or 3 or 4 described a kind of composition medicine preparations that contain levodopa, it is characterized in that: amantadine or amantadine salt are matrix type or film coating type in the described medicament slow release preparation.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106085651A (en) * | 2016-06-24 | 2016-11-09 | 南京为绿生物科技有限公司 | Green health spacetabs type cleaning toilet is precious |
| CN106333933A (en) * | 2016-09-19 | 2017-01-18 | 南京为绿生物科技有限公司 | Tegafur gimeracil oteracil potassium sustained-release bilayer tablet and preparation method thereof |
| CN107951875A (en) * | 2017-12-05 | 2018-04-24 | 王增强 | A kind of composite preparation containing levodopa |
| CN114617206A (en) * | 2022-04-01 | 2022-06-14 | 山东省淡水渔业研究院（山东省淡水渔业监测中心） | Microecological preparation for water diversion of snakehead fries in food conversion period and preparation method thereof |
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| WO2004087116A2 (en) * | 2003-03-05 | 2004-10-14 | Osmotica Corp. | Drug combination for motor dysfunction in parkinson's disease |
| US20070148238A1 (en) * | 2005-06-23 | 2007-06-28 | Spherics, Inc. | Dosage forms for movement disorder treatment |
| EP1909768A1 (en) * | 2005-08-05 | 2008-04-16 | Osmotica Corp. | Extended release solid pharmaceutical composition containing carbidopa and levodopa |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004087116A2 (en) * | 2003-03-05 | 2004-10-14 | Osmotica Corp. | Drug combination for motor dysfunction in parkinson's disease |
| US20070148238A1 (en) * | 2005-06-23 | 2007-06-28 | Spherics, Inc. | Dosage forms for movement disorder treatment |
| EP1909768A1 (en) * | 2005-08-05 | 2008-04-16 | Osmotica Corp. | Extended release solid pharmaceutical composition containing carbidopa and levodopa |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106085651A (en) * | 2016-06-24 | 2016-11-09 | 南京为绿生物科技有限公司 | Green health spacetabs type cleaning toilet is precious |
| CN106333933A (en) * | 2016-09-19 | 2017-01-18 | 南京为绿生物科技有限公司 | Tegafur gimeracil oteracil potassium sustained-release bilayer tablet and preparation method thereof |
| CN107951875A (en) * | 2017-12-05 | 2018-04-24 | 王增强 | A kind of composite preparation containing levodopa |
| CN114617206A (en) * | 2022-04-01 | 2022-06-14 | 山东省淡水渔业研究院（山东省淡水渔业监测中心） | Microecological preparation for water diversion of snakehead fries in food conversion period and preparation method thereof |
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| CN102755310B (en) | 2016-06-15 |
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