CN1159313C - Alkali-metal or alkali-earth metal salt of polyprotic acid delotadine and its medical composition - Google Patents
Alkali-metal or alkali-earth metal salt of polyprotic acid delotadine and its medical composition Download PDFInfo
- Publication number
- CN1159313C CN1159313C CNB021289980A CN02128998A CN1159313C CN 1159313 C CN1159313 C CN 1159313C CN B021289980 A CNB021289980 A CN B021289980A CN 02128998 A CN02128998 A CN 02128998A CN 1159313 C CN1159313 C CN 1159313C
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- China
- Prior art keywords
- salt
- delotadine
- sodium
- acid
- pharmaceutical composition
- Prior art date
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- Expired - Lifetime
Links
- 150000003839 salts Chemical class 0.000 title claims abstract description 94
- 239000000203 mixture Substances 0.000 title claims abstract description 12
- 229910052784 alkaline earth metal Chemical class 0.000 title claims abstract description 5
- 150000007519 polyprotic acids Chemical class 0.000 title claims description 27
- 229910052783 alkali metal Inorganic materials 0.000 title abstract 2
- 150000001340 alkali metals Chemical class 0.000 title abstract 2
- 239000002131 composite material Substances 0.000 claims abstract description 33
- -1 compound salt Chemical class 0.000 claims abstract description 9
- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 claims description 60
- 238000002360 preparation method Methods 0.000 claims description 30
- 229910052751 metal Inorganic materials 0.000 claims description 24
- 239000002184 metal Substances 0.000 claims description 24
- 239000003826 tablet Substances 0.000 claims description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 18
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims description 14
- BALXUFOVQVENIU-KXNXZCPBSA-N pseudoephedrine hydrochloride Chemical compound [H+].[Cl-].CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 BALXUFOVQVENIU-KXNXZCPBSA-N 0.000 claims description 14
- 229960003447 pseudoephedrine hydrochloride Drugs 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 10
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- 239000011734 sodium Substances 0.000 claims description 9
- 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 8
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 8
- 239000002775 capsule Substances 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- YQSHYGCCYVPRDI-UHFFFAOYSA-N (4-propan-2-ylphenyl)methanamine Chemical compound CC(C)C1=CC=C(CN)C=C1 YQSHYGCCYVPRDI-UHFFFAOYSA-N 0.000 claims description 7
- 229960003782 dextromethorphan hydrobromide Drugs 0.000 claims description 7
- 239000006188 syrup Substances 0.000 claims description 7
- 235000020357 syrup Nutrition 0.000 claims description 7
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 6
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 6
- 159000000000 sodium salts Chemical class 0.000 claims description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 239000008187 granular material Substances 0.000 claims description 5
- 229940095064 tartrate Drugs 0.000 claims description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
- 206010011224 Cough Diseases 0.000 claims description 4
- HSRJKNPTNIJEKV-UHFFFAOYSA-N Guaifenesin Chemical compound COC1=CC=CC=C1OCC(O)CO HSRJKNPTNIJEKV-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- 239000011575 calcium Substances 0.000 claims description 4
- 239000001530 fumaric acid Substances 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- NKAAEMMYHLFEFN-UHFFFAOYSA-M monosodium tartrate Chemical compound [Na+].OC(=O)C(O)C(O)C([O-])=O NKAAEMMYHLFEFN-UHFFFAOYSA-M 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 206010036790 Productive cough Diseases 0.000 claims description 3
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 3
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 229960001340 histamine Drugs 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- 235000015598 salt intake Nutrition 0.000 claims description 3
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- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 claims description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 229910052728 basic metal Inorganic materials 0.000 claims description 2
- 150000003818 basic metals Chemical class 0.000 claims description 2
- 238000013270 controlled release Methods 0.000 claims description 2
- 229960001193 diclofenac sodium Drugs 0.000 claims description 2
- 239000007919 dispersible tablet Substances 0.000 claims description 2
- 229960001680 ibuprofen Drugs 0.000 claims description 2
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims description 2
- 229960000991 ketoprofen Drugs 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229960002009 naproxen Drugs 0.000 claims description 2
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 claims description 2
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 claims description 2
- KZQSXALQTHVPDQ-UHFFFAOYSA-M sodium;butanedioate;hydron Chemical class [Na+].OC(=O)CCC([O-])=O KZQSXALQTHVPDQ-UHFFFAOYSA-M 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- ADVGKWPZRIDURE-UHFFFAOYSA-N 2'-Hydroxyacetanilide Chemical compound CC(=O)NC1=CC=CC=C1O ADVGKWPZRIDURE-UHFFFAOYSA-N 0.000 claims 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 48
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Abstract
The present invention relates to the 8-chlorine-6, 11-dihydro-11-(4-piperidylene)-5H-benzo [5, 6] cyclohepta [1, 2-6] pyridine, namely polyacid alkali metal called as delotadine or compound salt of alkaline-earth metal salts and a medicinal composition which is prepared by taking the composite salt as an active component.
Description
Technical field:
The present invention relates to 8-chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo [5,6] ring heptan [1,2-b] pyridine also, promptly be called the polybasic acids or bases metal of delotadine (Desloratadine) or alkaline earth salt composite salt and be the medicinal compositions that activeconstituents is made with this composite salt.
Background technology:
Delotadine is the active metabolite of non-sedating antihistaminic Loratadine (loratadine), the alternative H1 acceptor that suppresses.United States Patent (USP) 5,595,997 (1997.1.21 mandates) propose, delotadine both can provide effectively, the treatment of the antihistamine of no sedative effect, also can avoid many and often earn the relevant common serious side effects of antihistaminic agent (especially for example Loratadine, Triludan and astemizole) administration with common antihistaminic agent and other non-town.Importantly, the specific activity Loratadine of known delotadine in tumor enhancement low 5 to 7 times, and the validity of delotadine on Histamine Receptors is at least than high about 20 times of Loratadine.Therefore, compare with Loratadine, the delotadine effect is stronger, and security is better, at present listing application in worldwide.
Yet CN98802313.X discloses: can not under the prerequisite that has water to exist, contain especially lactose of monose and disaccharides in the delotadine preparation prescription, otherwise the stability of drug extreme difference.Promptly under its typical case's preparation and condition of storage, lactose and delotadine can form a kind of brown product, wherein delotadine height degraded.Brown intensity generally depends on content, condition of storage (for example humidity and temperature) and the length of shelf lives of delotadine.The solution that proposes has two kinds (1) not use especially lactose of monose and disaccharides in the pharmaceutical composition of delotadine and pharmaceutical salts thereof; (2) even must use, first mode that can take delotadine and pharmaceutical salts thereof and monose and disaccharides especially lactose are completely cut off is promptly at first with delotadine and pharmaceutical salts dressing thereof or after making micro-capsule, again with lactose blended mode.The second, also can be by the mode of strict control anhydrous condition.Under these two kinds of conditions, delotadine and pharmaceutical salts raw material thereof mix also with lactose can keep its stability.
But, it is to be noted: lactose is at many pharmaceutical dosage forms, for example is commonly used for the compound of weighting agent in tablet, capsule or the pulvis, does not use especially lactose of monose and disaccharides in the pharmaceutical composition prescription, can give to produce makes troubles, and influences the quality of medicine.The two kinds of conditions in back can only partly increase the stability of raw material, and operate loaded down with trivial detailsly, and cost is higher.More need further to be pointed out that: because delotadine solubleness in water is lower, the solubleness in 25 ℃ of water only is 0.0723mg/ml, may directly influence its absorption in vivo, and can not give full play to drug effect.
Summary of the invention:
The invention discloses delotadine polybasic acids or bases metal or alkaline earth salt composite salt and pharmaceutical composition thereof.It is moderate that composite salt of the present invention has good stability, good water solubility, pH value, solved the defective that delotadine can not be produced preparation with the glucide compatibility simultaneously.
Owing in the molecular structure of delotadine an amino is arranged, therefore might be that one mole the delotadine and the acidic-group of monovalent react and generation salt.The inventor studies show that through various test conditionss: as long as with delotadine and the polybasic acids or bases metal or the alkaline-earth metal reactant salt that contain the equivalent acidic-group, just can make it become water-soluble salt.Here said equivalent is meant wherein remaining carboxyl for polybasic acid sodium salt; For the inorganic multivariate hydrochlorate, be meant acidic-group unnecessary in the inorganic multivariate hydrochlorate.For example: contain a carboxyl in the disodium hydrogen citrate salt, such one mole delotadine can generate corresponding Water Soluble Compound salt with one mole disodium hydrogen citrate reactant salt; Contain an acidic-group in the sodium bisulfite, such one mole delotadine can generate corresponding Water Soluble Compound salt with one mole sodium bisulfite reaction.Other polybasic acids or bases metal-salt can and the like.The inventor finds under study for action: delotadine polybasic acids or bases metal or alkaline earth salt composite salt are by the thin layer inspection, the result show delotadine polybasic acids or bases metal or alkaline earth salt composite salt apparent principal spot identical with the Rf value of delotadine principal spot, the aqueous solution that they are described is easy to discharge delotadine, can bring into play the effect identical with delotadine in vivo.Experimentation on animals has also drawn same result.
Said polybasic acids or bases metal or alkaline earth salt must pharmaceutically allow among the present invention, and it is wanted and can have enough water miscible salt with the delotadine generation; Its pH value of water solution will suit, and can guarantee that contained delotadine is not damaged; Formed in addition composite salt is easy to discharge delotadine in the aqueous solution, can bring into play drug effect rapidly and fully to guarantee it.
Delotadine polybasic acids or bases metal of the present invention or alkaline earth salt composite salt, polyprotonic acid wherein, it is Citric Acid, tartrate, succsinic acid, fumaric acid, toxilic acid, oxalic acid, phosphoric acid, sulfuric acid, sulfurous acid, basic metal wherein or alkaline-earth metal, be sodium, potassium, calcium, magnesium, zinc, preferably: disodium hydrogen citrate salt, Citric Acid dihydro sodium salt, the hydrogen tartrate sodium salt, Sodium Bisuccinate salt, fumaric acid hydrogen sodium salt, toxilic acid hydrogen sodium salt, sodium bioxalate salt, the hydrogen sulfate sodium salt, sodium bisulfite salts, perlate salt, most preferably: disodium hydrogen citrate salt, Citric Acid dihydro sodium salt, the hydrogen tartrate sodium salt.
The invention still further relates to the pharmaceutical composition of delotadine polybasic acids or bases metal or alkaline earth salt composite salt, said composition exists with tablet, capsule, granule, syrup, oral liquid, dispersible tablet, fast disintegrating tablet, instant, the form of slow releasing tablet, controlled release tablet, delotadine polybasic acids or bases metal or alkaline earth salt composite salt add suitable thinner, tackiness agent, disintegrating agent, lubricant, glidant (also can add suitable correctives) through mixing, granulate, make tablet behind the compressing tablet (but dressing) in case of necessity; Adding thinner, disintegrating agent, lubricant, glidant, tackiness agent are made capsule, granule, dry syrup through mixing, granulation, can etc.; Add the suitable technology of warps such as sweeting agent, correctives, water and make oral liquid.Use delotadine polybasic acids or bases metal or alkaline earth salt composite salt to make solubility property good absorb fully of various oral preparations because of raw material, bioavailability is higher than the various oral preparations made from the delotadine raw material.
Pharmaceutical composition of the present invention, wherein delotadine polybasic acids or bases metal or alkaline earth salt composite salt consumption are 0.1mg to 10mg, preferably 0.1mg to 5mg by the treatment significant quantity of delotadine.
The present invention has tangible advantage from technical standpoint: one, add lactose in the tablet formulation of delotadine polybasic acids or bases metal or alkaline earth salt composite salt, stability is significantly better than being the tablet of raw material with the delotadine; Two,, be beneficial to absorption after entering in the body because delotadine polybasic acids or bases metal base earth metal salt composite salt is water-soluble good.
Pharmaceutical composition of the present invention also includes but not limited to a kind of other drug composition, compound medicament composition with their compositions, in the described composition except that delotadine polybasic acids or bases metal base earth metal salt composite salt component, can also contain non-steroid class anti-inflammatory agent or other non-narcotic analgesics for the treatment of significant quantity, for example acetylsalicylic acid, paracetamol, Ibuprofen BP/EP, Ketoprofen, diclofenac sodium or Naproxen Base or its pharmacologically acceptable salt.Also can contain Decongestant, as: pseudoephedrine hydrochloride.Also can contain the relieving cough and removing sputum agent, as: dextromethorphan hydrobromide, guaiacol glycerol ether.
The prescription of the preferred compound of the present invention has: delotadine disodium hydrogen citrate composite salt, paracetamol, pseudoephedrine hydrochloride, dextromethorphan hydrobromide.
Compound help coughing, catch a cold, catching a cold class and/or flu-like symptom and unhappiness, pain, headache, heating and relevant therewith general malaise so.
With the composite salt of delotadine polybasic acids or bases metal or alkaline earth salt is the various indications that various pharmaceutical compositions that raw material is made all are applicable to delotadine.Described composition helps many histamine and brings out the type treatment of diseases, and described histamine brings out the type disease and includes but not limited to: allergic rhinitis, allergic asthma, urticaria, symptomatic dermatographia, the diabetic retinopathy little vascular disease relevant with diabetes with other.
Below by the contrast experiment beneficial effect of the present invention is described:
The solubility test of delotadine polybasic acids or bases metal or alkaline earth salt composite salt and comparative tests
Precision takes by weighing the polynary hydrochlorate of delotadine or delotadine polybasic acids or bases metal-salt composite salt is put in the 25ml measuring bottle in right amount respectively, add the 5ml water dissolution and put in the constant temperature water bath vibrator (25 ℃) vibration half an hour, as whole dissolvings, till continuing to add sample and not dissolving to the half an hour of vibrating, filter, get the subsequent filtrate dilute with water and make need testing solution.Use high performance liquid chromatography (HPLC) to analyze subsequently at the 256nm place.
The solubleness of polynary hydrochlorate of table 1 delotadine and polybasic acid sodium salt complex salt thereof relatively
Sample title solubleness (mg/ml)
Delotadine 0.0723
Toxilic acid delotadine 116.28
FDCL 4.12
Oxalic acid delotadine 4.13
Tartrate delotadine 3.63
Delotadine sodium hydrotartrate double salt 170.38
Delotadine sodium bisulfite double salt 54.79
Delotadine disodium hydrogen citrate double salt 399.67
Can obviously draw such conclusion from table 1: the solubleness of the polynary hydrochlorate of delotadine is much higher than delotadine (being about 50～1608 times), and the solubleness of delotadine sodium hydrotartrate composite salt is 47 times of the tartrate delotadine.
Thin layer, crystallization experiment
1, thin-layer chromatography experiment
Material: silica GF254 thin layer plate; Ethyl acetate-methyl alcohol-ammoniacal liquor (20: 2: 0.5) is developping agent; The ultraviolet colour developing.
It is an amount of to get this product solution, and thin up becomes to contain approximately among every 1ml the 32mg solution of (being equivalent to the 20mg delotadine), as trial-product; It is an amount of that other gets delotadine raw material (highly finished product), adds dehydrated alcohol and make the solution that contains the 20mg delotadine among every 1ml approximately, product in contrast; Test according to tlc (two appendix V of Chinese Pharmacopoeia nineteen ninety-five version B), draw above-mentioned solution 5 μ l, point is on the silica GF254 thin layer plate, with ethyl acetate-methyl alcohol-ammoniacal liquor (20: 2: 0.5) is developping agent, dry after the expansion, the ultraviolet colour developing, the result shows that trial-product is identical with the principal spot Rf value of reference substance.
2, delotadine crystallization experiment
Get the aqueous solution 1ml of delotadine disodium hydrogen citrate salt double salt, dropping ammonia, the adularescent precipitation occurs; Continuing dropping ammonia separates out white precipitate fully.Filter washing (ice ammoniacal liquor), drying under reduced pressure.This white solid matter is carried out infrared measurement, and the gained data are compared with delotadine, and the result shows that both are in full accord.
By above-mentioned experimental result as can be seen delotadine disodium hydrogen citrate salt double salt in water, easily be decomposed into delotadine and corresponding disodium hydrogen citrate salt.
Stability experiment research
Respectively add in Brown Glass Brown glass bottles and jars only in 20: 80 ratio delotadine, delotadine disodium hydrogen citrate double salt (being called for short delotadine double salt) and lactose, add 5% water, seal, placed 60 ℃ of loft drier 10 days, and used high performance liquid chromatography (HPLC) to carry out analysing impurity content subsequently at the 256nm place.
Table 2 stability experiment result of study
| Time (my god) | Delotadine | Delotadine double salt |
| 1 | 0.17 | 0.16 |
| 3 | 0.52 | 0.18 |
| 5 | 0.86 | 0.20 |
| 10 | 1.22 | 0.29 |
Experimental result shows: although contain lactose in the delotadine disodium hydrogen citrate salt double salt tablet formulation, stability is significantly better than delotadine.
Use delotadine polybasic acids or bases metal or alkaline earth salt composite salt to make solubility property good absorb fully of various oral preparations because of raw material, the present invention has carried out the oral administration biaavailability contrast experiment, the result proves that the bioavailability of composite salt of the present invention is higher than the various oral preparations made from the delotadine raw material.
Below describe different embodiments of the present invention in detail by the preparation and the examples of pharmaceutical compositions of delotadine polybasic acids or bases metal or alkaline earth salt composite salt, these embodiment only produce any constraint to the present invention as an illustration and not.
Embodiment:
Embodiment 1
The preparation of delotadine disodium hydrogen citrate double salt
Accurate weighing sodium hydroxide (96%) solid 1.671g, be dissolved in the 50ml water, add Citric Acid monohydrate (99.5%) 4.235g, stirring and dissolving, survey pH and approximate 4.5, delotadine highly finished product 6.264g is added, be stirred to moltenly entirely under the room temperature, add 200mg gac (2.0%), continue under the room temperature to stir 30 minutes, filter, pH approximates 8, gets subsequent filtrate, after concentrating under reduced pressure removes about half volume water under the normal temperature, add the 150ml dehydrated alcohol, vibration shakes up, and takes out suction filtration after placing refrigerator and cooled to freeze 6h, a small amount of absolute ethanol washing, 80 ℃ of dry 6h get the about 8g of white powder, are delotadine disodium hydrogen citrate salt double salt (C
19H
19N
2ClC
6H
6O
7Na
2).Fusing point: greater than 300 ℃.
Embodiment 2
The preparation of delotadine sodium hydrotartrate double salt
Accurate weighing sodium hydroxide (96%) solid 0.4437g, be dissolved in the 50ml water, add tartrate (99.5%) 1.598g, stirring and dissolving, survey pH and approximate 3-3.5, delotadine highly finished product 3.310g is added, be stirred to moltenly entirely under the room temperature, add 200mg gac (2.0%), continue under the room temperature to stir 30 minutes, filter, pH gets subsequent filtrate between 7-8, after concentrating under reduced pressure removes about 2/3 volume water under the normal temperature, add the 150ml dehydrated alcohol, vibration shakes up, and takes out suction filtration after placing refrigerator and cooled to freeze 6h, a small amount of absolute ethanol washing, 80 ℃ of dry 6h get the about 3g of white powder, are delotadine sodium hydrotartrate double salt.
Embodiment 3
The preparation of delotadine sodium bisulfite double salt
Accurately take by weighing sodium bisulfite solid 1.04g, be dissolved in the 30ml water, add delotadine highly finished product 3.11g, be stirred to molten entirely under the room temperature, add 200mg gac (2.0%), continue under the room temperature to stir 30 minutes, filter, pH is between 7-8, get subsequent filtrate, after concentrating under reduced pressure removes about half volume water under the normal temperature, add the 100ml dehydrated alcohol, vibration shakes up, take out suction filtration after placing refrigerator and cooled to freeze 6h, a small amount of absolute ethanol washing, 80 ℃ of dry 6h, get the about 2g of white powder, be delotadine sodium bisulfite double salt.
Embodiment 4
The preparation of delotadine Citric Acid potassium dihydrogen double salt
Accurately take by weighing Citric Acid potassium dihydrogen solid 2.30g, be dissolved in the 30ml water, add delotadine highly finished product 6.21g, be stirred to molten entirely under the room temperature, add 200mg gac (2.0%), continue under the room temperature to stir 30 minutes, filter, get subsequent filtrate, after concentrating under reduced pressure removes about half volume water under the normal temperature, add the 80ml dehydrated alcohol, vibration shakes up, and takes out suction filtration after placing refrigerator and cooled to freeze 6h, a small amount of absolute ethanol washing, 80 ℃ of dry 6h get the about 5.46g of white powder, are delotadine Citric Acid potassium dihydrogen double salt.
Embodiment 5
The preparation of delotadine biphosphate calcium double salt
Accurately take by weighing monocalcium phosphate monohydrate 2.52g, be dissolved in the 50ml water, add delotadine highly finished product 12.42g, be stirred to molten entirely under the room temperature, add 400mg gac (2.0%), continue under the room temperature to stir 30 minutes, filter, get subsequent filtrate, after concentrating under reduced pressure removes about 1/3 volume water under the normal temperature, add the 120ml dehydrated alcohol, vibration shakes up, and takes out suction filtration after placing refrigerator and cooled to freeze 6h, a small amount of absolute ethanol washing, 80 ℃ of dry 6h get the about 9.25g of white powder, are delotadine biphosphate calcium double salt.
Embodiment 6
The preparation of delotadine secondary magnesium phosphate double salt
Accurately take by weighing secondary magnesium phosphate trihydrate 1.74g, be dissolved in the 30ml water, add delotadine highly finished product 3.11g, be stirred to molten entirely under the room temperature, add 200mg gac (2.0%), continue under the room temperature to stir 30 minutes, filter, get subsequent filtrate, after concentrating under reduced pressure removes about half volume water under the normal temperature, add the 100ml dehydrated alcohol, vibration shakes up, and takes out suction filtration after placing refrigerator and cooled to freeze 6h, a small amount of absolute ethanol washing, 80 ℃ of dry 6h get the about 2.20g of white powder, are delotadine secondary magnesium phosphate double salt.
Embodiment 7
The preparation of delotadine primary zinc phosphate double salt
Accurately take by weighing primary zinc phosphate dihydrate 1.48g, be dissolved in the 40ml water, add delotadine highly finished product 6.21g, be stirred to molten entirely under the room temperature, add 300mg gac (2.0%), continue under the room temperature to stir 30 minutes, filter, get subsequent filtrate, after concentrating under reduced pressure removes about half volume water under the normal temperature, add the 100ml dehydrated alcohol, vibration shakes up, and takes out suction filtration after placing refrigerator and cooled to freeze 6h, a small amount of absolute ethanol washing, 80 ℃ of dry 6h get the about 3.93g of white powder, are delotadine primary zinc phosphate double salt.
Embodiment 8
Delotadine disodium hydrogen citrate composite salt coating tablet
The label prescription:
The material name consumption
Delotadine disodium hydrogen citrate salt 8.0g (being equivalent to delotadine 5.0mg/ sheet approximately)
Low-substituted hydroxypropyl cellulose 30.0g
Sodium starch glycolate 10.0g
Lactose 35.0g
Magnesium Stearate 1.0g
30% ethanol is an amount of
Make 1000
Coating fluid prescription:
The material name consumption
Opadry 8.0g
80% ethanol 100ml
Label preparation technology:
Delotadine disodium hydrogen citrate salt, Magnesium Stearate are crossed 120 mesh sieves respectively, and low-substituted hydroxypropyl cellulose, sodium starch glycolate, lactose are crossed 80 mesh sieves respectively, and be standby; Take by weighing delotadine disodium hydrogen citrate salt, low-substituted hydroxypropyl cellulose, sodium starch glycolate and the lactose of prescription proportional quantity, cross 80 mesh sieve mixings by the equivalent incremental method, ethanolic soln with 30% is as wetting agent system softwood, 30 mesh sieves are granulated, 50 ℃～60 ℃ dryings 3～4 hours, the whole grain of 30 mesh sieves, the Magnesium Stearate that adds recipe quantity, mixing, compressing tablet, promptly.
Art for coating:
Preparation 80% ethanolic soln is put to stir on the slurry shape agitator and is made into a vortex, and the coating material Opadry of recipe quantity is slowly added in 80% ethanolic soln, stirs 45min and gets final product; Label is put in the coating pan, adjusted rotating speed and change to per minute 30, the drum hot blast makes temperature maintenance about 50 ℃, sprays into coating liquid, heavily increase about 3% to sheet after, stop heating, freely rolled about 30 minutes, cool off to label, get final product.
Embodiment 9
Delotadine disodium hydrogen citrate salt coating tablet
The label prescription:
The material name consumption
Delotadine disodium hydrogen citrate salt 8.0g (being equivalent to delotadine 5.0mg/ sheet approximately)
Microcrystalline Cellulose 30.0g
Secondary calcium phosphate 30.0g
Pregelatinized Starch 16.0g
Magnesium Stearate 1.0g
30% ethanol is an amount of
Make 1000
Coating fluid prescription:
The material name consumption
Opadry 8.0g
80% ethanol 100ml
Label preparation technology:
Delotadine disodium hydrogen citrate salt, Magnesium Stearate are crossed 120 mesh sieves respectively, and Microcrystalline Cellulose, secondary calcium phosphate, pregelatinized Starch are crossed 100 mesh sieves respectively, and be standby; Take by weighing delotadine disodium hydrogen citrate salt, Microcrystalline Cellulose, secondary calcium phosphate, the pregelatinized Starch of prescription proportional quantity, cross 80 mesh sieve mixings by the equivalent incremental method, the ethanolic soln with 30% is as wetting agent system softwood, and 26 mesh sieves are granulated, 50 ℃～60 ℃ dryings 3～4 hours, the whole grain of 26 mesh sieves; The Magnesium Stearate that adds recipe quantity, mixing, compressing tablet, promptly.
Art for coating:
Preparation 80% ethanolic soln is put to stir on the slurry shape agitator and is made into a vortex, and the coating material Opadry of recipe quantity is slowly added in 80% ethanolic soln, stirs 45min and gets final product; Label is put in the coating pan, adjusted rotating speed and change to per minute 30, the drum hot blast makes temperature maintenance about 50 ℃, sprays into coating liquid, heavily increase about 3% to sheet after, stop heating, freely rolled about 30 minutes, cool off to label, get final product.
Embodiment 10
Delotadine disodium hydrogen citrate salt ordinary tablet
The material name consumption
Delotadine disodium hydrogen citrate salt 8.0g (being equivalent to delotadine 5.0mg/ sheet approximately)
Microcrystalline Cellulose 30.0g
Sodium starch glycolate 10.0g
Lactose 35.0g
Magnesium Stearate 1.0g
30% ethanol is an amount of
Make 1000
Preparation technology:
Delotadine disodium hydrogen citrate salt, Magnesium Stearate are crossed 120 mesh sieves respectively, and Microcrystalline Cellulose, sodium starch glycolate, lactose are crossed 80 mesh sieves respectively, and be standby; Take by weighing delotadine disodium hydrogen citrate salt, Microcrystalline Cellulose, sodium starch glycolate and the lactose of prescription proportional quantity, cross 80 mesh sieve mixings by the equivalent incremental method, ethanolic soln with 30% is as wetting agent system softwood, 30 mesh sieves are granulated, 50 ℃～60 ℃ dryings 3～4 hours, the whole grain of 30 mesh sieves, the Magnesium Stearate that adds recipe quantity, mixing, compressing tablet, promptly.
Embodiment 11
Delotadine disodium hydrogen citrate salt capsule
The material name consumption
Delotadine disodium hydrogen citrate salt 8.0g (being equivalent to delotadine 5.0mg/ grain approximately)
Low-substituted hydroxypropyl cellulose 30.0g
Sodium starch glycolate 10.0g
Lactose 35.0g
Magnesium Stearate 1.0g
The about 85ml of 30% ethanol
Make 1000
Preparation technology:
Delotadine disodium hydrogen citrate salt, Magnesium Stearate are crossed 120 mesh sieves respectively, and low-substituted hydroxypropyl cellulose, sodium starch glycolate, lactose are crossed 80 mesh sieves respectively, and be standby; Take by weighing delotadine disodium hydrogen citrate salt, low-substituted hydroxypropyl cellulose, sodium starch glycolate and the lactose of prescription proportional quantity, by equivalent incremental method mixing, with 30% ethanol is that wetting agent is with above-mentioned mixing fine powders system softwood, crossing 30 mesh sieves granulates, 50 ℃～60 ℃ dryings 3～4 hours, the whole grain of 30 mesh sieves adds the Magnesium Stearate of recipe quantity, mixing, the can capsule gets final product.
Embodiment 12
Delotadine disodium hydrogen citrate salt capsule
The material name consumption
Delotadine disodium hydrogen citrate salt 8.0g (being equivalent to delotadine 5.0mg/ grain approximately)
Microcrystalline Cellulose 30.0g
Secondary calcium phosphate 30.0g
Pregelatinized Starch 16.0g
Magnesium Stearate 1.0g
The about 62ml of 30% ethanol
Make 1000
Preparation technology:
Delotadine disodium hydrogen citrate salt, Magnesium Stearate are crossed 120 mesh sieves respectively, and Microcrystalline Cellulose, secondary calcium phosphate, pregelatinized Starch are crossed 100 mesh sieves respectively, and be standby; Take by weighing delotadine disodium hydrogen citrate salt, Microcrystalline Cellulose, secondary calcium phosphate, the pregelatinized Starch of prescription proportional quantity, by equivalent incremental method mixing, ethanolic soln with 30% is as wetting agent system softwood, 30 mesh sieves are granulated, 50 ℃～60 ℃ dryings 3～4 hours, the whole grain of 26 mesh sieves adds the Magnesium Stearate of recipe quantity, mixing, the can capsule gets final product.
Embodiment 13
The agent of delotadine disodium hydrogen citrate salt particle
The material name consumption
Delotadine disodium hydrogen citrate double salt 8.0g (being equivalent to delotadine 5.0mg/ bag approximately)
Microcrystalline Cellulose 100.0g
Sucrose fine 700.0g
Sodium starch glycolate 120.0g
Lactose 100.0g
Aspartame 60.0g
Orange essence 15.0g
Sodium lauryl sulphate 5.0g
30% ethanol liquid of 3% polyvidone is an amount of
Make 1000 bags
Preparation technology:
Delotadine disodium hydrogen citrate salt, Microcrystalline Cellulose, cane sugar powder, sodium starch glycolate, lactose, aspartame are crossed 100 mesh sieves respectively, and orange essence, sodium lauryl sulphate are crossed 80 mesh sieves respectively, and be standby; The delotadine disodium hydrogen citrate salt, Microcrystalline Cellulose, sucrose fine, sodium starch glycolate, lactose, aspartame that take by weighing the prescription proportional quantity are by equivalent incremental method mixing, 30% ethanol liquid system softwood with 3% polyvidone, 20 mesh sieves are granulated, 50 ℃～60 ℃ dryings 3～4 hours, the whole grain of 18 mesh sieves, the orange essence, the sodium lauryl sulphate that add recipe quantity then, mixing, pack is sealed promptly.
Embodiment 14
Delotadine disodium hydrogen citrate salt oral liquid
The material name consumption
Delotadine disodium hydrogen citrate double salt 8.0g (being equivalent to delotadine 5.0mg/ bottle approximately)
Aspartame 20.0g
Orange essence 2.0g
Sodium Citrate 5.0g
Water for injection adds to 5000ml
Make 1000 bottles
Preparation technology:
Aspartame, orange essence, Sodium Citrate are dissolved in the existing system fresh water for injection, filter, normal temperature adds the delotadine disodium hydrogen citrate salt of recipe quantity down, and can is filtered in dissolving.
Embodiment 15
Delotadine disodium hydrogen citrate salt syrup
The material name consumption
Delotadine disodium hydrogen citrate double salt 1.6g (being equivalent to delotadine 1.0mg/ml approximately)
Sucrose 700.0g
Aspartame 20.0g
Orange essence 2.0g
Sodium Citrate 5.0g
Water for injection adds to 1000ml
Preparation technology:
Sucrose is added in the 900ml water for injection, heated and boiled, dissolving, filtered while hot is cooled to room temperature, and is standby; Delotadine disodium hydrogen citrate salt, aspartame, orange essence, the Sodium Citrate of recipe quantity are dissolved in 60ml water for injection, filter, add in the above-mentioned liquid syrup, add to the full amount of water for injection, mixing, can is promptly.
Embodiment 16
Compound delotadine disodium hydrogen citrate salt sheet
The material name consumption
Delotadine disodium hydrogen citrate salt 8.0g (being equivalent to delotadine 5.0mg/ sheet approximately)
Paracetamol 162.5g
Pseudoephedrine hydrochloride 15g
Microcrystalline Cellulose 20.0g
Sodium starch glycolate 10.0g
Lactose 35.0g
Magnesium Stearate 1.0g
30% ethanol is an amount of
Make 1000
Preparation technology:
Delotadine disodium hydrogen citrate salt, paracetamol, pseudoephedrine hydrochloride, Magnesium Stearate are crossed 120 mesh sieves respectively, and Microcrystalline Cellulose, sodium starch glycolate, lactose are crossed 80 mesh sieves respectively, and be standby; Take by weighing delotadine disodium hydrogen citrate salt, paracetamol, pseudoephedrine hydrochloride, Microcrystalline Cellulose, sodium starch glycolate and the lactose of prescription proportional quantity, cross 80 mesh sieve mixings by the equivalent incremental method, ethanolic soln with 30% is as wetting agent system softwood, 30 mesh sieves are granulated, 50 ℃～60 ℃ dryings 3～4 hours, the whole grain of 30 mesh sieves, the Magnesium Stearate that adds recipe quantity, mixing, compressing tablet, promptly.
Embodiment 17
Compound delotadine disodium hydrogen citrate salt sheet
The material name consumption
Delotadine disodium hydrogen citrate salt 8.0g (being equivalent to delotadine 5.0mg/ sheet approximately)
Pseudoephedrine hydrochloride 15g
Microcrystalline Cellulose 20.0g
Sodium starch glycolate 10.0g
Lactose 35.0g
Magnesium Stearate 1.0g
30% ethanol is an amount of
Make 1000
Preparation technology:
Delotadine disodium hydrogen citrate salt, pseudoephedrine hydrochloride, Magnesium Stearate are crossed 120 mesh sieves respectively, and Microcrystalline Cellulose, sodium starch glycolate, lactose are crossed 80 mesh sieves respectively, and be standby; Take by weighing delotadine disodium hydrogen citrate salt, pseudoephedrine hydrochloride, Microcrystalline Cellulose, sodium starch glycolate and the lactose of prescription proportional quantity, cross 80 mesh sieve mixings by the equivalent incremental method, ethanolic soln with 30% is as wetting agent system softwood, 30 mesh sieves are granulated, 50 ℃～60 ℃ dryings 3～4 hours, the whole grain of 30 mesh sieves, the Magnesium Stearate that adds recipe quantity, mixing, compressing tablet, promptly.
Embodiment 18
Compound delotadine disodium hydrogen citrate salt sheet
The material name consumption
Delotadine disodium hydrogen citrate salt 8.0g (being equivalent to delotadine 5.0mg/ sheet approximately)
Paracetamol 162.5g
Pseudoephedrine hydrochloride 15g
Dextromethorphan hydrobromide 15g
Microcrystalline Cellulose 20.0g
Sodium starch glycolate 10.0g
Lactose 35.0g
Magnesium Stearate 1.0g
30% ethanol is an amount of
Make 1000
Preparation technology:
Delotadine disodium hydrogen citrate salt, paracetamol, pseudoephedrine hydrochloride, dextromethorphan hydrobromide, Magnesium Stearate are crossed 120 mesh sieves respectively, and Microcrystalline Cellulose, sodium starch glycolate, lactose are crossed 80 mesh sieves respectively, and be standby; Take by weighing delotadine disodium hydrogen citrate salt, paracetamol, pseudoephedrine hydrochloride, Microcrystalline Cellulose, sodium starch glycolate and the lactose of prescription proportional quantity, cross 80 mesh sieve mixings by the equivalent incremental method, ethanolic soln with 30% is as wetting agent system softwood, 30 mesh sieves are granulated, 50 ℃～60 ℃ dryings 3～4 hours, the whole grain of 30 mesh sieves, the Magnesium Stearate that adds recipe quantity, mixing, compressing tablet, promptly.
Embodiment 19
Compound delotadine disodium hydrogen citrate salt syrup
The material name consumption
Delotadine disodium hydrogen citrate double salt 0.8g (being equivalent to delotadine 0.5mg/ml approximately)
Paracetamol 16.25g
Pseudoephedrine hydrochloride 1.5g
Dextromethorphan hydrobromide 1.5g
Guaiacol glycerol ether 10g
Sucrose 700.0g
Aspartame 20.0g
Orange essence 2.0g
Sodium Citrate 5.0g
Water for injection adds to 1000ml
Preparation technology:
Sucrose is added in the 800ml water for injection, heated and boiled, dissolving, filtered while hot is cooled to room temperature, and is standby; Delotadine disodium hydrogen citrate salt, paracetamol, pseudoephedrine hydrochloride, dextromethorphan hydrobromide, guaiacol glycerol ether, aspartame, orange essence, the Sodium Citrate of recipe quantity are dissolved in 150ml water for injection, filter, add in the above-mentioned liquid syrup, add to the full amount of water for injection, mixing, can are promptly.
Claims (14)
1, delotadine polybasic acids or bases metal or alkaline earth salt composite salt, polyprotonic acid wherein is selected from Citric Acid, tartrate, succsinic acid, fumaric acid, toxilic acid, oxalic acid, sulfuric acid, phosphoric acid, sulfurous acid, and basic metal wherein or alkaline-earth metal are selected from sodium, potassium, calcium, magnesium, zinc.
2, composite salt according to claim 1 is disodium hydrogen citrate salt, Citric Acid dihydro sodium salt, hydrogen tartrate sodium salt, Sodium Bisuccinate salt, fumaric acid hydrogen sodium salt, toxilic acid hydrogen sodium salt, sodium bioxalate salt, hydrogen sulfate sodium salt, sodium bisulfite salts.
3, composite salt according to claim 1 is disodium hydrogen citrate salt, Citric Acid dihydro sodium salt, hydrogen tartrate sodium salt.
4, the pharmaceutical composition that contains the composite salt of claim 1.
5, pharmaceutical composition according to claim 4, wherein delotadine polybasic acids or bases metal or alkaline earth salt composite salt consumption are 0.1mg to 10mg by the treatment significant quantity of delotadine.
6, pharmaceutical composition as claimed in claim 4, wherein delotadine polybasic acids or bases metal or alkaline earth salt composite salt consumption are 0.1mg to 5mg by the treatment significant quantity of delotadine.
7, pharmaceutical composition according to claim 4 wherein also contains the anodyne of significant quantity.
8, pharmaceutical composition according to claim 7, anodyne wherein are selected from acetylsalicylic acid, acetyl aminophenol, Ibuprofen BP/EP, Ketoprofen, diclofenac sodium, Naproxen Base or its pharmacologically acceptable salt.
9, pharmaceutical composition according to claim 4 wherein also contains the Decongestant of significant quantity.
10, pharmaceutical composition according to claim 9, Decongestant wherein is a pseudoephedrine hydrochloride.
11, pharmaceutical composition according to claim 4 wherein also contains the relieving cough and removing sputum agent of significant quantity.
12, pharmaceutical composition according to claim 11, relieving cough and removing sputum agent wherein is dextromethorphan hydrobromide, guaiacol glycerol ether.
13, pharmaceutical composition according to claim 4, wherein said composition exists with tablet, capsule, granule, syrup, oral liquid, dispersible tablet, fast disintegrating tablet, instant, the form of slow releasing tablet, controlled release tablet.
14, the purposes of the composite salt of claim 1 in a kind of medicine for the treatment of bringing out property of histamine disease of preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021289980A CN1159313C (en) | 2002-08-27 | 2002-08-27 | Alkali-metal or alkali-earth metal salt of polyprotic acid delotadine and its medical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021289980A CN1159313C (en) | 2002-08-27 | 2002-08-27 | Alkali-metal or alkali-earth metal salt of polyprotic acid delotadine and its medical composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1397556A CN1397556A (en) | 2003-02-19 |
| CN1159313C true CN1159313C (en) | 2004-07-28 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB021289980A Expired - Lifetime CN1159313C (en) | 2002-08-27 | 2002-08-27 | Alkali-metal or alkali-earth metal salt of polyprotic acid delotadine and its medical composition |
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| Country | Link |
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Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR057882A1 (en) | 2005-11-09 | 2007-12-26 | Novartis Ag | DOUBLE ACTION COMPOUNDS OF ANGIOTENSIN RECEPTOR BLOCKERS AND NEUTRAL ENDOPEPTIDASE INHIBITORS |
| CN101467988B (en) * | 2007-12-27 | 2014-07-09 | 北京德众万全医药科技有限公司 | Medicament composition containing paracetamol and pseudoephedrine hydrochloride and preparation method thereof |
| CN103242292B (en) * | 2013-05-27 | 2015-04-22 | 合肥医工医药有限公司 | Polymorphism of desloratadine disodium hydrogen citrate complex salt |
| CN103721265A (en) * | 2013-12-16 | 2014-04-16 | 扬子江药业集团广州海瑞药业有限公司 | Orally disintegrating composition with desloratadine citrate disodium |
| CN103720665A (en) * | 2013-12-16 | 2014-04-16 | 扬子江药业集团广州海瑞药业有限公司 | Desloratadine citrate disodium composition for injection |
| CN104000826A (en) * | 2014-06-10 | 2014-08-27 | 合肥医工医药有限公司 | Compound pharmaceutical composition containing desloratadine citrate disodium and dimemorfan phosphate |
| CN104042615A (en) * | 2014-06-10 | 2014-09-17 | 合肥医工医药有限公司 | Pharmaceutical composition containing desloratadine and dimemorfan phosphate |
| CN110638750B (en) * | 2019-10-28 | 2021-08-27 | 深圳市贝美药业有限公司 | Preparation method of desloratadine medicine and preparation thereof |
| CN111419820B (en) * | 2020-04-23 | 2022-03-25 | 合肥医工医药股份有限公司 | Desloratadine citrate disodium capsule and preparation method and application thereof |
-
2002
- 2002-08-27 CN CNB021289980A patent/CN1159313C/en not_active Expired - Lifetime
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| CN1397556A (en) | 2003-02-19 |
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