CN101816643B - Medicament composition containing diclofenac sodium and acetaminophen - Google Patents
Medicament composition containing diclofenac sodium and acetaminophen Download PDFInfo
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- CN101816643B CN101816643B CN 200910266012 CN200910266012A CN101816643B CN 101816643 B CN101816643 B CN 101816643B CN 200910266012 CN200910266012 CN 200910266012 CN 200910266012 A CN200910266012 A CN 200910266012A CN 101816643 B CN101816643 B CN 101816643B
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- acetaminophen
- diclofenac sodium
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- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 title claims abstract description 145
- 229960005489 paracetamol Drugs 0.000 title claims abstract description 82
- 229960001193 diclofenac sodium Drugs 0.000 title claims abstract description 73
- 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 title claims abstract description 61
- 239000000203 mixture Substances 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 title abstract description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 77
- 239000008194 pharmaceutical composition Substances 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 21
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 11
- 230000001954 sterilising effect Effects 0.000 claims description 10
- 238000004659 sterilization and disinfection Methods 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000012467 final product Substances 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000012982 microporous membrane Substances 0.000 claims description 6
- 239000004576 sand Substances 0.000 claims description 6
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 4
- 235000019345 sodium thiosulphate Nutrition 0.000 claims description 4
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 abstract description 21
- 229920001223 polyethylene glycol Polymers 0.000 abstract description 21
- 239000002904 solvent Substances 0.000 abstract description 12
- 230000000202 analgesic effect Effects 0.000 abstract description 9
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 abstract 2
- 239000000243 solution Substances 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- 229940090044 injection Drugs 0.000 description 17
- 238000002347 injection Methods 0.000 description 17
- 239000007924 injection Substances 0.000 description 17
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 12
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
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- 229960001259 diclofenac Drugs 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 238000003860 storage Methods 0.000 description 5
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
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- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 4
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- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 3
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- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- QQONPFPTGQHPMA-UHFFFAOYSA-N Propene Chemical group CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 2
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- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 238000005057 refrigeration Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000003637 steroidlike Effects 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 1
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- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 1
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 1
- 206010038419 Renal colic Diseases 0.000 description 1
- 229940086216 acetaminophen 150 mg Drugs 0.000 description 1
- 229940086244 acetaminophen 600 mg Drugs 0.000 description 1
- 229940050447 acetaminophen injection Drugs 0.000 description 1
- 229940016213 acetaminophen oral solution Drugs 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
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- 210000001772 blood platelet Anatomy 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
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- 229940100955 diclofenac sodium 100 mg Drugs 0.000 description 1
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- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention provides a medicament composition containing diclofenac sodium and acetaminophen, comprising acetaminophen and diclofenac sodium as active components, and propanediol and polyethylene glycol as solvents, wherein the weight ratio of the acetaminophen to the diclofenac sodium is 1:0.1 to 1; 1 to 6 weight portions of propanediol are used for each weight portion of acetaminophen; and 1 to 5 weight portions of polyethylene glycol are used for each weight portion of acetaminophen. The composition can be used as an analgesic, and has good solubility and medicament stability.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition, relate more specifically to a kind of injection.
Background technology
Acetaminophen (APAP) is acetophenone amine antipyretic analgesic.By suppressing hypothalamus thermotaxic centre prostaglandin synthetase, reduce the synthetic and release of Prostaglandin PGE1, cause the peripheral blood vessel expansion, perspire and reach analgesic effect, its refrigeration function intensity is similar to aspirin; By suppressing the synthetic of Prostaglandin PGE1, Kallidin I and histamine etc. and discharge, improve the threshold of pain and play analgesic activity, belong to the periphery analgesic, effect is than a little less than the aspirin, only to light, moderate pain is effective.This product is without obvious antiinflammatory action.
In fact, similar with aspirin, acetaminophen shows its activity by the synthesizing of prostaglandin of suppressing to be produced by COX-2.Yet, be different from most of nonsteroidal antiinflammatory drugs (NSAID), its inhibitory action almost only works to brain and the effect of peripheral tissues's (stomach, kidney and platelet) is in extremely low level, owing to this reason, the side effect that its application can not produce typical N SAID is followed possible losing blood such as heartburn and gastric damage.
The unique possible complication relevant with its application is hepatolysis, and (Flower R., " nature " (Nature) 240,410-411,1972 although this situation only occurs in the situation of overdose; Lanz R., poster p. " pharmacology's magazine " (J.Pharmacol.) 130,105-109,1986; Black M., " medicine yearbook " (Annual Reviews ofMedicine) 35,577-593,1984).
Diclofenac (DS) is a kind of non-steroidal anti-inflammatory analgesics that is derived from the phenylacetic acid class, is that effect is stronger a kind of in the non-steroidal antibiotic medicine, and it is better than aspirin and indomethacin etc. to the synthetic inhibitory action of prostaglandin.Be mainly used in the verification treatment of the acute pain that causes after the heating of various febrile diseases and renal colic, Severe Rheumatoid Arthritis and osteoarthritis, acute gout, acute trauma, fracture and the operation.The per injection administration needs 50mg.
Diclofenac is often used with the pharmaceutically acceptable sodium salt form; its oral medical value is approved by clinical; but compare injection; its bioavailability and onset speed also are not very desirable; and oral administration often can cause some gastrointestinal reactions; so the injection of diclofenac is worth further research and development, especially compound preparation.When itself and acetaminophen drug combination, then can mutually remedy the other side's defective, have mutual synergism, both had anti-inflammatory analgesic action, have again antipyretic effect.
In order to reduce toxic and side effects, reduce single-dose dosage, compound preparation becomes primary goal in research.
Experimental study shows: the compound preparation that contains diclofenac sodium+acetaminophen has stronger refrigeration function. and its obvious effective rate is 92.94%, and total effective rate is 100%; And the obvious effective rate of matched group 1 (containing diclofenac sodium 50mg) is 83.91%, total effective rate is 98.85%, and the obvious effective rate of matched group 2 (containing acetaminophen 150mg) is 81.71%, and total effective rate is that 94.68%, three group curative effect compares without remarkable significant difference; But the fever time of compound preparation injection is very fast.54 examples (63.5%) began to bring down a fever in 15 minutes, matched group 1 then is 39 to fall (44.9%), 2 of matched groups are 32 to fall (36.9%), and three groups relatively, has significant difference (P＜0.05) to illustrate that diclofenac and acetaminophen have certain synergism.
But known acetaminophen is slightly soluble in water (" the 12nd edition the 9th page of No 45,1996 of Merck index (The Merck Index)).70ml water can only dissolve 1g acetaminophen (" solubilization studies of acetaminophen oral solution " " Shandong medical industry " 4 phases of 15 volumes in 1996); Diclofenac sodium (DS) dissolubility in water less (9mg/ml, 25 ℃); Both do not reach the formulation concentrations requirement.In addition, in the situation that water exists, acetaminophen produces pink to the degraded of brown derivant.The degraded of common type is to be hydrolyzed into para-aminophenol (PAP) and/or by for example oxygen oxidation soluble in water.And still contain easy oxide group in the molecular structure of DS, as after being made into injection, can make the stability decreases of medicine, these features represent the major obstacle that they exist by drug administration by injection.Therefore seek suitable solvent system and improve the key issue that preparation stability becomes research.
For research report and the patent of invention of the administration concentration that improves diclofenac sodium or acetaminophen more.Such as patent application WO98/05314, CN1711996A, " technique of acetaminophen injection and quality research " modern medicine health the 23rd phases of 23 volumes in 2007 etc. report is arranged all.
But improve research report and the patent of invention Shang Xiaojian of the administration concentration of injection diclofenac sodium and acetaminophen compound preparation.Only " acetaminophen, diclofenac compound preparation prescription overview and prospect " Shanghai medicine the 2nd phase of the 26th volume in 2005 is upper on the books.
Especially, described in above-mentioned document, the mixed solution that is comprised of 30% propylene glycol, 40%PEG-400 and 30% water can be under 20 ℃ be dissolved to acetaminophen many 200mg/ml (WO98/05314, the 9th page of 7-12 is capable).The mixed solution that also adopts 50% propylene glycol and 50% water to form by report; Or 10% the mixed solution that forms of ethanol and 40% Polyethylene Glycol and 50% water acetaminophen can be dissolved to many 250mg/ml (CN1146413C).
Yet the above two mix extremely sticking (referring to comparative example 1) this solvent, produce cicatrix (weals) side effect when haemolysis and injection are arranged; The latter is large because containing the ethanol zest, and especially is unsuitable for passing through drug administration by injection.And be dissolved to the diclofenac sodium of many 12.5mg/ml and the compound preparation of 75mg/ml acetaminophen still has poor stability by the mixed solution that long-term low-temperature study 50% propylene glycol and 50% water form, idol has the crystallization phenomenon.
Therefore, based on still existing except the diclofenac sodium that contains treatment level and acetaminophen, can also easily injecting and can not produce the very big demand of the pharmaceutical composition of cicatrix (weals).Experimentation, diclofenac sodium and acetaminophen drug combination had both overcome acetaminophen without obvious antiinflammatory action, had strengthened again the diclofenac sodium anti-inflammatory analgesic action, and significantly reduced individually dosed single dose, the clinical reduced side effects of seeing, and safer.
Summary of the invention
The object of the present invention is to provide a kind of pharmaceutical composition with specific solvent component, to overcome stability and the drug safety problem of diclofenac sodium and acetaminophen compound recipe in the prior art.
A first aspect of the present invention provides a kind of pharmaceutical composition, it comprises as the acetaminophen of active component and diclofenac sodium, and as propylene glycol and the Polyethylene Glycol of solvent, wherein, the weight ratio of acetaminophen and diclofenac sodium is 1: 0.1-1, the propylene glycol of the 1-6 weight portion that every weight portion acetaminophen uses, the Polyethylene Glycol of the 1-5 weight portion that every weight portion acetaminophen uses.
A second aspect of the present invention provides a kind of pharmaceutical composition, it comprises as the acetaminophen of active component and diclofenac sodium, and as propylene glycol, Polyethylene Glycol and the water of solvent, wherein, the weight ratio of acetaminophen and diclofenac sodium is 2-10: 1, and the diclofenac sodium of every weight portion uses propylene glycol, the Polyethylene Glycol of 5-15 weight portion and the water that is not less than the 50-80 weight portion of 15-25 weight portion.
In pharmaceutical composition according to the present invention, active component can be dissolved in the solvent well, and presents good stability.In addition, adopt pharmaceutical composition of the present invention, the curative effect that not only shows, and haemolysis does not appear.
The specific embodiment
The inventor is surprised to find that: Polyethylene Glycol can promote the dissolving in propylene glycol of diclofenac sodium and acetaminophen.And stability is better.
As viewed in an embodiment, the diclofenac sodium that is dissolved by the mixture of propylene glycol and Polyethylene Glycol and the amount (embodiment 1) of acetaminophen are higher than the independent low propylene glycol alcohol of the weight such as using or Polyethylene Glycol dissolving to the amount of diclofenac sodium and acetaminophen.
Of the present invention aspect first, a kind of pharmaceutical composition is provided, it comprises as the acetaminophen of active component and diclofenac sodium, and as propylene glycol and the Polyethylene Glycol of solvent, wherein, the weight ratio of acetaminophen and diclofenac sodium is 1: 0.1-1, preferred 1: 0.1-0.35, more preferably 1: 0.15-0.25, most preferably 6: 1; Every weight portion acetaminophen uses the propylene glycol of 1-6 weight portion.Be no more than in half the situation of acetaminophen at the diclofenac sodium consumption, every weight portion acetaminophen preferably uses 2-4 weight portion, the more preferably propylene glycol of 2.5-3.0 weight portion; The Polyethylene Glycol of the 1-5 weight portion that every weight portion acetaminophen uses, be no more than in half the situation of acetaminophen at the diclofenac sodium consumption, every weight portion acetaminophen preferably uses 2-4 weight portion, the more preferably Polyethylene Glycol of 2.5-3.0 weight portion.
Can suitably regulate according to acetaminophen and the relative weight ratio of diclofenac sodium the consumption of used propylene glycol and Polyethylene Glycol.Generally speaking, along with the increase of diclofenac sodium consumption, the consumption of corresponding increase propylene glycol and Polyethylene Glycol.
Use the organic solvent of aforementioned proportion can guarantee that acetaminophen and diclofenac sodium in above-mentioned scope can dissolve well.Because this pharmaceutical composition is substantially not moisture, active component wherein can not separated out from solvent, has excellent stability.In addition, because this double solvents is very low to the dissolubility of oxygen, said composition has good antioxygenic property, though do not have antioxidant in the presence of, active substance also can be in the system of opening wide stable existence.
Because this aforementioned pharmaceutical compositions can also further contain other auxiliary elements, such as antioxidant, antiseptic etc.
It should be noted that when using this pharmaceutical composition, should use for every weight portion acetaminophen the water of 6-10 weight, said composition is deployed into the clear and bright solution of injection.This clear and bright liquid should be after configuring in 2 hours, are preferably in 1 hour to use.Use the water of this ratio can avoid well haemolysis after medicine enters human body.
Adult's consumption general control is acetaminophen 150-600mg. every day.Diclofenac sodium then is corresponding proportion compatibility.
The diclofenac sodium of first aspect of the present invention and the organic solution of acetaminophen are very stable, this be because even 121 ℃ of lower sterilizations 30 minutes, subsequently 30 ℃ and 11,000 strangle lower constant illumination store at least 1 month after acetaminophen can not be precipitated out or degrade.Even in the situation that does not have antiseptic, stabilizing agent, surfactant, buffer agent, the reagent that is used for the seizure free radical and/or antioxidant to exist, also found this stability.
Aspect second of the present invention, relate to a kind of pharmaceutical composition by the clear and bright solution composition of injection, it comprises as the acetaminophen of active component and diclofenac sodium, and as propylene glycol, Polyethylene Glycol and the water of solvent, wherein, the weight ratio of acetaminophen and diclofenac sodium is 2-10: 1, and preferred 3-7: 1, more preferably 5-7: 1, most preferably 6: 1; For the diclofenac sodium of every weight portion, the weight portion of the propylene glycol that uses is 15-25, and preferred 18-22, most preferably 20; For the diclofenac sodium of every weight portion, the weight portion of the Polyethylene Glycol of use is preferably 5-15, and even more preferably 12; For the diclofenac sodium of every weight portion, the weight portion of the water of use is not less than 50, but usually is not higher than 80.For example can use the water of 55,60,65 weight portions.
Can suitably regulate according to acetaminophen and the relative weight ratio of diclofenac sodium the consumption of used propylene glycol and Polyethylene Glycol.Generally speaking, along with the increase of acetaminophen consumption, the consumption of corresponding increase propylene glycol and Polyethylene Glycol.
Use the organic solvent of aforementioned proportion can guarantee that acetaminophen and diclofenac sodium in above-mentioned scope can dissolve well.Owing to adopted above-mentioned specific solvent ratios, active component wherein also can steady in a long-termly exist, and is difficult for separating out from water.In addition, when said composition is used as final injection, can not cause haemolysis yet.
In general, the clear and bright aqueous solution of thus obtained injection has the viscosity of 2-10mPa.s.The preferred consumption of adjusting low propylene glycol, Polyethylene Glycol and water is so that described viscosity is 4-7mPa.s.
Adult's consumption general control is acetaminophen 150-600mg every day.Diclofenac sodium then is corresponding proportion compatibility.
This solution also have the reagent that do not contain any antiseptic, stabilizing agent, surfactant, buffer agent, be used for catching free radical and/or further advantage.
The degree of polymerization that can be used for Polyethylene Glycol of the present invention can between 200 to 4000, preferably between 300-1000, more preferably between 300-600, most preferably be 400.
Use propylene glycol can be 1,2-PD and 1,3-PD among the present invention.
Can prepare pharmaceutical composition of the present invention according to well-known technology in the pharmaceutical chemistry that comprises the steps such as mixing, dissolving, sterilization.
Further describe the present invention by the following example, these embodiment that provide should not be taken merely the implication of restriction for the purpose of explaining.
Embodiment 1
Solution A forms
The composition consumption
Diclofenac sodium 15g
Cys 1g
Acetaminophen 75g
1.2-propylene glycol 200g
PEG-400 200g
Preparation
At room temperature with 1.2-propylene glycol, PEG-400, Cys dissolving mixing, then add diclofenac sodium and acetaminophen.Till this mixture is stirred to diclofenac sodium and acetaminophen and dissolves fully (about 30 minutes).Solution filters by active carbon layer sand rod first, passes through filtering with microporous membrane again.Thus obtained solution is divided in about 400 ampoules, every bottled 1ml, the sterilization and get final product.
Some samples to recently preparation (0 o'clock) carry out following check:
-diclofenac sodium titre, HPLC (mg/ml);
-para-aminophenol titre: HPLC (mg/ml);
Any painted catabolite of-detection: the spectrophotography at 475nm place;
-clarity: detect by official method in 2005.
The result who obtains is as follows:
-diclofenac sodium average titer: 14.6;
-acetaminophen average titer: 74.8;
-para-aminophenol: nothing
-average absorption degree: 0.0075
-clarity: achromatism and clarity solution
Then above-mentioned sample was stored 1 month under following condition, then tested its stability, test result is listed in the table 1.Wherein, sample a is that sample b at room temperature stores 4 ℃ of lower storages, and sample c is in the indoor storage of 30 ℃ and 11,000 illuminations of strangling.
Table 1
| Sample | DS (mg/ml) | APAP (mg/ml) | PAP (mg/ml) | Trap (475nm) | Clarity |
| a | 14.9 | 74.8 | 0.00 | 0.0039 | Clear and bright |
| b | 14.6 | 75.2 | 0.00 | 0.0042 | Clear and bright |
| c | 14.7 | 74.6 | 0.00 | 0.0125 | Clear and bright |
PAP represents p-aminophenol
As can be seen from Table 1: adopt the sample of embodiment 1 preparation stable under above-mentioned condition stores.
Recently other sample (sample d) for preparing () by same method at 0 o'clock shows following properties;
-diclofenac sodium titre: 14.6
-acetaminophen titre: 74.6
-para-aminophenol: nothing
-trap: 0.0032
-clarity: clear and bright, without crystallization
At 25 ℃ with listing they is kept at indoor 12 months under the terms of packing and they show following properties:
-diclofenac sodium titre: 14.5
-acetaminophen titre: 74.2
-para-aminophenol: 0.008
-trap: 0.0082
-clarity: clear and bright, without crystallization
Recently prepare () at 0 o'clock and the sample (sample e) of sterilization after (121 ℃, 30 minutes) shows following feature by same method:
-diclofenac sodium: 14.6
-acetaminophen titre: 74.5
-para-aminophenol: nothing
-trap: 0.0048
-clarity: clear and bright, without crystallization
Descending at 30 ℃ and 11,000 lighting conditions of strangling, they are kept at indoor 1 month and they show following properties:
-diclofenac sodium: 14.4
-acetaminophen titre: 74.0
-para-aminophenol: nothing
-trap: 0.0049
Clarity: clear and bright, without crystallization
Above result shows: adopt the sample of embodiment 1 preparation stable in for a long time lower placement of above-mentioned condition of storage.
In brief, the result from embodiment 1 can find out that qualified according to the described pharmaceutical composition content of invention first aspect, good stability produces without crystallization or precipitate.
During use, the solution A 1 (1ml/ props up) of getting such as the preparation of above-mentioned embodiment 1 method adds 1ml water for injection, then with the hands jolting until form the clear and bright solution of a kind of injection (about 30 seconds).
Thus obtained solution shows following properties:
Outward appearance is clear and bright, and is colourless
Viscosity * (mPa.s) 5.128
The Morie osmolarity (mosmol/ liter) 526.1 of calculating
Density * * (g/ml) 1.0230
Embodiment 2
Solution B forms
The composition consumption
Diclofenac sodium 25g
Sodium pyrosulfite 2g
Acetaminophen 75g
1,2-PD 250g
PEG-400 200g
Water for injection adds to 1000ml
Preparation
At room temperature with 1,2-PD, PEG-400, sodium pyrosulfite dissolving mixing, add in diclofenac sodium and the acetaminophen.Then till this mixture being stirred to diclofenac sodium and acetaminophen and dissolving fully (about 30 minutes).Adjust pH value to 7-9 with sodium hydroxide solution, solution filters by active carbon layer sand rod first, passes through filtering with microporous membrane again.Thus obtained solution is divided in about 500 ampoules, every bottled 2ml, the sterilization and get final product.
Some samples to recently preparation (0 o'clock) carry out following check:
-diclofenac sodium titre, HPLC (mg/ml);
-para-aminophenol titre: HPLC (mg/ml);
Any painted catabolite of-detection: the spectrophotography at 475nm place;
-clarity: detect by official method in 2005
The result who obtains is as follows:
-diclofenac sodium average titer: 24.6;
-acetaminophen average titer: 74.8;
-para-aminophenol: nothing
-average absorption degree: 0.0075
-clarity: clear and bright, without crystallization
Then above-mentioned sample was stored 1 month under following condition, then tested its stability, with the results are shown in the following table 2 of obtaining.Wherein, sample a ' is that sample b ' at room temperature stores 4 ℃ of lower storages, and sample c ' is in the indoor storage of 30 ℃ and 11,000 illuminations of strangling.
Table 2
| Sample | DS (mg/ml) | APAP (mg/ml) | PAP (mg/ml) | The trap of 475nm | Clarity |
| a′ | 24.9 | 74.8 | 0.00 | 0.0039 | Clear and bright |
| b′ | 24.6 | 75.2 | 0.00 | 0.0042 | Clear and bright |
| c′ | 24.7 | 74.6 | 0.00 | 0.0125 | Clear and bright |
As can be seen from Table 2: adopt the sample of embodiment 1 preparation stable under above-mentioned condition stores
Recently other sample for preparing () by embodiment 2 at 0 o'clock shows following properties;
-diclofenac sodium titre: 24.6
-acetaminophen titre: 74.0
-para-aminophenol: nothing
-trap: 0.0032
At 25 ℃ with listing they is kept at indoor 12 months under the terms of packing and they show following properties:
-diclofenac sodium titre: 24.3
-acetaminophen titre: 74.5
-para-aminophenol: nothing
-trap: 0.0086
Clarity: clear and bright, without crystallization
The sample (sample V) that embodiment 2 prepares after (0 o'clock) and the sterilization (121 ℃, 30 minutes) recently shows following feature:
-diclofenac sodium: 24.2
-acetaminophen titre: 74.4
-to the stupid phenol of amino: nothing
-trap: 0.0048
-clarity: clear and bright, without crystallization
Descending at 30 ℃ and 11,000 lighting conditions of strangling, they are kept at indoor 1 month and they show following properties:
-diclofenac sodium: 23.8
-acetaminophen titre: 74.0
-to the stupid phenol of amino: nothing
-trap: 0.0051
-clarity: clear and bright, without crystallization
In brief, the result from embodiment 1-3 can find out that qualified according to the described pharmaceutical composition content of invention first aspect, good stability produces without crystallization or precipitate.
Embodiment 3
Solution C
The composition consumption
Diclofenac sodium 7.5g
Sodium thiosulfate 2g
Acetaminophen 75g
A 1.2 propylene glycol 200g
PEG-400 200g
Water for injection adds to 1000ml
Solution D
The composition consumption
Diclofenac sodium 12.5g
Sodium thiosulfate 2g
Acetaminophen 75g
A 1.2 propylene glycol 150g
PEG-400 200g
Water for injection adds to 1000ml
The same solution B of compound method
At room temperature with 1.2 1 propylene glycol, PEG-400, sodium thiosulfate dissolving mixing, add in diclofenac sodium and the acetaminophen.Then till this mixture being stirred to diclofenac sodium and acetaminophen and dissolving fully (about 30 minutes).Adjust pH value to 7-9, solution filters by active carbon layer sand rod first, passes through filtering with microporous membrane again.Thus obtained solution is divided in about 500 ampoules, every bottled 2ml, the sterilization and get final product.Thus obtained solution shows following physicochemical characteristic:
| Detect index | Solution B | Solution C | Solution D |
| Outward appearance | Clear and bright, colourless | Clear and bright, colourless | Clear and bright, colourless |
| Viscosity * (mPa.s) | 5.068 | 5.125 | 5.116 |
| The Morie osmolarity (m0smol/ liter) of calculating | 529.2 | 530.6 | 532.7 |
| Density * * (g/ml) | 1.02600 | 1.02765 | 1.02791 |
Pharmacological evaluation:
Analgesic test: adopt hot plate method, measured diclofenac sodium and acetaminophen ED50 value separately, then respectively cooperate in 4/5: 1/5,1/2: 1/2,1/5: 4/5 ratio and obtain 3 kinds of composition of medicine, find that they are respectively 1.26,1.12 and 1.50 times of theoretical value to the analgesic effect of mice, clear and definite this synergism on the dose-effect relationship.
Hemolytic test: the sample with solution B is tested
A certain amount of test sample is added in the 2% Sanguis Leporis seu oryctolagi normal saline suspension, and observation has or not haemolysis and agglutination phenomenon, as one of injection safety inspection project.
The preparation of (one) 2% Sanguis Leporis seu oryctolagi normal saline suspension is from healthy rabbits ear vein or heart extracting blood 2ml, adds normal saline dilution and shakes up and get final product to 100ml.
(2) the test sample weighing apparatus preparation first liquid of releasing liquid is got need testing solution 0.5ml, adds normal saline dilution to 100ml, shakes up and get final product.Second liquid is got the need testing solution 1.0ml of injection for intravenous, adds normal saline dilution to 10ml, shakes up and get final product.
(3) test method is got 3 of clean tube, adds in the following order various solution, and each pipe shakes up, and puts to leave standstill in 37 ℃ of waters bath with thermostatic control and observes 1 hour.
Test tube 1 pipe 2 pipes 3 pipes
Sample B diluent (first) 2ml--
Sample B diluent (second)-2ml-
The normal saline contrast--2ml
2% Sanguis Leporis seu oryctolagi suspension 2ml 2ml 2ml
The 1st pipe, the 2nd pipe, the 3rd pipe matched group occur without haemolysis and agglutination phenomenon
Adopt the product of solution D to carry out clinical trial, carried out a double blinding, at random, parallel study, 60 tumor operation patients usefulness acetaminophen 600mg, diclofenac sodium 100mg before the operation beginning.Intra-operative and the pain relieving of used after operation codeine, the consumption of codeine is determined by the self-administered cover controlled analgesia system of patient, found that with independent use acetaminophen and compare, still have enough analgesic activities even two medicines and time spent codeine consumption reduce nearly 40%.
The explanation of the specific embodiment of front can disclose general features of the present invention fully, so that other people are easily concrete application by existing knowledge these specific embodiment are adjusted and/or adaptations, these all do not depart from scope of the present invention, so these adjustment and revise the replacement that is equal to be considered as embodiment disclosed in the present invention.Should also be understood that simultaneously expression herein or technical term are for illustrative purposes, rather than be used for limiting its implication.
Claims (3)
1. a pharmaceutical composition is characterized in that,
Described pharmaceutical composition comprises following composition:
The preparation method of described pharmaceutical composition comprises: at room temperature with 1.2-propylene glycol, PEG-400, Cys dissolving mixing, then add diclofenac sodium and acetaminophen, till this mixture is stirred to diclofenac sodium and acetaminophen and dissolves fully, solution filters by active carbon layer sand rod first, pass through again filtering with microporous membrane, thus obtained solution is divided in 400 ampoules, every bottled 1ml, sterilization namely gets described pharmaceutical composition.
2. a pharmaceutical composition is characterized in that,
Described pharmaceutical composition comprises following composition:
The preparation method of described pharmaceutical composition comprises: at room temperature with 1,2-propylene glycol, PEG-400, sodium pyrosulfite dissolving mixing, add in diclofenac sodium and the acetaminophen, then till this mixture being stirred to diclofenac sodium and acetaminophen and dissolving fully, adjust pH value to 7-9 with sodium hydroxide solution, solution filters by active carbon layer sand rod first, pass through again filtering with microporous membrane, thus obtained solution is divided in 500 ampoules, every bottled 2ml, the sterilization and get final product.
3. a pharmaceutical composition is characterized in that,
The preparation method of described pharmaceutical composition comprises: at room temperature with 1,2-propylene glycol, PEG-400, sodium thiosulfate dissolving mixing, add in diclofenac sodium and the acetaminophen, then till this mixture being stirred to diclofenac sodium and acetaminophen and dissolving fully, adjust pH value to 7-9 with sodium hydroxide solution, solution filters by active carbon layer sand rod first, pass through again filtering with microporous membrane, thus obtained solution is divided in 500 ampoules, every bottled 2ml, the sterilization and get final product.
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| CN106214632A (en) * | 2016-08-30 | 2016-12-14 | 天津市中升挑战生物科技有限公司 | A kind of acetaminophen, Diclofenac Sodium Injection and preparation method thereof |
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| CN102349887A (en) * | 2011-08-02 | 2012-02-15 | 天津市嵩锐医药科技有限公司 | Diclofenac sodium acetaminophen gastrointestinal type capsule medicinal composition |
| CN105982853B (en) * | 2015-03-17 | 2019-03-29 | 成都医学院 | Big infusion of a kind of paracetamol and its preparation method and application |
| AU2022264500A1 (en) * | 2021-04-28 | 2023-11-09 | Glaxosmithkline Consumer Healthcare Holdings (Us) Llc | Alkali metal salt combinations of incompatible active pharmaceutical ingredients |
| WO2025042689A1 (en) * | 2023-08-18 | 2025-02-27 | R.P. Scherer Technologies, Llc | Softgel capsule including a non-steroidal anti-inflammatory drug and acetaminophen |
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| CN1311672A (en) * | 1998-07-31 | 2001-09-05 | 方济各安吉利克化学联合股份有限公司 | Pharmaceutical composition for injection based on paracetamol |
| CN101015542A (en) * | 2007-02-13 | 2007-08-15 | 天津生机集团有限公司 | Compound paracetamol injection for livestock and process for preparing same |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1311672A (en) * | 1998-07-31 | 2001-09-05 | 方济各安吉利克化学联合股份有限公司 | Pharmaceutical composition for injection based on paracetamol |
| CN101015542A (en) * | 2007-02-13 | 2007-08-15 | 天津生机集团有限公司 | Compound paracetamol injection for livestock and process for preparing same |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106214632A (en) * | 2016-08-30 | 2016-12-14 | 天津市中升挑战生物科技有限公司 | A kind of acetaminophen, Diclofenac Sodium Injection and preparation method thereof |
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