CN104027315B - A kind of submicron emulsion lyophilized formulations of diclofenac sodium lidocaine hydrochloride, its preparation method and application thereof - Google Patents
A kind of submicron emulsion lyophilized formulations of diclofenac sodium lidocaine hydrochloride, its preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to medical art, specifically, relate to a kind of submicron emulsion lyophilized formulations of diclofenac sodium lidocaine hydrochloride, its preparation method and application thereof.Described submicron emulsion lyophilized formulations is made up of following raw material components: diclofenac sodium 50 ~ 100 weight portion, lidocaine hydrochloride 10 ~ 30 weight portion, water for injection 2000 ~ 3000 weight portion, cosolvent 30 ~ 70 weight portion, oils and fats 80 ~ 120 weight portion, emulsifying agent 80 ~ 120 weight portion, stabilizing agent 5 ~ 15 weight portion, freeze-dried excipient 150 ~ 250 weight portion and pH value regulator are appropriate.Submicron emulsion lyophilized formulations of the present invention not only overcomes the common layering of common freeze drying technology, solution colour heterogeneity, diclofenac sodium are difficult to make the technical barriers such as stable W/O/W type Emulsion, and obtained submicron emulsion lyophilized formulations has good stability and good clinical efficacy.
Description
Technical field
The invention belongs to medical art, specifically, relate to a kind of submicron emulsion lyophilized formulations of diclofenac sodium lidocaine hydrochloride, its preparation method and application thereof.
Background technology
Diclofenac sodium, its chemical name is 2-[(2,6-Dichlorobenzene base) is amino] phenylacetic acid list sodium salt, and this product is applied to rheumatoid arthritis, osteoarthritis.Various soft tissue rheumatism pain, as injury pain after shoulder pain, tenosynovitis, bursitis myalgia and motion etc.; Acute light, moderate pain is as the pain after operation, wound, strain etc.; Primary dysmenorrhea, toothache, headache etc.
Lidocaine hydrochloride is local anaesthetics and anti-arrhythmic.Be mainly used in infiltration anesthesia, epidural anesthesia, topical anesthesia (being used as mucomembranous anesthesia when being included in thoracoscopy or abdominal operation) and nerve block.Can be used for ventricular premature contraction and ventricular tachycardia after acute myocardial infarction, also can be used for that digitalis is poisoning, ventricular arrhythmia that cardiac operation and cardiac catheter cause.
Both share and make injection, can effectively reduce patient injection local pain.
CN1689561A discloses a kind of freeze-dried powder preparation containing diclofenac salt and lignocaine, it is by the Tween 80 containing solubilization, the pharmaceutically acceptable pH adjusting agent regulating solution ph, the treatment diclofenac salt of effective dose and the solution of lignocaine, the pH value of solution is greater than 7.0, obtained after lyophilization.This solution also can contain other pharmaceutically acceptable adjuvants.Preparation stable performance of the present invention, convenient transportation, storage period is long, and does not deposit in use because of untoward reaction that the organic solvents such as ethanol cause.
But due to lidocaine hydrochloride slightly soluble in water, the freeze-drying prods adopting existing common freeze drying technology to make, there will be lamination, and the color of product solution also occurs underproof situation due to the precipitation of lidocaine hydrochloride.
Emulsion studies comparatively deep in laboratory, and clinical practice is more, is also easy to a kind of dosage form of large-scale production." taking PLURONICS F87 as the research that co-emulsifier prepares diclofenac sodium submicron emulsion " [Wang Hao, Gu Jijin, Deng. take PLURONICS F87 as the research [J] that co-emulsifier prepares diclofenac sodium submicron emulsion. China Dispensary, 2008,19 (25): 1965-1967] take diclofenac sodium as model drug, PLURONICS F87 is co-emulsifier, adopts high pressure homogenize-colostrum pH regulator legal system for obtaining O/W type diclofenac sodium submicron emulsion preparation.
External somebody adopts W/O/W type Emulsion by the water inlet mutually of anti-inflammation analgesia medicine diclofenac sodium parcel, contact with the direct of blood vessel when high concentration uses to reduce its injection type, and then reduce its zest to blood vessel, but the Emulsion existence and stability problem of the type, at lay up period diclofenac sodium meeting breakdown of emulsion, thus present stage can't be developed to the product that can go on the market.
Visible, the technical barrier that diclofenac sodium is difficult to make stable W/O/W type Emulsion is there is in prior art, and the product that the W/O/W type Emulsion of the diclofenac sodium how preparing a kind of good stability is made it be developed to can to go on the market the and how compound preparation of diclofenac sodium and lidocaine hydrochloride is made stable W/O/W type Emulsion prior art and all do not provide the enlightenment of any technology, in view of this, special proposition the present invention.
Summary of the invention
The object of the present invention is to provide a kind of submicron emulsion lyophilized formulations of diclofenac sodium lidocaine hydrochloride, wrapped up by oil phase, diclofenac sodium and lidocaine hydrochloride are contacted with air as far as possible less, avoids oxidation, not only can Long-term Storage, can also product quality be ensured.
For realizing object of the present invention, the present invention adopts following technical scheme:
A submicron emulsion lyophilized formulations for diclofenac sodium lidocaine hydrochloride, wherein, described submicron emulsion lyophilized formulations is made up of following raw material components:
Preferably, described submicron emulsion lyophilized formulations is made up of following raw material components:
Wherein the amount of lidocaine hydrochloride is in lignocaine.
In the present invention, described submicron emulsion lyophilized formulations is W/O/W type submicron emulsion lyophilized formulations.
At present, due to the W/O/W type Emulsion existence and stability problem of diclofenac sodium, at lay up period diclofenac sodium meeting breakdown of emulsion, make the Emulsion of the type there is certain difficulty in preparation, and then make the Emulsion of the type can't be developed to the product that can go on the market in present stage.
Therefore, the product that W/O/W type Emulsion for the diclofenac sodium how preparing a kind of good stability makes it be developed to can to go on the market the and how compound preparation of diclofenac sodium and lidocaine hydrochloride is made stable W/O/W type Emulsion prior art and all do not provide the enlightenment of any technology, the present invention after a large amount of tests, surprisingly obtained a kind of good stability and W/O/W type submicron emulsion lyophilized formulations containing lidocaine hydrochloride diclofenac sodium two kinds of active component.
The results showed, submicron emulsion lyophilized formulations of the present invention not only has good stability, and has good clinical efficacy.
Described oils and fats is one or more in ethyl oleate, Miglyol 812N, oleic acid polyethyleneglycol glyceride, median chain triglyceride oil or soybean oil, preferred median chain triglyceride oil and/or soybean oil.
Described emulsifying agent is one or more in polyvinyl alcohol, Ovum Gallus domesticus Flavus lecithin, PLURONICS F87, Tween 80, cholesterol, glycerol, propylene glycol or PEG400, preferred Ovum Gallus domesticus Flavus lecithin and/or Tween 80.
Described stabilizing agent is one or more in oleic acid or its salt, cholic acid or its salt or deoxycholic acid or its salt, more preferably oleic acid or its salt.
Described freeze-dried excipient is at least one in mannitol, lactose, glucose, maltose, sorbitol, sucrose and pharmaceutically acceptable excipient, preferably sucrose, mannitol or lactose.
Described cosolvent is propylene glycol; Described pH value regulator is sodium hydroxide.
After described submicron emulsion lyophilized formulations redissolves, mean diameter is 100nm ~ 200nm.
In the present invention, be dissolved in water by obtained submicron emulsion lyophilized formulations, detect, result with laser diffraction particle size instrument, mean diameter is 50 ~ 200nm, meets the requirement of submicron emulsion dosage form.
Diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations provided by the present invention, carry out stability test investigation, place 10 days under high temperature 60 DEG C, high humidity 90% and illumination 4500Lx condition, every Testing index has no significant change, accelerate 6 months under high temperature 40 DEG C, relative humidity 75% ± 5% condition, every Testing index does not have significant change, and long term test 24 months under temperature 25 DEG C, relative humidity 60% ± 10% condition, every Testing index does not have significant change.
Diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations provided by the present invention, carry out zest, sensitivity test, all conform with the regulations, safety is proven.
The present invention also aims to provide the preparation method of described submicron emulsion lyophilized formulations, described preparation method comprises the steps:
1) diclofenac sodium is dissolved in water for injection, lidocaine hydrochloride is added cosolvent and dissolve, then both are mixed and stirs, form aqueous phase;
2) oils and fats, stabilizing agent and emulsifying agent are mixed, stirring and dissolving, form oil phase;
3) aqueous phase is slowly added in oil phase, form W/O emulsion;
4) freeze-dried excipient is dissolved in water for injection, more above-mentioned W/O emulsion is added, form W/O/W type colostrum;
5) colostrum is by pH value regulator adjust ph to 7.0 ~ 8.5, then by high pressure homogenizer, prepares diclofenac sodium lidocaine hydrochloride breast eventually;
6) breast eventually of gained is filtered postlyophilization, obtain described submicron emulsion lyophilized formulations.
At present, due to the W/O/W type Emulsion existence and stability problem of diclofenac sodium, the Emulsion of the type is made to there is certain difficult problem in preparation, and then limiting the research and development of Emulsion of diclofenac sodium and lidocaine hydrochloride the type, prior art is also there are no the report of the W/O/W type submicron emulsion preparation of diclofenac sodium and lidocaine hydrochloride.
The present invention with diclofenac sodium and lidocaine hydrochloride for active component, add the pharmaceutically acceptable adjuvants such as oils and fats, cosolvent, stabilizing agent, emulsifying agent, freeze-dried excipient, adopt multi-emulsion method to be prepared into submicron emulsion preparation, then freeze-drying preparation for injection is made in lyophilizing further.Not only efficiently solving the product colour heterogeneity in existing conventional lyophilizing technique, there is the technological deficiencies such as layering in preparation technology.What is more important, overcome the technical barrier that diclofenac sodium in prior art is difficult to make stable W/O/W type Emulsion, adopt the W/O/W type submicron emulsion lyophilized formulations good stability being active component with diclofenac sodium and lidocaine hydrochloride that the inventive method obtains, redissolve after the visible insoluble matter of thing, particulate matter and visible foreign matters inspection completely qualified.
Above-mentioned preparation method, wherein, step 5) in, described is by high pressure homogenizer 3 ~ 4 times by high pressure homogenizer, first time pressure 500 ~ 600mpa, second time pressure 600 ~ 800mpa, third time pressure 800 ~ 1000mpa, the 4th pressure 1000 ~ 1200mpa.
Step 6) in, described being filtered into by 0.2 μm of membrane filtration is degerming.
The present invention also provides the described application of submicron emulsion lyophilized formulations in the medicine preparing the pain that treatment orthopaedic disease causes further.
Compared with prior art, tool of the present invention has the following advantages:
(1) in the present invention, diclofenac sodium and lidocaine hydrochloride are wrapped in submicron emulsion, substantially increase the stability of preparation, ensure that the quality of product;
(2) the submicron emulsion lyophilized formulations of diclofenac sodium provided by the present invention and lidocaine hydrochloride, has certain targeting, can improve drug therapeutic indices, reduces drug toxicity and reduces drug side effect;
(3) the submicron emulsion lyophilized formulations of diclofenac sodium provided by the present invention and lidocaine hydrochloride, can adopt conventional process equipment, can suitability for industrialized production, constant product quality;
(4) the submicron emulsion lyophilized formulations of diclofenac sodium provided by the present invention and lidocaine hydrochloride overcomes layering common in existing common freeze drying technology, the uneven first-class technical barrier of solution colour.
Detailed description of the invention
By the following examples the present invention is further described, but should not be construed as limitation of the present invention.
Embodiment 1, prepare the submicron emulsion lyophilized formulations of diclofenac sodium lidocaine hydrochloride
Formula:
Preparation method:
1) 75g diclofenac sodium 100g water for injection is dissolved, 20g lidocaine hydrochloride 50g propylene glycol is dissolved, then both is mixed and stir, form aqueous phase;
2) under nitrogen protection 100g median chain triglyceride oil, 10g oleic acid and 100g Ovum Gallus domesticus Flavus lecithin are mixed, stirring and dissolving, form oil phase;
3) above-mentioned aqueous phase is slowly added in oil phase, stir, form W/O emulsion;
4) 200g sucrose 2400g water for injection is dissolved, the W/O emulsion of above-mentioned preparation is added in sucrose solution, uses high speed dispersion cutter, shear evenly, make W/O/W type colostrum;
5) W/O/W type colostrum regulates pH value to 7.0 ~ 8.5 of medicinal liquid with 10% sodium hydroxide solution, pass through high pressure homogenizer 3 ~ 4 times again, first time pressure 500 ~ 600mpa, second time pressure 600 ~ 800mpa, third time pressure 800 ~ 1000mpa, 4th pressure 1000 ~ 1200mpa, makes whole breast;
6) sampling detects intermediate, and after qualified, breast is degerming by 0.2 μm of membrane filtration eventually, and fill, partly jumps a queue, and enters freeze drying box, and lyophilization obtains finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations getting preparation is dissolved in water, and be added in 300ml water, detect, result with laser diffraction particle size instrument, mean diameter is 110nm, meets the related request of preparation used for intravenous injection.
Embodiment 2, prepare diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations
Formula:
Preparation method:
1) 75g diclofenac sodium 100g water for injection is dissolved, 20g lidocaine hydrochloride 50g propylene glycol is dissolved, then both is mixed and stir, form aqueous phase;
2) under nitrogen protection 100g median chain triglyceride oil, 10g oleic acid and 100g Tween 80 are mixed, stirring and dissolving, form oil phase;
3) above-mentioned aqueous phase is slowly added in oil phase, stir, form W/O emulsion;
4) 200g mannitol 2400g water for injection is dissolved, the W/O emulsion of above-mentioned preparation is added in mannitol solution, uses high speed dispersion cutter, shear evenly, make W/O/W type colostrum;
5) W/O/W type colostrum regulates pH value to 7.0 ~ 8.5 of medicinal liquid with 10% sodium hydroxide solution, pass through high pressure homogenizer 3 ~ 4 times again, first time pressure 500 ~ 600mpa, second time pressure 600 ~ 800mpa, third time pressure 800 ~ 1000mpa, 4th pressure 1000 ~ 1200mpa, makes whole breast;
6) sampling detects intermediate, and after qualified, breast is degerming by 0.2 μm of membrane filtration eventually, and fill, partly jumps a queue, and enters freeze drying box, and lyophilization obtains finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations getting preparation is dissolved in water, and be added in 300ml water, detect, result with laser diffraction particle size instrument, mean diameter is 120nm, meets the related request of preparation used for intravenous injection.
Embodiment 3, prepare diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations
Formula:
Preparation method:
1) 75g diclofenac sodium 100g water for injection is dissolved, 20g lidocaine hydrochloride 50g propylene glycol is dissolved, then both is mixed and stir, form aqueous phase;
2) under nitrogen protection 100g soybean oil, 10g oleic acid and 100g Ovum Gallus domesticus Flavus lecithin are mixed, stirring and dissolving, form oil phase;
3) above-mentioned aqueous phase is slowly added in oil phase, stir, form W/O emulsion;
4) 200g lactose 2400g water for injection is dissolved, the formation W/O emulsion of above-mentioned preparation is added in lactose solution, uses high speed dispersion cutter, shear evenly, make W/O/W type colostrum;
5) W/O/W type colostrum regulates pH value to 7.0 ~ 8.5 of medicinal liquid with 10% sodium hydroxide solution, pass through high pressure homogenizer 3 ~ 4 times again, first time pressure 500 ~ 600mpa, second time pressure 600 ~ 800mpa, third time pressure 800 ~ 1000mpa, 4th pressure 1000 ~ 1200mpa, makes whole breast;
6) sampling detects intermediate, and after qualified, breast is degerming by 0.2 μm of membrane filtration eventually, and fill, partly jumps a queue, enters freeze drying box, lyophilization, obtain finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations getting preparation is dissolved in water, and be added in 300ml water, detect, result with laser diffraction particle size instrument, mean diameter is 120nm, meets the related request of preparation used for intravenous injection.
Embodiment 4, prepare diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations
Formula:
Preparation method:
1) 50g diclofenac sodium 100g water for injection is dissolved, 13g lidocaine hydrochloride 30g propylene glycol is dissolved, then both is mixed and stir, form aqueous phase;
2) under nitrogen protection 80g ethyl oleate, 5g oleic acid and 80g Ovum Gallus domesticus Flavus lecithin are mixed, stirring and dissolving, form oil phase;
3) above-mentioned aqueous phase is slowly added in oil phase, stir, form W/O emulsion;
4) 150g glucose 1900g water for injection is dissolved, the formation W/O emulsion of above-mentioned preparation is added in glucose solution, uses high speed dispersion cutter, shear evenly, make W/O/W type colostrum;
5) W/O/W type colostrum regulates the pH value to 7.0 of medicinal liquid with 10% sodium hydroxide solution, then passes through high pressure homogenizer 3 ~ 4 times, first time pressure 500 ~ 600mpa, second time pressure 600 ~ 800mpa, third time pressure 800 ~ 1000mpa, the 4th pressure 1000 ~ 1200mpa, makes whole breast;
6) sampling detects intermediate, and after qualified, breast is degerming by 0.2 μm of membrane filtration eventually, and fill, partly jumps a queue, and enters freeze drying box, and lyophilization obtains finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations getting preparation is dissolved in water, and be added in 300ml water, detect, result with laser diffraction particle size instrument, mean diameter is 120nm, meets the related request of preparation used for intravenous injection.
Embodiment 5, prepare diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations
Formula:
Preparation method:
1) 100g diclofenac sodium 100g water for injection is dissolved, 30g lidocaine hydrochloride 70g propylene glycol is dissolved, then both is mixed and stir, form aqueous phase;
2) under nitrogen protection 120g Miglyol 812N, 15g oleic acid and 120gPEG400 are mixed, stirring and dissolving, form oil phase;
3) above-mentioned aqueous phase is slowly added in oil phase, stir, form W/O emulsion;
4) 250g maltose 2900g water for injection is dissolved, the formation W/O emulsion of above-mentioned preparation is added in maltose solution, uses high speed dispersion cutter, shear evenly, make W/O/W type colostrum;
5) W/O/W type colostrum regulates the pH value to 8.5 of medicinal liquid with 10% sodium hydroxide solution, then passes through high pressure homogenizer 3 ~ 4 times, first time pressure 500 ~ 600mpa, second time pressure 600 ~ 800mpa, third time pressure 800 ~ 1000mpa, the 4th pressure 1000 ~ 1200mpa, makes whole breast;
6) sampling detects intermediate, and after qualified, breast is degerming by 0.2 μm of membrane filtration eventually, and fill, partly jumps a queue, and enters freeze drying box, and lyophilization obtains finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations getting preparation is dissolved in water, and be added in 300ml water, detect, result with laser diffraction particle size instrument, mean diameter is 120nm, meets the related request of preparation used for intravenous injection.
Embodiment 6, prepare diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations
Formula:
Preparation method:
1) 60g diclofenac sodium 100g water for injection is dissolved, 15g lidocaine hydrochloride 45g propylene glycol is dissolved, then both is mixed and stir, form aqueous phase;
2) under nitrogen protection by 90g oleic acid polyethyleneglycol glyceride, 12g oleic acid and 90g mixed with propylene glycol, stirring and dissolving, forms oil phase;
3) above-mentioned aqueous phase is slowly added in oil phase, stir, form W/O emulsion;
4) 180g sorbitol 2200g water for injection is dissolved, the formation W/O emulsion of above-mentioned preparation is added in sorbitol solution, uses high speed dispersion cutter, shear evenly, make W/O/W type colostrum;
5) W/O/W type colostrum regulates the pH value to 7.5 of medicinal liquid with 10% sodium hydroxide solution, then passes through high pressure homogenizer 3 ~ 4 times, first time pressure 500 ~ 600mpa, second time pressure 600 ~ 800mpa, third time pressure 800 ~ 1000mpa, the 4th pressure 1000 ~ 1200mpa, makes whole breast;
6) sampling detects intermediate, and after qualified, breast is degerming by 0.2 μm of membrane filtration eventually, and fill, partly jumps a queue, and enters freeze drying box, and lyophilization obtains finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations getting preparation is dissolved in water, and be added in 300ml water, detect, result with laser diffraction particle size instrument, mean diameter is 120nm, meets the related request of preparation used for intravenous injection.
Embodiment 7, prepare diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations
Formula:
Preparation method:
1) 80g diclofenac sodium 100g water for injection is dissolved, 25g lidocaine hydrochloride 60g propylene glycol is dissolved, then both is mixed and stir, form aqueous phase;
2) under nitrogen protection 110g soybean oil, 14g cholic acid and 110g glycerol are mixed, stirring and dissolving, form oil phase;
3) above-mentioned aqueous phase is slowly added in oil phase, stir, form W/O emulsion;
4) 230g lactose 2700g water for injection is dissolved, the formation W/O emulsion of above-mentioned preparation is added in lactose solution, uses high speed dispersion cutter, shear evenly, make W/O/W type colostrum;
5) W/O/W type colostrum regulates the pH value to 8.0 of medicinal liquid with 10% sodium hydroxide solution, then passes through high pressure homogenizer 3 ~ 4 times, first time pressure 500 ~ 600mpa, second time pressure 600 ~ 800mpa, third time pressure 800 ~ 1000mpa, the 4th pressure 1000 ~ 1200mpa, makes whole breast;
6) sampling detects intermediate, and after qualified, breast is degerming by 0.2 μm of membrane filtration eventually, and fill, partly jumps a queue, and enters freeze drying box, and lyophilization obtains finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations getting preparation is dissolved in water, and be added in 300ml water, detect, result with laser diffraction particle size instrument, mean diameter is 120nm, meets the related request of preparation used for intravenous injection.
Embodiment 8, prepare diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations
Formula:
Preparation method:
1) 55g diclofenac sodium 100g water for injection is dissolved, 10g lidocaine hydrochloride 38g propylene glycol is dissolved, then both is mixed and stir, form aqueous phase;
2) under nitrogen protection 105g soybean oil, 7g deoxycholic acid and 115g cholesterol are mixed, stirring and dissolving, form oil phase;
3) above-mentioned aqueous phase is slowly added in oil phase, stir, form W/O emulsion;
4) 245g lactose 2000g water for injection is dissolved, the formation W/O emulsion of above-mentioned preparation is added in lactose solution, uses high speed dispersion cutter, shear evenly, make W/O/W type colostrum;
5) W/O/W type colostrum regulates the pH value to 7.2 of medicinal liquid with 10% sodium hydroxide solution, then passes through high pressure homogenizer 3 ~ 4 times, first time pressure 500 ~ 600mpa, second time pressure 600 ~ 800mpa, third time pressure 800 ~ 1000mpa, the 4th pressure 1000 ~ 1200mpa, makes whole breast;
6) sampling detects intermediate, and after qualified, breast is degerming by 0.2 μm of membrane filtration eventually, and fill, partly jumps a queue, and enters freeze drying box, and lyophilization obtains finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations getting preparation is dissolved in water, and be added in 300ml water, detect, result with laser diffraction particle size instrument, mean diameter is 120nm, meets the related request of preparation used for intravenous injection.
Embodiment 9, prepare diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations
Formula:
Preparation method:
1) 82g diclofenac sodium 100g water for injection is dissolved, 26g lidocaine hydrochloride 68g propylene glycol is dissolved, then both is mixed and stir, form aqueous phase;
2) under nitrogen protection 98g soybean oil, 8g oleic acid and 88g polyvinyl alcohol are mixed, stirring and dissolving, form oil phase;
3) above-mentioned aqueous phase is slowly added in oil phase, stir, form W/O emulsion;
4) 168g lactose 2700g water for injection is dissolved, the formation W/O emulsion of above-mentioned preparation is added in lactose solution, uses high speed dispersion cutter, shear evenly, make W/O/W type colostrum;
5) W/O/W type colostrum regulates the pH value to 8.2 of medicinal liquid with 10% sodium hydroxide solution, then passes through high pressure homogenizer 3 ~ 4 times, first time pressure 500 ~ 600mpa, second time pressure 600 ~ 800mpa, third time pressure 800 ~ 1000mpa, the 4th pressure 1000 ~ 1200mpa, makes whole breast;
6) sampling detects intermediate, and after qualified, breast is degerming by 0.2 μm of membrane filtration eventually, and fill, partly jumps a queue, and enters freeze drying box, and lyophilization obtains finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations getting preparation is dissolved in water, and be added in 300ml water, detect, result with laser diffraction particle size instrument, mean diameter is 120nm, meets the related request of preparation used for intravenous injection.
Embodiment 10, prepare diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations
Formula:
Preparation method:
1) 78g diclofenac sodium 100g water for injection is dissolved, 23g lidocaine hydrochloride 58g propylene glycol is dissolved, then both is mixed and stir, form aqueous phase;
2) under nitrogen protection 112g soybean oil, 9g oleic acid and 92g PLURONICS F87 are mixed, stirring and dissolving, form oil phase;
3) above-mentioned aqueous phase is slowly added in oil phase, stir, form W/O emulsion;
4) 186g lactose 2430g water for injection is dissolved, the formation W/O emulsion of above-mentioned preparation is added in lactose solution, uses high speed dispersion cutter, shear evenly, make W/O/W type colostrum;
5) W/O/W type colostrum regulates the pH value to 7.5 of medicinal liquid with 10% sodium hydroxide solution, then passes through high pressure homogenizer 3 ~ 4 times, first time pressure 500 ~ 600mpa, second time pressure 600 ~ 800mpa, third time pressure 800 ~ 1000mpa, the 4th pressure 1000 ~ 1200mpa, makes whole breast;
6) sampling detects intermediate, and after qualified, breast is degerming by 0.2 μm of membrane filtration eventually, and fill, partly jumps a queue, and enters freeze drying box, and lyophilization obtains finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations getting preparation is dissolved in water, and be added in 300ml water, detect, result with laser diffraction particle size instrument, mean diameter is 120nm, meets the related request of preparation used for intravenous injection.
The selection of test example 1, pH value
Investigate 6.5,7.0,7.5,8.0,8.5,9.0 preparation stabilities under totally six kinds of pH value condition respectively, the appropriate sodium hydroxide solution of the colostrum of the formula preparation by embodiment 1 is adjusted to different pH value.By the nitrogen-filled seal of different pH value colostrum sample in tubular injection bottle, in 121 DEG C of heating 15 minutes.Sampling measures different prescription sample particle diameter with 380ZLS type granularity/Zeta potential analyzer, to investigate the impact of different pH value on emulsion stability.Investigation the results are shown in Table 1:
The pH of table 1, medicinal liquid investigates result (particle diameter unit: nm)
The basic particle size distribution that laser particle analyzer generates is light intensity distributions, by Mie theory, can be converted into volume distributed median and distributed number.Usually, volumetric diameter better can embody the uniformity of the micro-nano grain of rice in solution system.From granulometry result, after the heating of pH6.5 and pH9.0 high-temperature sample, granularity increases, and outward appearance occurs analysing oily phenomenon simultaneously.Under all the other four kinds of pH value condition, after heat treatment, change of granularity is little, and outward appearance does not have significant change, and visible pH value range is that in 7.0-8.5, dispersion stability is good.Therefore, in the present invention, the amount of pH adjusting agent sodium hydroxide solution is regulate the pH value of colostrum to 7.0-8.5.
Test example 2, stability test
The diclofenac sodium lidocaine hydrochloride lyophilized injectable powder (ShanXi BoSen Biology Pharmacy Stock Group Co., Ltd of sample prepared by the present invention and listing, lot number 20110306) place under high temperature 60 DEG C, high humidity 90% and illumination 4500Lx condition and carry out influence factor's experiment investigation in 10 days, the results are shown in Table 2; Under high temperature 40 DEG C ± 2 DEG C, relative humidity 75% ± 5% condition 6 months, carry out accelerated test investigation, the results are shown in Table 3; Under temperature 25 DEG C ± 2 DEG C, relative humidity 60% ± 10% condition 24 months, carry out long-time stability investigation, detect the situation of change of all standard, the results are shown in Table 4.
Table 2, influence factor's result of the test
Table 3, accelerated test result
Table 4, long-term test results
Found by the above results, when accelerating June, long-term 18,24 months, there is irregular colour one, lamination in the character of listing product, and the clarity and the color that detect discovery solution are all against regulation, and pH changes greatly, and related substance raises obviously, and content declines obviously; And sample prepared by the present invention, character does not have significant change, does not occur sample lamination, and after testing, indices all conforms with the regulations, and pH value, related substance, content have no significant change.Illustrate that sample Long-term Storage quality stability prepared by the present invention is better.
Also carried out above-mentioned test to the submicron emulsion lyophilized formulations of the diclofenac sodium lidocaine hydrochloride obtained by other embodiment of the present invention, its result obtained is similar.
Test example 3, specific safety Journal of Sex Research
Muscle irritation is tested: sample of the present invention (embodiment of the present invention 1 obtains), 2ml sterilized water for injection of often drawing dissolves, get healthy rabbits 2, doe, without pregnant, injects 1ml with aseptic manipulation respectively in its left and right lower limb quadriceps femoris, within 48 hours, puts to death after injection, dissect and take out quadriceps femoris, longitudinally cut, observation injection site irritant reaction is corresponding order of reaction and according to the form below converts, and then calculates the summation of 4 pieces of quadriceps femoris order of reactions.
Rabbit muscular irritation test scores table
| Order of reaction | Irritant reaction |
| 0 | Without significant change |
| 1 | Mild hyperaemia, its scope is at 0.5 × below 1.0cm |
| 2 | Moderate is congested, and its scope is at 0.5 × more than 1.0cm |
| 3 | Severe is congested, with myodegeneration |
| 4 | Occur downright bad, have brown degeneration |
| 5 | Occur that popularity is downright bad |
Result of the test, perusal 2 rabbit 4 pieces of quadriceps femoris have no significant change, and order of reaction is 0. check pathological section: 4 pieces of quadriceps femoris Fiber structures are normal, and clean mark, includes a large amount of sarcostyles, sarcostyle has light and dark band.Result surface, sample of the present invention, to the effect of muscle nonirritant.
Sensitivity test gets healthy guinea pig 18, is divided into three groups at random by body weight, often organizes 6.Inject inventive samples group (embodiment of the present invention 1 obtains), ovalbumin positive controls and sodium chloride injection negative control group respectively.Systemic anaphylaxis standards of grading and result of the test see the following form.
Systemic anaphylaxis standards of grading
| Scoring | Sign |
| 0 | Without significant reaction |
| 1 | Slightly grab nose, tremble or perpendicular hair |
| 2 | There is cough, repeatedly grab nose, tremble or perpendicular hair |
| 3 | Repeatedly or continuously cough, with dyspnea or spasm, tic |
| 4 | Spasm, tic, gatism, shock death |
Result of the test
Result surface, inventive samples to animal subject without sensitization, without anaphylaxis.
Also carried out above-mentioned test to the submicron emulsion lyophilized formulations of the diclofenac sodium lidocaine hydrochloride obtained by other embodiment of the present invention, its result obtained is similar.
Test example 4, clinical trial
1, clinical data
1.1 inclusion criterias: the 1. patient such as osteoarthritis (OA), osteoporosis, soft tissue injury, cervical spondylosis, prolapse of lumbar intervertebral disc of clinical definite; 2. at 23 ~ 65 years old age, men and women does not limit; 3. the tested and person that signs Informed Consent Form is ready.
1.2 exclusion standards: 1. used oral sustained-release analgesic excessively in analgesic or 12h before test in 4h, used monoamine oxidase, MAO (MAO) inhibitor in 2 weeks, accept immunosuppressant in 3 weeks, the patient of chloroquine, adrenocortical hormone local or whole body therapeutic; 2. addicted to tobacco and wine, respiration inhibition, respiratory tract obstruction person; 3. participated in other drug test in 1 ~ 3mo or used the prejudicial medicine of internal organs; 4. conscience kidney merit and hemopoietic system grievous injury person or suffer from other serious disease persons; 5. the identical or similar medicine allergies person of any one composition in this observation is had; 6. the women of gestation and age of sucking, plan remaining Women of childbearing age at no distant date; 7. neural organic disease is suffered from, psychological problem and can not partner.
1.3 case scenario: selected patient 264 example is all be in hospital or outpatient, adopt the single blind controlled trial of simple randomization (1:1), random employing SAS software, envelope card method, be divided into treatment group (132 example) and matched group (132 example) by selected patient by medical sequencing.Wherein, treatment group man 83 example, female 49 example, 54.3 ± 7 years old age, body weight 73.6 ± 10kg, VAS scoring 5.1276 ± 1.3187, the course of disease 3.1 ± 2.4 years; Matched group man 81 example, female 51 example, 53.3 ± 7 years old age, body weight 72.6 ± 10kg, VAS scoring 5.0986 ± 1.3812, the course of disease 3.0 ± 2.3 years.In sex, age, body weight, the course of disease, compare between two groups that there are no significant, good comparability.
2, method
2.1 medicament sources
Curative: diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations (embodiment of the present invention 1 obtains, specification: diclofenac sodium 75mg, lidocaine hydrochloride (in lignocaine) 20mg);
Contrast medicine: injection diclofenac sodium lidocaine hydrochloride (beautiful five too: Hainan Shuan Cheng pharmaceutcal corporation, Ltd produces, specification: diclofenac sodium 75mg, lidocaine hydrochloride (in lignocaine) 20mg, injectable powder).
2.2 therapeutic schemes: the outside upper limit intramuscular injection of buttocks after routine disinfection local skin, 1/1 time/d, continuous 7d, treatment group and matched group inject at every turn and prop up with water 2ml/.Drug withdrawal post-evaluation curative effect.Treatments period is mismatched and is used any other remedy measures.
2.3 observation item
2.3.1 safety observation: blood, urine, stool routine examination are chemically examined.Liver and kidney function checks.
2.3.2 health giving quality is observed:
2.3.3 analgesic effect index: pain intensity adopts VAS method, and 0 indicates without pain, and 1 ~ 3 is mild pain, and 4 ~ 6 is moderate pain, and more than 7 is severe pain.1 ~ 7d every day is by patient's record before medication and after medication.
2.4 statistical method: data handling utility statistic software SPSS 14.0 and Traditional Chinese Medicine University Of Guangzhou's graduate text " summary statistics software ", all data mean standard deviations
represent.Enumeration data X
2inspection, ranked data Ridit analyzes, and measurement data t checks, and compares and use variance analysis between many groups.
3, result
3.1 efficacy assessment standards are (with reference to related documents: carry out thoroughly evaluating to curative effect during evaluation of clinical curative effect off-test: invalidly improve < 30% for clinical symptoms and sign; Be effectively that 30%≤clinical symptoms and sign improve < 75%; Effective is that clinical symptoms and sign improve >=75%.Add up to both effective and effective and calculate total effective rate.
3.2 efficacy analysis
3.2.1 before and after two groups of treatments, VAS scoring is compared: in table 5.
Before and after table 5, two groups of treatments, VAS scoring is compared
| Group | Before treatment | After treatment |
| Treatment group | 5.1276±1.3187 | 1.0081±0.3129 |
| Matched group | 5.0986±1.3812 | 1.9842±0.3871 |
3.2.2 before and after two groups of treatments, the pain state of an illness compares: in table 6.
Before and after table 6, two groups of treatments, the pain state of an illness compares
3.2.2 two groups of Clinical efficacy comparisons: in table 7.
Table 7, two groups of Clinical efficacy comparisons
| Group | Number of cases | Invalid (%) | Effectively (%) | Effective (%) | Total effective rate (%) |
| Treatment group | 132 | 9(6.82％) | 58(43.94) | 65(49.24) | 123(93.18％) |
| Matched group | 132 | 17(12.88) | 52(39.39) | 63(47.73) | 115(87.12％) |
As can be seen from the above results, before and after two groups of treatments, VAS scoring is compared, the pain state of an illness compare and two groups of Clinical efficacy comparisons before and after two groups of treatments, treatment group is all better than matched group, and the submicron emulsion lyophilized formulations of the diclofenac sodium lidocaine hydrochloride namely adopting the present invention to obtain is better than the injectable powder of prior art.
Also carried out above-mentioned test to the submicron emulsion lyophilized formulations of the diclofenac sodium lidocaine hydrochloride obtained by other embodiment of the present invention, its result obtained is similar.
Claims (11)
1. a submicron emulsion lyophilized formulations for diclofenac sodium lidocaine hydrochloride, is characterized in that, described submicron emulsion lyophilized formulations is made up of following raw material components:
The preparation method of described submicron emulsion lyophilized formulations comprises the steps:
1) diclofenac sodium is dissolved in water for injection, lidocaine hydrochloride is added cosolvent and dissolve, then both are mixed and stirs, form aqueous phase;
2) oils and fats, stabilizing agent and emulsifying agent are mixed, stirring and dissolving, form oil phase;
3) aqueous phase is slowly added in oil phase, form W/O emulsion;
4) freeze-dried excipient is dissolved in water for injection, more above-mentioned W/O emulsion is slowly added, form W/O/W type colostrum;
5) colostrum is by pH value regulator adjust ph to 7.0 ~ 8.5, then by high pressure homogenizer, prepares diclofenac sodium lidocaine hydrochloride breast eventually;
6) breast eventually of gained is filtered postlyophilization, obtain described submicron emulsion preparation;
Wherein, described stabilizing agent is one or more in oleic acid or its salt, cholic acid or its salt or deoxycholic acid or its salt;
Described oils and fats is one or more in ethyl oleate, Miglyol 812N, oleic acid polyethyleneglycol glyceride, median chain triglyceride oil or soybean oil;
Described emulsifying agent is one or more in polyvinyl alcohol, Ovum Gallus domesticus Flavus lecithin, PLURONICS F87, Tween 80, cholesterol, glycerol, propylene glycol or PEG400;
Described cosolvent is propylene glycol.
2. submicron emulsion lyophilized formulations according to claim 1, is characterized in that, described submicron emulsion lyophilized formulations is made up of following raw material components:
3. submicron emulsion lyophilized formulations according to claim 1 and 2, is characterized in that, described oils and fats is median chain triglyceride oil and/or soybean oil.
4. submicron emulsion lyophilized formulations according to claim 1 and 2, is characterized in that, described emulsifying agent is Ovum Gallus domesticus Flavus lecithin and/or Tween 80.
5. submicron emulsion lyophilized formulations according to claim 1 and 2, is characterized in that, described stabilizing agent is oleic acid or its salt.
6. submicron emulsion lyophilized formulations according to claim 1 and 2, is characterized in that, described freeze-dried excipient is at least one in mannitol, lactose, glucose, maltose, sorbitol, sucrose and pharmaceutically acceptable excipient.
7. submicron emulsion lyophilized formulations according to claim 6, is characterized in that, described freeze-dried excipient is sucrose, mannitol or lactose.
8. submicron emulsion lyophilized formulations according to claim 1 and 2, is characterized in that, described pH value regulator is sodium hydroxide solution, and its consumption is regulate the pH value of colostrum to 7.5-8.0.
9. the submicron emulsion lyophilized formulations according to claim 1 or 2 or 7, is characterized in that, after described submicron emulsion preparation redissolves, mean diameter is 100nm ~ 200nm.
10. a preparation method for the submicron emulsion lyophilized formulations described in claim 1 ~ 9 any one, is characterized in that, described preparation method comprises the steps:
1) diclofenac sodium is dissolved in water for injection, lidocaine hydrochloride is added cosolvent and dissolve, then both are mixed and stirs, form aqueous phase;
2) oils and fats, stabilizing agent and emulsifying agent are mixed, stirring and dissolving, form oil phase;
3) aqueous phase is slowly added in oil phase, form W/O emulsion;
4) freeze-dried excipient is dissolved in water for injection, more above-mentioned W/O emulsion is slowly added, form W/O/W type colostrum;
5) colostrum is by pH value regulator adjust ph to 7.0 ~ 8.5, then by high pressure homogenizer, prepares diclofenac sodium lidocaine hydrochloride breast eventually;
6) breast eventually of gained is filtered postlyophilization, obtain described submicron emulsion preparation.
Submicron emulsion lyophilized formulations described in 11. 1 kinds of claim 1 ~ 9 any one treats the application in the medicine of the pain that orthopaedic disease causes in preparation.
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