CN104027315A - Submicron emulsion freeze-dried preparation of diclofenac sodium lidocaine hydrochloride as well as preparation method and application of submicron emulsion freeze-dried preparation - Google Patents
Submicron emulsion freeze-dried preparation of diclofenac sodium lidocaine hydrochloride as well as preparation method and application of submicron emulsion freeze-dried preparation Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and in particular relates to a submicron emulsion freeze-dried preparation of diclofenac sodium lidocaine hydrochloride as well as a preparation method and application of submicron emulsion freeze-dried preparation. The submicron emulsion freeze-dried preparation consists of the following raw material components in parts by weight: 50-100 parts of diclofenac sodium, 10-30 parts of lidocaine hydrochloride, 2000-3000 parts of water for injection, 30-70 parts of accessory solvent, 80-120 parts of grease, 80-120 parts of emulsifying agent, 5-15 parts of stabilizing agent, 150-250 parts of freeze-dried excipient and a proper amount of pH value regulator. By adopting the submicron emulsion freeze-dried preparation disclosed by the invention, the technical difficulties that an ordinary freeze-drying process usually has delamination and non-uniform solution color, and diclofenac sodium is hard to be prepared into a stable W/O type emulsifying agent and the like can be solved; meanwhile, the prepared submicron emulsion freeze-dried preparation has relatively good stability and clinical curative effects.
Description
Technical field
The invention belongs to medical technical field, specifically, relate to a kind of submicron emulsion lyophilized formulations, its preparation method and application thereof of diclofenac sodium lidocaine hydrochloride.
Background technology
Diclofenac sodium, its chemical name is 2-[(2,6-Dichlorobenzene base) amino] phenylacetic acid list sodium salt, this product is applied to rheumatoid arthritis, osteoarthritis.Various soft tissue rheumatism pain, as shoulder pain, tenosynovitis, bursitis myalgia and the rear damaging pain of motion etc.; The pain of acute light, moderate pain after as 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 while being included in thoracoscopy or abdominal operation) and nerve block.Can be used for ventricular premature contraction and ventricular tachycardia after acute myocardial infarction, the ventricular arrhythmia that also can be used for that digitalis is poisoning, cardiac operation and cardiac catheter causes.
Both share and make injection, can effectively reduce patient injection local pain.
CN1689561A discloses a kind of freeze-dried powder preparation that contains diclofenac salt and lignocaine, its pharmaceutically acceptable pH adjusting agent by the Tween 80 that contains solubilization, regulator solution pH value, the treatment diclofenac salt of effective dose and the solution of lignocaine, the pH value of solution is greater than 7.0, after lyophilization, makes.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 the untoward reaction causing because of organic solvents such as ethanol in use.
Yet due to lidocaine hydrochloride slightly soluble in water, the freeze-drying prods that adopts existing common freeze drying technology to make, there will be lamination, the color of product solution is also because underproof situation appears in separating out of lidocaine hydrochloride.
Emulsion is that in laboratory, research is comparatively deep, and clinical practice is more, is also easy to a kind of dosage form of large-scale production." take PLURONICS F87 prepare the research of diclofenac sodium submicron emulsion for co-emulsifier " [Wang Hao, Gu Jijin, Deng. the PLURONICS F87 of take is prepared the research [J] of diclofenac sodium submicron emulsion as co-emulsifier. 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 method to prepare 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, to reduce its injection type, when being used, high concentration contacts with the direct of blood vessel, and then reduce its zest to blood vessel, but the Emulsion existence and stability problem of the type, at lay up period diclofenac sodium, understand breakdown of emulsion, thereby present stage can't be developed to the product that can go on the market.
Visible, in prior art, exist the technical barrier that diclofenac sodium is difficult to make stable W/O/W type Emulsion, and make it be developed to the product that can go on the market and how the compound preparation of diclofenac sodium and lidocaine hydrochloride be made to stable W/O/W type Emulsion prior art and all do not provide any technology enlightenment for W/O/W type Emulsion how to prepare a kind of diclofenac sodium of good stability, 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, by oil phase, wrap up, diclofenac sodium and lidocaine hydrochloride are contacted with air as far as possible less, avoid oxidation, not only can Long-term Storage, can also guarantee product quality.
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 comprised of following raw material components:
Preferably, described submicron emulsion lyophilized formulations is comprised 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, W/O/W type Emulsion existence and stability problem due to diclofenac sodium, at lay up period diclofenac sodium meeting breakdown of emulsion, make the Emulsion of the type have 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, for W/O/W type Emulsion how to prepare a kind of diclofenac sodium of good stability, make it be developed to the product that can go on the market and how the compound preparation of diclofenac sodium and lidocaine hydrochloride be made to stable W/O/W type Emulsion prior art and all do not provide any technology enlightenment, the present invention, after a large amount of tests, has made W/O/W type submicron emulsion lyophilized formulations a kind of good stability and that contain two kinds of active component of lidocaine hydrochloride diclofenac sodium pleasantly surprisedly.
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, preferably 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, preferably 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, the submicron emulsion lyophilized formulations making is dissolved in water, with laser light scattering particle size analyzer, detects, result, 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, under 60 ℃ of high temperature, high humidity 90% and illumination 4500Lx condition, place 10 days, every detection index has no significant change, under 40 ℃ of high temperature, relative humidity 75% ± 5% condition, accelerate 6 months, every detection index does not have significant change, and under 25 ℃ of temperature, relative humidity 60% ± 10% condition, long term test is 24 months, and every detection index does not have significant change.
Diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations provided by the present invention, carries out zest, sensitivity test, and all up to specification, safety is proven.
The preparation method that the present invention also aims to provide described submicron emulsion lyophilized formulations, described preparation method comprises the steps:
1) diclofenac sodium is dissolved in to water for injection, lidocaine hydrochloride is added to cosolvent and dissolve, then both are mixed and stir, form water;
2) oils and fats, stabilizing agent and emulsifying agent are mixed, stirring and dissolving, forms oil phase;
3) water 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 regulates pH value to 7.0～8.5 by pH value regulator, then by high pressure homogenizer, prepares diclofenac sodium lidocaine hydrochloride breast eventually;
6) breast eventually of gained is filtered to postlyophilization, obtain described submicron emulsion lyophilized formulations.
At present, W/O/W type Emulsion existence and stability problem due to diclofenac sodium, make the Emulsion of the type have certain difficult problem in preparation, and then having limited the research and development of the 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.
It is active component that diclofenac sodium and lidocaine hydrochloride are take in the present invention, 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, more further freeze-drying preparation for injection is made in lyophilizing.Not only efficiently solving the product colour heterogeneity in existing conventional freeze drying technology, 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, what adopt that the inventive method makes take the W/O/W type submicron emulsion lyophilized formulations good stability that diclofenac sodium and lidocaine hydrochloride be active component, the visible insoluble matter of thing after redissolving, particulate matter and visible foreign matters inspection are completely qualified.
Above-mentioned preparation method, wherein, step 5) in, described is to pass through high pressure homogenizer 3～4 times by high pressure homogenizer, for the first time pressure 500～600mpa, for the second time pressure 600～800mpa, pressure 800～1000mpa for the third time, the 4th pressure 1000～1200mpa.
Step 6), in, described is filtered into by 0.2 μ m membrane filtration degerming.
Application in the medicine of the pain that the submicron emulsion lyophilized formulations described in the present invention also further provides causes in preparation treatment orthopaedic disease.
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, have greatly improved the stability of preparation, have guaranteed 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 therapy index, 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, and constant product quality;
(4) the submicron emulsion lyophilized formulations of diclofenac sodium provided by the present invention and lidocaine hydrochloride has overcome layering common in existing common freeze drying technology, the uneven first-class technical barrier of solution colour.
The specific embodiment
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 is dissolved with 100g water for injection, 20g lidocaine hydrochloride is dissolved with 50g propylene glycol, then both mixed and stir, form water;
2) under nitrogen protection, 100g median chain triglyceride oil, 10g oleic acid and 100g Ovum Gallus domesticus Flavus lecithin are mixed, stirring and dissolving, forms oil phase;
3) above-mentioned water is slowly added in oil phase, stir, form W/O emulsion;
4) 200g sucrose is dissolved with 2400g water for injection, the W/O emulsion of above-mentioned preparation is added in sucrose solution, use 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, pressure 500～600mpa for the first time, pressure 600～800mpa for the second time, pressure 800～1000mpa for the third time, the 4th pressure 1000～1200mpa, makes whole breast;
6) sampling detects intermediate, qualified after, breast is by 0.2 μ m membrane filtration degerming eventually, fill, partly jumps a queue, and enters freeze drying box, lyophilization obtains finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations of getting preparation is dissolved in water, and is added in 300ml water, with laser light scattering particle size analyzer, detect, and result, mean diameter is 110nm, meets the related request of used for intravenous injection preparation.
Embodiment 2, prepare diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations
Formula:
Preparation method:
1) 75g diclofenac sodium is dissolved with 100g water for injection, 20g lidocaine hydrochloride is dissolved with 50g propylene glycol, then both mixed and stir, form water;
2) under nitrogen protection, 100g median chain triglyceride oil, 10g oleic acid and 100g Tween 80 are mixed, stirring and dissolving, forms oil phase;
3) above-mentioned water is slowly added in oil phase, stir, form W/O emulsion;
4) 200g mannitol is dissolved with 2400g water for injection, the W/O emulsion of above-mentioned preparation is added in mannitol solution, use 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, pressure 500～600mpa for the first time, pressure 600～800mpa for the second time, pressure 800～1000mpa for the third time, the 4th pressure 1000～1200mpa, makes whole breast;
6) sampling detects intermediate, qualified after, breast is by 0.2 μ m membrane filtration degerming eventually, fill, partly jumps a queue, and enters freeze drying box, lyophilization obtains finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations of getting preparation is dissolved in water, and is added in 300ml water, with laser light scattering particle size analyzer, detect, and result, mean diameter is 120nm, meets the related request of used for intravenous injection preparation.
Embodiment 3, prepare diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations
Formula:
Preparation method:
1) 75g diclofenac sodium is dissolved with 100g water for injection, 20g lidocaine hydrochloride is dissolved with 50g propylene glycol, then both mixed and stir, form water;
2) under nitrogen protection, 100g soybean oil, 10g oleic acid and 100g Ovum Gallus domesticus Flavus lecithin are mixed, stirring and dissolving, forms oil phase;
3) above-mentioned water is slowly added in oil phase, stir, form W/O emulsion;
4) 200g lactose is dissolved with 2400g water for injection, the formation W/O emulsion of above-mentioned preparation is added in lactose solution, use 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, pressure 500～600mpa for the first time, pressure 600～800mpa for the second time, pressure 800～1000mpa for the third time, the 4th pressure 1000～1200mpa, makes whole breast;
6) sampling detects intermediate, qualified after, breast is by 0.2 μ m membrane filtration degerming eventually, fill, partly jumps a queue, enters freeze drying box, lyophilization, obtains finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations of getting preparation is dissolved in water, and is added in 300ml water, with laser light scattering particle size analyzer, detect, and result, mean diameter is 120nm, meets the related request of used for intravenous injection preparation.
Embodiment 4, prepare diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations
Formula:
Preparation method:
1) 50g diclofenac sodium is dissolved with 100g water for injection, 13g lidocaine hydrochloride is dissolved with 30g propylene glycol, then both mixed and stir, form water;
2) under nitrogen protection, 80g ethyl oleate, 5g oleic acid and 80g Ovum Gallus domesticus Flavus lecithin are mixed, stirring and dissolving, forms oil phase;
3) above-mentioned water is slowly added in oil phase, stir, form W/O emulsion;
4) 150g glucose is dissolved with 1900g water for injection, the formation W/O emulsion of above-mentioned preparation is added in glucose solution, use 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, for the first time pressure 500～600mpa, pressure 600～800mpa for the second time, pressure 800～1000mpa for the third time, the 4th pressure 1000～1200mpa, makes whole breast;
6) sampling detects intermediate, qualified after, breast is by 0.2 μ m membrane filtration degerming eventually, fill, partly jumps a queue, and enters freeze drying box, lyophilization obtains finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations of getting preparation is dissolved in water, and is added in 300ml water, with laser light scattering particle size analyzer, detect, and result, mean diameter is 120nm, meets the related request of used for intravenous injection preparation.
Embodiment 5, prepare diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations
Formula:
Preparation method:
1) 100g diclofenac sodium is dissolved with 100g water for injection, 30g lidocaine hydrochloride is dissolved with 70g propylene glycol, then both mixed and stir, form water;
2) under nitrogen protection, 120g Miglyol 812N, 15g oleic acid and 120gPEG400 are mixed, stirring and dissolving, forms oil phase;
3) above-mentioned water is slowly added in oil phase, stir, form W/O emulsion;
4) 250g maltose is dissolved with 2900g water for injection, the formation W/O emulsion of above-mentioned preparation is added in maltose solution, use 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, for the first time pressure 500～600mpa, pressure 600～800mpa for the second time, pressure 800～1000mpa for the third time, the 4th pressure 1000～1200mpa, makes whole breast;
6) sampling detects intermediate, qualified after, breast is by 0.2 μ m membrane filtration degerming eventually, fill, partly jumps a queue, and enters freeze drying box, lyophilization obtains finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations of getting preparation is dissolved in water, and is added in 300ml water, with laser light scattering particle size analyzer, detect, and result, mean diameter is 120nm, meets the related request of used for intravenous injection preparation.
Embodiment 6, prepare diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations
Formula:
Preparation method:
1) 60g diclofenac sodium is dissolved with 100g water for injection, 15g lidocaine hydrochloride is dissolved with 45g propylene glycol, then both mixed and stir, form water;
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 water is slowly added in oil phase, stir, form W/O emulsion;
4) 180g sorbitol is dissolved with 2200g water for injection, the formation W/O emulsion of above-mentioned preparation is added in sorbitol solution, use 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, for the first time pressure 500～600mpa, pressure 600～800mpa for the second time, pressure 800～1000mpa for the third time, the 4th pressure 1000～1200mpa, makes whole breast;
6) sampling detects intermediate, qualified after, breast is by 0.2 μ m membrane filtration degerming eventually, fill, partly jumps a queue, and enters freeze drying box, lyophilization obtains finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations of getting preparation is dissolved in water, and is added in 300ml water, with laser light scattering particle size analyzer, detect, and result, mean diameter is 120nm, meets the related request of used for intravenous injection preparation.
Embodiment 7, prepare diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations
Formula:
Preparation method:
1) 80g diclofenac sodium is dissolved with 100g water for injection, 25g lidocaine hydrochloride is dissolved with 60g propylene glycol, then both mixed and stir, form water;
2) under nitrogen protection, 110g soybean oil, 14g cholic acid and 110g glycerol are mixed, stirring and dissolving, forms oil phase;
3) above-mentioned water is slowly added in oil phase, stir, form W/O emulsion;
4) 230g lactose is dissolved with 2700g water for injection, the formation W/O emulsion of above-mentioned preparation is added in lactose solution, use 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, for the first time pressure 500～600mpa, pressure 600～800mpa for the second time, pressure 800～1000mpa for the third time, the 4th pressure 1000～1200mpa, makes whole breast;
6) sampling detects intermediate, qualified after, breast is by 0.2 μ m membrane filtration degerming eventually, fill, partly jumps a queue, and enters freeze drying box, lyophilization obtains finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations of getting preparation is dissolved in water, and is added in 300ml water, with laser light scattering particle size analyzer, detect, and result, mean diameter is 120nm, meets the related request of used for intravenous injection preparation.
Embodiment 8, prepare diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations
Formula:
Preparation method:
1) 55g diclofenac sodium is dissolved with 100g water for injection, 10g lidocaine hydrochloride is dissolved with 38g propylene glycol, then both mixed and stir, form water;
2) under nitrogen protection, 105g soybean oil, 7g deoxycholic acid and 115g cholesterol are mixed, stirring and dissolving, forms oil phase;
3) above-mentioned water is slowly added in oil phase, stir, form W/O emulsion;
4) 245g lactose is dissolved with 2000g water for injection, the formation W/O emulsion of above-mentioned preparation is added in lactose solution, use 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, for the first time pressure 500～600mpa, pressure 600～800mpa for the second time, pressure 800～1000mpa for the third time, the 4th pressure 1000～1200mpa, makes whole breast;
6) sampling detects intermediate, qualified after, breast is by 0.2 μ m membrane filtration degerming eventually, fill, partly jumps a queue, and enters freeze drying box, lyophilization obtains finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations of getting preparation is dissolved in water, and is added in 300ml water, with laser light scattering particle size analyzer, detect, and result, mean diameter is 120nm, meets the related request of used for intravenous injection preparation.
Embodiment 9, prepare diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations
Formula:
Preparation method:
1) 82g diclofenac sodium is dissolved with 100g water for injection, 26g lidocaine hydrochloride is dissolved with 68g propylene glycol, then both mixed and stir, form water;
2) under nitrogen protection, 98g soybean oil, 8g oleic acid and 88g polyvinyl alcohol are mixed, stirring and dissolving, forms oil phase;
3) above-mentioned water is slowly added in oil phase, stir, form W/O emulsion;
4) 168g lactose is dissolved with 2700g water for injection, the formation W/O emulsion of above-mentioned preparation is added in lactose solution, use 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, for the first time pressure 500～600mpa, pressure 600～800mpa for the second time, pressure 800～1000mpa for the third time, the 4th pressure 1000～1200mpa, makes whole breast;
6) sampling detects intermediate, qualified after, breast is by 0.2 μ m membrane filtration degerming eventually, fill, partly jumps a queue, and enters freeze drying box, lyophilization obtains finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations of getting preparation is dissolved in water, and is added in 300ml water, with laser light scattering particle size analyzer, detect, and result, mean diameter is 120nm, meets the related request of used for intravenous injection preparation.
Embodiment 10, prepare diclofenac sodium lidocaine hydrochloride submicron emulsion lyophilized formulations
Formula:
Preparation method:
1) 78g diclofenac sodium is dissolved with 100g water for injection, 23g lidocaine hydrochloride is dissolved with 58g propylene glycol, then both mixed and stir, form water;
2) under nitrogen protection, 112g soybean oil, 9g oleic acid and 92g PLURONICS F87 are mixed, stirring and dissolving, forms oil phase;
3) above-mentioned water is slowly added in oil phase, stir, form W/O emulsion;
4) 186g lactose is dissolved with 2430g water for injection, the formation W/O emulsion of above-mentioned preparation is added in lactose solution, use 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, for the first time pressure 500～600mpa, pressure 600～800mpa for the second time, pressure 800～1000mpa for the third time, the 4th pressure 1000～1200mpa, makes whole breast;
6) sampling detects intermediate, qualified after, breast is by 0.2 μ m membrane filtration degerming eventually, fill, partly jumps a queue, and enters freeze drying box, lyophilization obtains finished product.
The mensuration of particle diameter:
The submicron emulsion lyophilized formulations of getting preparation is dissolved in water, and is added in 300ml water, with laser light scattering particle size analyzer, detect, and result, mean diameter is 120nm, meets the related request of used for intravenous injection preparation.
The selection of test example 1, pH value
Investigate respectively 6.5,7.0,7.5,8.0,8.5,9.0 preparation stabilities under totally six kinds of pH value conditions, will with appropriate sodium hydroxide solution, be adjusted to different pH value by the colostrum of the formula preparation of embodiment 1.The nitrogen-filled seal of different pH value colostrum sample, in tubular injection bottle, is heated 15 minutes in 121 ℃.Sampling is measured different prescription sample particle diameters 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, theoretical by Michaelis, can be converted into volume distributed median and distributed number.Usually, volumetric diameter can better embody the uniformity of the micro-nano grain of rice in solution system.From granulometry result, after pH6.5 and the heating of pH9.0 high-temperature sample, granularity increases, and oily phenomenon appears analysing in outward appearance simultaneously.Under all the other four kinds of pH value conditions, after heat treatment, change of granularity is little, and outward appearance does not have significant change, and visible pH value scope is that in 7.0-8.5, dispersion stability is good.Therefore the pH value that, in the present invention, the amount of pH adjusting agent sodium hydroxide solution is adjusting colostrum is 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) under 60 ℃ of high temperature, high humidity 90% and illumination 4500Lx condition, place and within 10 days, carry out influence factor and test investigation, the results are shown in Table 2; Under 40 ℃ ± 2 ℃ of high temperature, relative humidity 75% ± 5% condition 6 months, carry out accelerated test investigation, the results are shown in Table 3; Under 25 ℃ ± 2 ℃ of temperature, 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
By the above results, found, while accelerating June, long-term 18,24 months, there is irregular colour one, lamination in the character of listing product, detects and find that clarity and the color of 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 is all up to specification, 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.
Submicron emulsion lyophilized formulations to the prepared diclofenac sodium lidocaine hydrochloride of other embodiment of the present invention has also carried out above-mentioned test, and the result of its acquisition is similar.
Test example 3, specific safety Journal of Sex Research
Muscle irritation test: sample of the present invention (embodiment of the present invention 1 makes), the 2ml sterilized water for injection of often drawing dissolves, get 2 of healthy rabbits, doe, without pregnant, is injected 1ml with aseptic manipulation respectively in its left and right lower limb quadriceps femoris, in injection, within latter 48 hours, puts to death, dissect and take out quadriceps femoris, longitudinally cut, observe injection site irritant reaction the according to the form below corresponding order of reaction that converts, then calculate the summation of 4 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 below 0.5 * 1.0cm |
| 2 | Moderate is congested, and its scope is more than 0.5 * 1.0cm |
| 3 | Severe is congested, with myodegeneration |
| 4 | There is necrosis, have brown degeneration |
| 5 | Occur that popularity is downright bad |
Result of the test, 4 quadriceps femoris of 2 rabbit of perusal have no significant change, and order of reaction is 0. check pathological section: 4 quadriceps femoris Fiber structures are normal, and clean mark includes a large amount of sarcostyles, has light and dark band on sarcostyle.Result surface, sample of the present invention, to the effect of muscle nonirritant.
Sensitivity test is got 18 of healthy guinea pigs, by body weight, is divided at random three groups, 6 every group.Inject respectively sample sets of the present invention (embodiment of the present invention 1 makes), ovalbumin positive controls and sodium chloride injection negative control group.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, sample of the present invention to animal subject without sensitization, without anaphylaxis.
Submicron emulsion lyophilized formulations to the prepared diclofenac sodium lidocaine hydrochloride of other embodiment of the present invention has also carried out above-mentioned test, and the result of its acquisition is similar.
Test example 4, clinical trial
1, clinical data
1.1 inclusion criterias: the 1. patient such as the osteoarthritis of clinical definite (OA), osteoporosis, soft tissue injury, cervical spondylosis, prolapse of lumbar intervertebral disc; 2. at 23～65 years old age, men and women does not limit; 3. be ready the tested and person that signs Informed Consent Form.
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, accepted immunosuppressant in 3 weeks, the patient of chloroquine, adrenocortical hormone part or whole body therapeutic; 2. have a liking for tobacco and wine, respiration inhibition, respiratory tract obstruction person; 3. in 1～3mo, participated in other drug test 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. there is in this observation the identical or similar medicine allergies person of any composition; 6. the women of gestation and age of sucking, plan at no distant date remaining reproduction age women; 7. suffers from neural organic disease, psychological problem and can not partner.
1.3 case situations: selected patient's 264 examples are to be all in hospital or outpatient, adopt the single blind controlled trial of simple randomization (1:1), random SAS software, the envelope card method of adopting, will be selected in patient and be divided into treatment group (132 example) and matched group (132 example) by medical sequencing.Wherein, treatment group man 83 examples, female's 49 examples, 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 examples, female's 51 examples, 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.Between two groups, aspect sex, age, body weight, the course of disease, relatively 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 makes, 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 water 2ml/ at every turn and prop up.Drug withdrawal post-evaluation curative effect.During treatment, mismatch any other treatment measure of using.
2.3 observation item
2.3.1 safety observation: blood, urine, stool routine examination chemical examination.Liver, kidney function test.
2.3.2 health giving quality observation:
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, 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 " simple and clear statistical software ", all data mean standard deviations
represent.Enumeration data X
2check, ranked data are analyzed with Ridit, and measurement data is checked with t, relatively uses variance analysis between many groups.
3, result
3.1 efficacy assessment standards are (with reference to related documents: during evaluation of clinical curative effect off-test, curative effect is carried out to thoroughly evaluating: invalidly improve <30% for clinical symptoms and sign; Be effectively that 30%≤clinical symptoms and sign are improved <75%; Effective is that clinical symptoms and sign improve >=75%.It is effective and effective that both add up to calculating 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 relatively
| 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 pain state of an illness comparison before and after two groups of treatments: in Table 6.
Pain state of an illness comparison before and after table 6, two groups of treatments
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％) |
From the above results, can find out, before and after two groups of treatments, VAS scoring relatively, the pain state of an illness are relatively and two groups of Clinical efficacy comparisons before and after two groups of treatments, treatment group is all better than matched group, adopts the submicron emulsion lyophilized formulations of the diclofenac sodium lidocaine hydrochloride that the present invention makes to be better than the injectable powder of prior art.
Submicron emulsion lyophilized formulations to the prepared diclofenac sodium lidocaine hydrochloride of other embodiment of the present invention has also carried out above-mentioned test, and the result of its acquisition is similar.
Claims (10)
1. a submicron emulsion lyophilized formulations for diclofenac sodium lidocaine hydrochloride, is characterized in that, described submicron emulsion lyophilized formulations is comprised of following raw material components:
2. submicron emulsion lyophilized formulations according to claim 1, is characterized in that, described submicron emulsion lyophilized formulations is comprised of following raw material components:
3. submicron emulsion lyophilized formulations according to claim 1 and 2, it is characterized in that, described oils and fats is one or more in ethyl oleate, Miglyol 812N, oleic acid polyethyleneglycol glyceride, median chain triglyceride oil or soybean oil, preferably median chain triglyceride oil and/or soybean oil.
4. submicron emulsion lyophilized formulations according to claim 1 and 2, it is characterized in that, 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, preferably 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 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.
6. submicron emulsion lyophilized formulations according to claim 1 and 2, it is characterized in that, described freeze-dried excipient is at least one in mannitol, lactose, glucose, maltose, sorbitol, sucrose and pharmaceutically acceptable excipient, preferably sucrose, mannitol or lactose.
7. submicron emulsion lyophilized formulations according to claim 1 and 2, is characterized in that, described cosolvent is propylene glycol; Described pH value regulator is sodium hydroxide solution, and its consumption is for regulating the pH value of colostrum to 7.5-8.0.
8. according to the submicron emulsion lyophilized formulations described in claim 1～7 any one, it is characterized in that, after described submicron emulsion preparation redissolves, mean diameter is 100nm～200nm.
9. a preparation method for the submicron emulsion lyophilized formulations described in claim 1～7 any one, is characterized in that, described preparation method comprises the steps:
1) diclofenac sodium is dissolved in to water for injection, lidocaine hydrochloride is added to cosolvent and dissolve, then both are mixed and stir, form water;
2) oils and fats, stabilizing agent and emulsifying agent are mixed, stirring and dissolving, forms oil phase;
3) water 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 regulates pH value to 7.0～8.5 by pH value regulator, then by high pressure homogenizer, prepares diclofenac sodium lidocaine hydrochloride breast eventually;
6) breast eventually of gained is filtered to postlyophilization, obtain described submicron emulsion preparation.
10. the application in the medicine of the pain that the submicron emulsion lyophilized formulations described in claim 1～8 any one causes in preparation treatment orthopaedic disease.
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Denomination of invention: The invention relates to a submicron emulsion lyophilized preparation of diclofenac sodium lidocaine hydrochloride, a preparation method and application thereof Effective date of registration: 20210929 Granted publication date: 20160210 Pledgee: Bank of Hainan Limited by Share Ltd. Pledgor: HAINAN ZHONGYU PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980010183 |