CN110051620A - The application of medical transformation formula, kit, method of converting and the transformation formula - Google Patents
The application of medical transformation formula, kit, method of converting and the transformation formula Download PDFInfo
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- CN110051620A CN110051620A CN201810046186.2A CN201810046186A CN110051620A CN 110051620 A CN110051620 A CN 110051620A CN 201810046186 A CN201810046186 A CN 201810046186A CN 110051620 A CN110051620 A CN 110051620A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
- A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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Abstract
The present invention discloses the application of a kind of medical transformation formula, kit, method of converting and the transformation formula.The transformation formula is the solution that pH value is not less than 10, and changing formula includes water and alkaline matter.The transformation formula is mixed with the preparation containing local anesthetic up to end formulation；Wherein, the dosage for changing formula makes the pH value of end formulation be 6.5-13, and the mass percent of amides local anesthetic or esters local anesthetic in end formulation is made to be respectively 0.5% or more or 0.1% or more.The existing preparation containing local anesthetic easily can be changed into transdermal absorption formulation or sustained release preparation by the transformation formula.The transdermal absorption formulation can anaesthetize intact skin in 120 minutes, complete facial skin is anaesthetized in 30 minutes.It, can be with slow release effective component, to extend duration of efficacy when the sustained release preparation is applied directly over the human body surface without the same barrier function of intact skin.
Description
Technical field
The present invention relates to the applications of a kind of medical transformation formula, kit, method of converting and the transformation formula.
Background technique
Injection, gelling agent or the pulvis generally used in the prior art, if be applied directly on complete skin, no
Effectively effective component therein can be transferred in skin.
For example, if 2% lidocaine hydrochloride or lidocaine carbonate injection or 2% lidocaine hydrochloride jelly are consolidated
Surely it is applied on intact skin, the injection and gel are unable to anesthesia completely in 120 minutes, even in 180 minutes
Skin.For another example pure lidocaine hydrochloride pulvis is placed on skin surface, complete skin can not be anaesthetized.
This is because administration route used in tradition and the injection, gelling agent and the pulvis that generally use is not Transdermal absorption
(injection is directly injected into tissue, and gelling agent is generally used for mucous membrane or damaged skin surface, and pulvis is generally used for preparing note
Penetrate liquid or gelling agent), so their not strong driving force effective component transmitted into skin of formula.
In addition, if injection (solution containing effective component) is applied in the barrier function the same without intact skin
Human body surface (such as damaged skin surface, the surface of burn and scald, mucomembranous surface, wound, operative incision), it is exhausted in injection
Most of effective component soon can enter systemic blood circulation through the human body surface.It is the effective of local organization for target
For ingredient (such as local anesthetic lidocaine), quick in this way and of short duration absorption process will lead to it is unnecessary even
Harmful high peak plasma concentrations and too short duration of efficacy.
But many diseases need to absorb (i.e. drug molecule is absorbed by intact skin) by efficient transdermal drug
It obtains medical treatment.For example, the lidocaine of efficient Transdermal absorption can be used to that post-herpetic neuralgia is greatly reduced.
It is envisioned that if there is a kind of formula and method can be convenient injection, gelling agent or the pulvis generally used
Ground is transformed into efficient transdermal drug absorbable preparation, and the treatments of many diseases can be more efficient and conveniently.However, present market
Upper no such formula and method.
Therefore, seek it is a kind of the injection generally used, gelling agent or pulvis can be easily transformed into it is efficient
The technical issues of transformation formula and method of transdermal drug absorbable preparation are current urgent need to resolve.
Summary of the invention
The technical problem to be solved by the present invention is to still will can generally use without one kind in the prior art to overcome
Injection, gelling agent or pulvis be easily transformed into the transformation formula and method of efficient transdermal drug absorbable preparation, and
The application of a kind of medical transformation formula, kit, method of converting and the transformation formula is provided.Transformation formula of the invention can
The existing preparation containing local anesthetic is easily changed into end formulation, the end formulation can be used as transdermal absorption formulation or
Sustained release preparation.The transdermal absorption formulation can expeditiously transmit effective component and enter intact skin, which can be
Intact skin is anaesthetized in 120 minutes, 90 minutes, 75 minutes, even 60 minutes, which can anaesthetize completely in 30 minutes
Facial skin.The sustained release preparation is applied directly over the human body surface without the same barrier function of intact skin (as damaged
Skin surface, the surface of burn and scald, mucomembranous surface, wound, operative incision) when, it can be with slow release effective component, to extend
Duration of efficacy and avoid unnecessary even harmful high peak plasma concentrations.
The present invention solves above-mentioned technical problem by the following technical programs:
The present invention provides a kind of medical transformation formula, and the alkalinity of the transformation formula is higher than the solution that pH value is 8, and institute
Stating transformation formula includes water and alkaline matter.
In the present invention, it is 9,11 or 12 that the alkalinity of the transformation formula, which is higher than pH value,.The pH value of the transformation formula is preferable
Ground is 9-14, is more preferably 10-13, is more preferably further 12-13, may be, for example, 11.
In the present invention, the water is preferably pure water, such as deionized water or distilled water.
In the present invention, the alkaline matter can be the conventional use of basic species that can be improved solution ph of pharmaceutical arts
Matter.Preferably, the alkaline matter is one in sodium tripolyphosphate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide
Kind is a variety of.More preferably, the alkaline matter is sodium hydroxide and/or potassium hydroxide.
Wherein, when the alkaline matter in the transformation formula is only sodium tripolyphosphate, the alkaline matter is in institute
The mass percent stated in transformation formula is preferably 0.1wt%-6wt%, is more preferably 0.2wt%-4wt%, further more
It goodly is 0.3wt%-3wt%.
Wherein, when the alkaline matter of the transformation formula is only sodium hydroxide and/or potassium hydroxide, the alkalinity
Mass percent of the substance in the transformation formula is preferably 0.05wt%-15wt%, may be, for example, 0.05wt%-
12wt%, 0.1wt%, 0.2wt%, 0.3wt%, 0.4wt%, 0.5wt%, 0.8wt%, 1.0wt%, 1.2wt%,
1.5wt%, 2wt%, 3wt%, 4wt%, 5wt%, 8wt% or 12wt%；It is more preferably 0.07wt%-6wt%；Further
It is more preferably 0.1wt%-2wt%.
Wherein, when the alkaline matter in the transformation formula is only in sodium hydroxide, potassium hydroxide and lithium hydroxide
Any one when, the alkaline matter it is described transformation formula in mass percent be preferably 0.05wt%-15wt%, example
It can be such as 0.05wt%-12wt%, be more preferably 0.07wt%-6wt%, further more preferably be 0.1wt%-2wt%.
Wherein, when the alkaline matter in the transformation formula is only sodium bicarbonate, the alkaline matter is described
Mass percent in transformation formula is preferably 0.1wt%-8wt%, is more preferably 0.2wt%-5wt%, further more preferably
Ground is 0.3wt%-3wt%.
In the present invention, the transformation formula can also contain thickener, and the dosage of the thickener is formulated the transformation
Viscosity be 100-800000 centipoise, the transformation formula of above-mentioned range of viscosities exists in the form of gel.Preferably, described
The dosage of thickener makes the viscosity of the transformation formula be 1000-200000 centipoise, may be, for example, 5000-10000 centipoise.More
Goodly, the thickener is carbomer, polyvinyl alcohol, propyl cellulose, ethyl cellulose, hydroxyethyl cellulose and polyethylene pyrrole
One of pyrrolidone is a variety of, and the carbomer may be, for example, Carbomer981.Further more preferably, the thickener is second
Base cellulose.The thickener it is described transformation formula in mass percent be 0.8%-20%, may be, for example, 2%-20%,
3%-12% or 4%-6%.
In the present invention, the transformation formula may also include glycerol, and the dosage of the glycerol can be this field conventional amount used, example
If mass percent of the glycerol in the transformation formula is 5%-10%.Skin can be alleviated or avoided in the addition of glycerol
Stimulation.
In the present invention, the transformation formula is for obtaining the end formulation that pH value is 6.5-13 after mixing with initial preparation；
Wherein, the initial preparation is the preparation containing local anesthetic, and the local anesthetic in the preparation containing local anesthetic is
Amides local anesthetic or esters local anesthetic, the amides local anesthetic are lidocaine hydrochloride, carbonic acid benefit
One of cacaine, bupivacaine HCl, prilocaine hydrochloride, Ropivacaine HCL and hydrochloric acid levobupivacaine are a variety of；
The esters local anesthetic is hydrochloric acid Kerocaine and/or tetracaine hydrochloride；The amides local anesthetic it is described most
The mass percent in formula is 0.5% or more eventually；Quality percentage of the esters local anesthetic in the end formulation
Than being 0.1% or more.
In the present invention, preferably, the transformation formula is 7-13's for obtaining pH value after mixing with the initial preparation
End formulation；More preferably, the transformation formula is 7-11,7-9.5,7-9 for obtaining pH value after mixing with the initial preparation
Or the end formulation of 7.5-9.
In the present invention, preferably, mass percent of the amides local anesthetic in the end formulation is
0.5%-9.1%, 0.5%-5% or 0.5%-2%；Quality percentage of the esters local anesthetic in the end formulation
Than for 0.1%-9.1%, 0.1%-5% or 0.2%-2%.
In the present invention, preferably, the preparation containing local anesthetic can be to be existing by China or other countries' medicine
Prison office ratifies any preparation containing local anesthetic used on the market, may be, for example, what contained local anesthetic all dissolved
Preparation and/or pulvis containing local anesthetic.It specifically, can be that (local anesthetic is all molten for the solution containing local anesthetic
Solution is wherein), one in gel containing local anesthetic (local anesthetic all dissolution wherein) and pulvis containing local anesthetic
Kind is a variety of.Further more preferably, the preparation containing local anesthetic is solution containing local anesthetic, contains local anesthetic
Gel and pulvis containing local anesthetic in any one.For example, the solution containing local anesthetic, it is described containing part
Local anesthetic in the gel of arcotic and the pulvis containing local anesthetic is lidocaine hydrochloride, carbonic acid benefit card
Cause, tetracaine hydrochloride, hydrochloric acid Kerocaine or bupivacaine HCl；For example, the local anesthetic contains local anaesthesia described
Mass percent in the solution of medicine is 0.75%-5%；The local anesthetic is in the gel containing local anesthetic
Mass percent is 0.75%-5%.For another example the solution containing local anesthetic is the injection of 2wt% lidocaine hydrochloride
Liquid, 2wt% lidocaine carbonate injection, 1wt% lidocaine hydrochloride injection, 1wt% lidocaine carbonate injection,
1wt% hydrochloric acid Kerocaine injection, 1wt% tetracaine hydrochloride injection or 0.75wt% bupivacaine hydrochloride injection；Institute
Stating the gel containing local anesthetic is 2wt% lidocaine hydrochloride jelly or 1wt% tetracaine hydrochloride gel；The fiber crops containing part
The pulvis of liquor-saturated medicine is lidocaine hydrochloride powder, lidocaine carbonate powder, hydrochloric acid Kerocaine powder, tetracaine hydrochloride powder or hydrochloric acid cloth
Than cacaine powder.
In the present invention, the end formulation can anaesthetize intact skin in 120 minutes, and the end formulation is preferably 90
Intact skin is anaesthetized in minute, and intact skin is more preferably anaesthetized in 75 minutes, has further more preferably been anaesthetized in 60 minutes
Whole skin.
In the present invention, the end formulation can anaesthetize complete facial skin in 30 minutes.
The present invention also provides a kind of kit, the kit includes box body, and the box body is equipped with storage unit and mixing unit,
The storage unit is for storing transformation formula above-mentioned, and the mixing unit is for the transformation formula and initial preparation above-mentioned
Mixing.
In the present invention, the storage unit can be used as the mixing unit, for transformation formula to be contained part with described
The preparation of arcotic mixes.
In the present invention, preferably, the storage unit stores the 2-500 milliliters of transformation formulas；More preferably, the storage
Portion stores the 5-200 milliliters of transformation formulas；Further more preferably, the storage unit stores the 10-50 milliliters of transformations
Formula.
It is described the present invention also provides a kind of method of converting that initial preparation is changed into transdermal absorption formulation or sustained release preparation
Method of converting includes the following steps: that initial preparation and transformation formula mix up to the end formulation, the end formulation
As transdermal absorption formulation or sustained release preparation；Wherein, the initial preparation is the preparation above-mentioned containing local anesthetic；Described turn
Become formula dosage make the pH value of the end formulation into 6.5-13, and make the amides local anesthetic it is described most
The mass percent in formula is 0.5% or more or makes quality of the esters local anesthetic in the end formulation eventually
Percentage is 0.1% or more.
The present inventor has found in an experiment, and the existing initial preparation containing local anesthetic is turned with certain alkalinity
Become formula be mixed in a certain ratio after, resulting ph be 6.5-13, local anesthetic mass percent meet above-mentioned numerical value model
The end formulation enclosed has the transdermal driving preferably local anesthetic transmitted than the initial preparation into complete human body's skin
Power, therefore the end formulation has the ability of anesthesia intact skin more stronger than the initial preparation.The end formulation can be 120
Complete non-facial skin is anaesthetized in minute, 90 minutes, 75 minutes, even 60 minutes, and complete face can be anaesthetized in 30 minutes
Skin.
In the present invention, when the initial preparation is the pulvis containing local anesthetic, preferably, first by the initial preparation
It is dissolved in the water after forming initial soln, then the initial soln is mixed with transformation formula up to the end formulation.
In the present invention, preferably, the dosage of the transformation formula makes the pH value of the end formulation be 6.5-11, more preferably
Ground is 7-9.5, is more preferably further 7-9, may be, for example, 7.5.
In the present invention, in general, mass percent of the amides local anesthetic in the end formulation can
For 0.5% or more any value, except 100%；Mass percent of the esters local anesthetic in the end formulation
It can be 0.1% or more any value, except 100%.But in actual use, it will usually according to surgery duration
Or required duration of anaesthesia determines the specific value of its mass percent in end formulation, otherwise, excessively high matter
When amount percentage can make operation end or required duration of anaesthesia terminate, there are also a large amount of unconsumed in end formulation
Local anesthetic will increase cost in this way, cause to waste.Preferably, the amides local anesthetic is in the end formulation
In mass percent be 0.5%-9.1%, 0.5%-5% or 0.5%-2%；The esters local anesthetic is described final
Mass percent in formula is 0.1%-9.1%, 0.1%-5% or 0.2%-2%.
In the present invention, preferably, the percentage of thickener contained by the transformation formula and the dosage of transformation formula make
The viscosity of the end formulation is 100-800000 centipoise, is more preferably 1000-200000 centipoise, may be, for example, 3000-10000
Centipoise or 6000-10000 centipoise.
In the present invention, when the initial preparation is for the solution containing local anesthetic and/or containing the gel of local anesthetic,
Preferably, the volume of the initial preparation and it is described transformation formula quality ratio be 0.05-10, unit mL/g, such as
It can be 0.75,0.1,0.125,0.2,0.25,1/3,0.4,1,2,2.5,3.3,4 or 5, unit mL/g；It is more preferably 0.1-
10, unit mL/g；It is further more preferably 0.2-5, unit mL/g.
In the present invention, when the initial preparation is the pulvis containing local anesthetic, preferably, the matter of the initial preparation
The ratio of amount and the quality of the transformation formula is 0.001-0.2, may be, for example, 0.00125,0.00167,0.0025,0.005,
0.01,0.033,0.04,0.05,0.091 or 0.1；It is more preferably 0.002-0.02.
In the present invention, when the initial preparation is that 2wt% lidocaine hydrochloride solution or 2wt% lidocaine carbonate are molten
When liquid, 2wt% lidocaine hydrochloride jelly or 2wt% lidocaine carbonate gel, preferably, the alkalinity in the transformation formula
Substance is sodium hydroxide or potassium hydroxide, and mass percent of the alkaline matter in the transformation formula is 0.2wt%-
12wt%, may be, for example, 3wt% or 4wt%, and the quality of the transformation formula used in every milliliter of initial preparation is 0.1-5
Gram, it may be, for example, 0.2 gram, 0.5 gram or 3 grams.More preferably, mass percent of the alkaline matter in the transformation formula is
0.2wt%-3wt%, the quality of the transformation formula used in every 5 milliliters of initial preparations are 0.1-15 grams.
In the present invention, when the initial preparation be 1wt% lidocaine hydrochloride solution, 1wt% lidocaine carbonate solution,
When 1wt% lidocaine hydrochloride jelly or 1wt% lidocaine carbonate gel, preferably, the basic species in the transformation formula
Matter is sodium hydroxide or potassium hydroxide, and mass percent of the alkaline matter in the transformation formula is 0.1wt%-
6wt% may be, for example, 0.8wt%, 2wt% or 4wt%, the quality of the transformation formula used in every milliliter of initial preparation
It is 0.1-5 grams, may be, for example, 0.5 gram or 1 gram.More preferably, mass percent of the alkaline matter in the transformation formula
For 0.1wt%-1.5wt%, the quality of the transformation formula used in every 5 milliliters of initial preparations is 0.1-15 grams.
In the present invention, when the initial preparation is lidocaine hydrochloride powder or lidocaine carbonate powder, preferably, described
Alkaline matter in transformation formula is sodium hydroxide or potassium hydroxide, and the alkaline matter is in the quality changed in formula
Percentage is 0.1wt%-8wt%, may be, for example, 0.5wt%, 2wt% or 4wt%, used in every 50 milligrams of initial preparations
The quality of the transformation formula is 0.25-30 grams, may be, for example, 0.5 gram, 1 gram, 5 grams or 9.95 grams.More preferably, the basic species
Mass percent of the matter in the transformation formula is 0.1wt%-4wt%, and the quality of the initial preparation is matched with the transformation
The ratio of the quality of side is 0.005-0.2.
In the present invention, when the initial preparation is 1wt% hydrochloric acid Kerocaine solution or 1wt% hydrochloric acid Kerocaine gel
When, preferably, the alkaline matter in the transformation formula is sodium hydroxide or potassium hydroxide, and the alkaline matter is at described turn
Become the mass percent in formula as 0.05wt%-5wt%, may be, for example, 0.1wt%, 0.3wt% or 2wt%, every 5 milliliters of institutes
The quality for stating the transformation formula used in initial preparation is 1-40 grams, may be, for example, 2.5 grams or 25 grams.More preferably, the alkali
Property mass percent of the substance in the transformation formula be 0.05wt%-2wt%, used in every 5 milliliters of initial preparations
The quality of the transformation formula is 0.25-40 grams.
In the present invention, when the initial preparation is hydrochloric acid Kerocaine powder, preferably, the alkalinity in the transformation formula
Substance is sodium hydroxide or potassium hydroxide, and mass percent of the alkaline matter in the transformation formula is
0.05wt%-8wt%, may be, for example, 0.1wt%, 0.3wt% or 3wt%, described used in every 50 milligrams of initial preparations to turn
Become the quality of formula as 0.25-50 grams, may be, for example, 0.5 gram, 1.5 grams, 30 grams or 40 grams.More preferably, the alkaline matter exists
Mass percent in the transformation formula is 0.05wt%-3wt%, the quality of the initial preparation and the transformation formula
The ratio of quality is 0.001-0.1.
In the present invention, when the initial preparation is 1wt% Tetracaine Hydrochloride Solution or 1wt% tetracaine hydrochloride gel,
Preferably, the alkaline matter in the transformation formula is sodium hydroxide or potassium hydroxide, and the alkaline matter is in the transformation
Mass percent in formula is 0.05wt%-5wt%, may be, for example, 0.1wt% or 2wt%, every 5 milliliters of initial preparations
The quality of the transformation formula used is 1-40 grams, may be, for example, 2.5 grams or 25 grams.More preferably, the alkaline matter is in institute
Stating the mass percent in transformation formula is 0.1wt%-2wt%, the transformation formula used in every 5 milliliters of initial preparations
Quality be 0.25-40 grams.
In the present invention, when the initial preparation is tetracaine hydrochloride powder, preferably, the basic species in the transformation formula
Matter is sodium hydroxide or potassium hydroxide, and mass percent of the alkaline matter in the transformation formula is 0.1wt%-
8wt% may be, for example, 0.2wt%, 0.3wt% or 3wt%, the transformation formula used in every 50 milligrams of initial preparations
Quality is 0.25-40 grams, may be, for example, 0.5 gram, 1.2 grams, 0.5 gram or 30 grams.More preferably, the alkaline matter is in the transformation
Mass percent in formula is 0.1wt%-3wt%, the matter of the transformation formula used in every 50 milligrams of initial preparations
Amount is 1-40 grams.
In the present invention, when the initial preparation is 0.75wt% bupivacaine HCl solution or 0.75wt% hydrochloric acid Bu Bika
When because of gel, preferably, the alkaline matter in the transformation formula is sodium hydroxide or potassium hydroxide, and the alkaline matter exists
Mass percent in the transformation formula is 0.1wt%-4wt%, may be, for example, 1.2wt% or 2wt%, described in every 5 milliliters
The quality of the transformation formula used in initial preparation is 0.5-10 grams, may be, for example, 1 gram, 1.5 grams or 2.5 grams.More preferably, institute
Stating mass percent of the alkaline matter in the transformation formula is 0.1wt%-1.2wt%, every 5 milliliters of initial preparation institutes
The quality of the transformation formula is 2-8 grams.
In the present invention, when the initial preparation is bupivacaine HCl powder, preferably, the alkalinity in the transformation formula
Substance is sodium hydroxide or potassium hydroxide, and alkaline matter mass percent in transformation formula is 0.1wt%-
8wt% may be, for example, 0.5wt%, 2wt% or 4wt%, the quality of the transformation formula used in every 50 milligrams of initial preparations
It is 0.25-30 grams, may be, for example, 0.5 gram, 1 gram, 5 grams or 9.95 grams.More preferably, the alkaline matter is in transformation formula
Mass percent be 0.05wt%-3wt%, the ratio of quality that the quality of the initial preparation and the transformation are formulated is
0.001-0.1。
In the present invention, preferably, the dosage of the transformation formula makes the part of 50wt% or more in the end formulation
Arcotic exists in the form of undissolved.More preferably, the dosage of the transformation formula make in the end formulation 70wt% with
On local anesthetic exist in the form of undissolved, above-mentioned percentage may be, for example, any numerical value between 50%-100%,
And not be 100%, may be, for example, 52wt%, 55wt%, 56wt%, 58wt%, 62wt%, 64wt%, 67wt%, 70wt%,
73wt%, 80wt%, 82wt%, 84wt%, 85wt%, 88wt%, 90wt%, 92wt%, 94wt%, 95wt%, 97wt%
Or 99wt%.End formulation in above-mentioned technical proposal can be used as transdermal absorption formulation, and can be used as sustained release preparation.This is delayed
Release formulation is applied directly over the human body surface without the same barrier function of intact skin and (such as damaged skin surface, burns and scald
The surface of wound, mucomembranous surface, wound, operative incision) when, it can be with slow release effective component, to extend duration of efficacy
And avoid unnecessary even harmful high peak plasma concentrations.
In the present invention, preferably, the end formulation can anaesthetize complete non-facial skin in 90 minutes.
In the present invention, preferably, the end formulation can anaesthetize complete facial skin in 30 minutes.
The present invention also provides a kind of transformation above-mentioned be formulated by initial preparation above-mentioned be changed into transdermal absorption formulation or
Application in the method for converting of sustained release preparation.
In the present invention, preferably, the transdermal absorption formulation or the sustained release preparation can anaesthetize completely in 90 minutes
Non- facial skin.
In the present invention, preferably, the transdermal absorption formulation or the sustained release preparation can anaesthetize completely in 30 minutes
Facial skin.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably
Example.
The reagents and materials used in the present invention are commercially available, wherein " commercially available " refers to all market sales, including must be through
Cross prescription and the various sale for permitting just carry out.
In the present invention, described pH value refers to the pH value under the conditions of 25 DEG C.
In the present invention, the time needed for described anesthesia intact skin, which refers to, is applied to healthy skin for the formula
On, the time needed for (25 ± 2 degree of room temperatures) measures formula anesthesia intact skin at the standard conditions (namely when anesthesia onset
Between).
The positive effect of the present invention is that: the present invention provides the medical transformation formula of one kind, kit, method of converting
And the application of the transformation formula.The existing preparation containing local anesthetic can easily be changed by the transformation formula finally matches
Side, and the end formulation can expeditiously transmit effective component and enter intact skin.The end formulation can 120 minutes,
Intact skin is anaesthetized in 90 minutes, 75 minutes, in even 60 minutes, should match can anaesthetize complete facial skin in 30 minutes.
The end formulation be applied directly over without the same barrier function of intact skin human body surface (such as damaged skin surface,
The surface of burn and scald, mucomembranous surface, wound, operative incision) when, it can be with slow release effective component, to extend drug effect maintenance
Time and avoid unnecessary even harmful high peak plasma concentrations.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
In following embodiments, 2% lidocaine hydrochloride injection refers to the quality of lidocaine hydrochloride in the injection
The injection that score is 2%；2% lidocaine carbonate injection refers to the mass fraction of lidocaine carbonate in the injection
For 2% injection；1% tetracaine hydrochloride injection refers to that the mass fraction of tetracaine hydrochloride in the injection is 1%
Injection；1% lidocaine hydrochloride injection refers to that the mass fraction of lidocaine hydrochloride in the injection is 1% injection
Liquid；1% lidocaine carbonate injection refers to that the mass fraction of lidocaine carbonate in the injection is 1% injection；
1% hydrochloric acid Kerocaine injection refers to that the mass fraction of hydrochloric acid Kerocaine in the injection is 1% injection；
0.75% bupivacaine hydrochloride injection refers to that the mass fraction of bupivacaine HCl in the injection is 0.75% injection
Liquid；1% tetracaine hydrochloride gel refers to that the mass fraction of tetracaine hydrochloride in the gel is 1% gel；1% hydrochloric acid benefit
Cacaine gel refers to that the mass fraction of lidocaine hydrochloride in the gel is 1% gel.
In following embodiments, the percentage refers to mass percent.
Embodiment 1-3
In the end formulation of embodiment 1, about 50% lidocaine exists with undissolved particle form.In embodiment
In 2 end formulation, about 82% totokaine exists in the form for not dissolving (particle or oil droplet).In finally matching for embodiment 3
Fang Li, about 88% totokaine exist in the form for not dissolving (particle or oil droplet).
Effect example 1
The skin of forearm that the 1 gained end formulation of embodiment of 1 layer of 2 millimeters thick is covered on a subject is (healthy complete
Skin) on and with plastic film cover end formulation layer.After 75 minutes, it is anesthetized by the skin that end formulation layer is covered
(analgesis).
Herein it should be noted that inventor is in R&D process, the lidocaine hydrochloride in embodiment 1 is substituted for carbon
When lidocaine hydrochloride, bupivacaine HCl, prilocaine hydrochloride, Ropivacaine HCL or hydrochloric acid levobupivacaine, there is phase
Same anaesthetic effect.
Effect example 2
The facial skin that the 2 gained end formulation of embodiment of 1 layer of about 2 millimeters thick is covered on a subject is (healthy complete
Whole skin) after upper 25 minute, (analgesis) has been anesthetized by the skin that end formulation layer is covered.
Herein it should be noted that inventor is in R&D process, the tetracaine hydrochloride in embodiment 2 is replaced into hydrochloric acid
When Kerocaine, there is identical anaesthetic effect.
Embodiment 4
Contain 30 grams of transformation formulas in the container (kit) of one 50 milliliters of volume.The transformation formula is a kind of water-setting
Glue contains 0.5% sodium hydroxide, and 10% glycerine, 0.8% Carbomer981,88.7% water, pH value is about 13.
10 milliliter of 2% lidocaine hydrochloride injection (initial preparation) is put into said vesse and is quickly stirred 5 minutes
A new hydrogel (end formulation) is obtained afterwards, and pH value is about 7, and mass percent of the local anesthetic in end formulation is
0.5%.
Effect example 4
The skin of forearm that the 4 gained end formulation of embodiment of 1 layer of 2 millimeters thick is covered on a subject is (healthy complete
Skin) on and with plastic film cover end formulation layer.After 75 minutes, it is anesthetized by the skin that end formulation layer is covered
(analgesis).
Herein it should be noted that inventor has found in R&D process, the lidocaine hydrochloride in embodiment 4 is replaced
For appointing in lidocaine carbonate, bupivacaine HCl, prilocaine hydrochloride, Ropivacaine HCL and hydrochloric acid levobupivacaine
When anticipating a kind of, there is identical anaesthetic effect.
Embodiment 5
Contain 38 grams of transformation formulas in the container (kit) that one volume is 60 milliliters.The transformation formula is a kind of water-setting
Glue contains 0.4% sodium hydroxide, and 10% glycerine, 2% hydroxyethyl cellulose, 87.6% water, viscosity is about 10000 centipoises, pH
Value about 13.
5 milliliter of 2% tetracaine hydrochloride injection (initial preparation) is put into said vesse and is quickly stirred and is obtained after five minutes
The hydrogel (end formulation) new to one, pH value is about 9, and mass ratio of the local anesthetic in end formulation is 0.15%.
In the end formulation of embodiment 5, about 67% totokaine exists in the form for not dissolving (particle or oil droplet).
Effect example 5
The skin of forearm that the 5 gained end formulation of embodiment of 1 layer of 2 millimeters thick is covered on a subject is (healthy complete
Skin) on and with plastic film cover end formulation layer.After 45 minutes, it is anesthetized by the skin that end formulation layer is covered
(analgesis).
Herein it should be noted that inventor has found in R&D process, the tetracaine hydrochloride in embodiment 5 is replaced with
When hydrochloric acid Kerocaine, there is identical anaesthetic effect.
Effect example 6
The skin of back of one patient suffers from post-herpetic neuralgia.Medical staff finally matches 1 gained of embodiment
Side is applied to affected part, and affected part is completely covered by the end formulation layer of about 2 millimeters thicks.Then medical staff is covered with plastic film
The end formulation layer.The neuralgia of the patient disappears substantially after about 75 minutes.After 6 hours, medical staff takes layer is formulated
Under.The neuralgia analgesic effect of the patient has continued for about 2 hours.
Effect example 7
The skin of abdomen of one patient suffers from post-herpetic neuralgia.Medical staff is finally matching in embodiment 3
Side is applied to affected part, and affected part is completely covered by the end formulation layer of about 2 millimeters thicks.Then medical staff is covered with plastic film
The end formulation layer.The neuralgia of the patient disappears substantially after about 45 minutes.After 6 hours, medical staff takes layer is formulated
Under.The neuralgia analgesic effect of the patient has continued for about 4 hours.
Effect example 8
End formulation in embodiment 1 and 3 is applied on the operative incision of two patients being sutured respectively, is made
The operative incision is completely covered by the end formulation layer of about 3 millimeters thicks.Then it is covered most with one layer of Medical plastic film
Formula layer eventually.Lidocaine or totokaine in these end formulations enter incision tissue and anaesthetize in the form being sustained to be connect
The tissue contacted thus greatly reduces the post-surgical incisions pain of patient.Lidocaine or totokaine meeting contained therein
It is gone in being slowly released to incision tissue.Therefore, these end formulations can lead to much lower benefit than the initial preparation
Cacaine or totokaine peak blood drug level (safer) and generate much longer analgesia duration.
Embodiment 6-9
It is all or be all dissolved in solution close to all lidocaines in the end formulation of embodiment 6.In embodiment
In the end formulation of 7-9, the percentage that the lidocaine being not dissolved in solution accounts for total lidocaine amount in solution be respectively may be about
62%, 73%, 70%.
Effect data: end formulation obtained by the embodiment 6-9 of 1 layer of 2 millimeters thick is covered on to the forearm skin of a subject
End formulation layer is covered on skin (healthy intact skin) and with plastic film.In 90 minutes, covered by end formulation layer
Skin has been anesthetized (analgesis).
Embodiment 10-13
It is all or be all dissolved in solution close to all lidocaines in the end formulation of embodiment 10.Implementing
In the end formulation of example 11-13, the lidocaine being not dissolved in solution accounts for the percentage difference of total lidocaine amount in solution
About 25%, 45%, 45%.
Effect data: end formulation obtained by the embodiment 10-13 of 1 layer of 2 millimeters thick is covered on to the forearm of a subject
End formulation layer is covered on skin (healthy intact skin) and with plastic film.In 90 minutes, covered by end formulation layer
Skin be anesthetized (analgesis).
Embodiment 14-17
In the end formulation of embodiment 14, about 10% Kerocaine exists with undissolved particle form.Implementing
In the end formulation of example 15, about 40% Kerocaine exists in the form for not dissolving (particle or oil droplet).In embodiment 16
In end formulation, about 85% Kerocaine exists in the form for not dissolving (particle or oil droplet).In finally matching for embodiment 17
Fang Li, about 88% Kerocaine exist in the form for not dissolving (particle or oil droplet).
Effect data: end formulation obtained by the embodiment 14-17 of 1 layer of 2 millimeters thick is covered on to the forearm of a subject
End formulation layer is covered on skin (healthy intact skin) and with plastic film.In 60 minutes, covered by end formulation layer
Skin be anesthetized (analgesis).
Embodiment 18-21
In the end formulation of embodiment 18, about 55% totokaine exists with undissolved particle form.In embodiment
In 19 end formulation, about 70% totokaine exists in the form for not dissolving (particle or oil droplet).In the final of embodiment 20
In formula, about 92% totokaine exists in the form for not dissolving (particle or oil droplet).In the end formulation of embodiment 21, about
94% totokaine exists in the form for not dissolving (particle or oil droplet).
Effect data: end formulation obtained by the embodiment 18-21 of 1 layer of 2 millimeters thick is covered on to the face of a subject
On skin (healthy intact skin).In 30 minutes, (analgesis) has been anesthetized by the skin that end formulation layer is covered.
Embodiment 22-25
In the end formulation of embodiment 22, about 56% Bupivacaine exists with undissolved particle form.Implementing
In the end formulation of example 23, about 40% Bupivacaine exists in the form for not dissolving (particle or oil droplet).In embodiment 24
In end formulation, about 48% Bupivacaine exists in the form for not dissolving (particle or oil droplet).In finally matching for embodiment 25
Fang Li, about 52% Bupivacaine exist in the form for not dissolving (particle or oil droplet).
Effect data: end formulation obtained by the embodiment 22-25 of 1 layer of 2 millimeters thick is covered on to the forearm of a subject
End formulation layer is covered on skin (healthy intact skin) and with plastic film.In 90 minutes, covered by end formulation layer
Skin be anesthetized (analgesis).
Embodiment 26-29
Embodiment 28A: 50 milligrams of lidocaine hydrochlorides are first dissolved in 1 milliliter of water with the hydrochloric acid benefit card of formation 5%
Because of solution, then the solution and the transformation formula in 1 gram of embodiment 28 are mixed, obtained containing 2.5% lidocaine hydrochloride
End formulation.
In the end formulation of embodiment 26, all or almost all of lidocaine dissolution is in the solution.Implementing
In the end formulation of example 27, about 50% lidocaine exists in the form for not dissolving (particle or oil droplet).In embodiment 28
In end formulation, about 90% lidocaine exists in the form for not dissolving (particle or oil droplet).In finally matching for embodiment 28A
Fang Li, about 80% lidocaine exist in the form for not dissolving (particle or oil droplet).In the end formulation of embodiment 29, about
95% lidocaine exists in the form for not dissolving (particle or oil droplet).
Effect data: end formulation obtained by the embodiment 26-29 and embodiment 28A of 1 layer of 2 millimeters thick is covered on one
End formulation layer is covered on the skin of forearm (healthy intact skin) of subject and with plastic film.It is final in 90 minutes
The skin that formula layer is covered has been anesthetized (analgesis).
Embodiment 30-33
In the end formulation of embodiment 30, about 40% Bupivacaine is deposited in the form for not dissolving (particle or oil droplet)
?.In the end formulation of embodiment 31, about 70% Bupivacaine exists in the form for not dissolving (particle or oil droplet).In reality
In the end formulation for applying example 32, about 94% Bupivacaine exists in the form for not dissolving (particle or oil droplet).In embodiment 33
End formulation in, about 97% Bupivacaine exists in the form for not dissolving (particle or oil droplet).
Effect data: end formulation obtained by the embodiment 30-33 of 1 layer of 2 millimeters thick is covered on to the forearm of a subject
End formulation layer is covered on skin (healthy intact skin) and with plastic film.In 90 minutes, covered by end formulation layer
Skin be anesthetized (analgesis).
Embodiment 34-37
In the end formulation of embodiment 34, about 58% Kerocaine is deposited in the form for not dissolving (particle or oil droplet)
?.In the end formulation of embodiment 35, about 70% Kerocaine exists in the form for not dissolving (particle or oil droplet).In reality
In the end formulation for applying example 36, about 84% Kerocaine exists in the form for not dissolving (particle or oil droplet).In embodiment 37
End formulation in, about 95% Kerocaine exists in the form for not dissolving (particle or oil droplet).
Effect data: end formulation obtained by the embodiment 34-37 of 1 layer of 2 millimeters thick is covered on to the face of a subject
On skin (healthy intact skin).In 30 minutes, (analgesis) has been anesthetized by the skin that end formulation layer is covered.
Embodiment 38-41
Embodiment 38A: 50 milligrams of tetracaine hydrochlorides are first dissolved in 5 milliliters of water molten to form 1% tetracaine hydrochloride
Then liquid mixes the solution and the transformation formula in 30 grams of embodiments 38, obtain final containing 0.14% tetracaine hydrochloride
Formula.
In the end formulation of embodiment 38, about 70% totokaine exists in the form for not dissolving (particle or oil droplet).
In the end formulation of embodiment 38A, about 64% totokaine exists in the form for not dissolving (particle or oil droplet).In embodiment
In 39 end formulation, about 58% totokaine exists in the form for not dissolving (particle or oil droplet).In the final of embodiment 40
In formula, about 88% totokaine exists in the form for not dissolving (particle or oil droplet).In the end formulation of embodiment 41, about
95% totokaine exists in the form for not dissolving (particle or oil droplet).
Effect data: end formulation obtained by the embodiment 38-41 and embodiment 38A of 1 layer of 2 millimeters thick is covered on one
On the skin of face (healthy intact skin) of subject.In 30 minutes, (pain has been anesthetized by the skin that end formulation layer is covered
Feel disappears).
Embodiment 42-45
In the end formulation of embodiment 42, about 70% totokaine exists in the form for not dissolving (particle or oil droplet).
In the end formulation of embodiment 43, all or almost all lidocaine dissolutions are in the solution.Embodiment 44 and 45 most
Eventually in formula, about 94% totokaine exists in the form for not dissolving (particle or oil droplet).
Embodiment 6-45 and embodiment 28A and 38A is analyzed it is found that when the tetracaine hydrochloride and general sieve of hydrochloric acid in end formulation
The mass percent of cacaine at 0.1% or more, end formulation can be anaesthetized in 60 minutes complete non-facial skin or
Complete facial skin is anaesthetized in 30 minutes；When the mass percent of lidocaine hydrochloride and bupivacaine HCl in end formulation
At 0.5% or more, end formulation can anaesthetize complete non-facial skin in 90 minutes.
Comparative example 1
Initial preparation used in embodiment 1 and embodiment 3 is placed directly in the incision tissue of effect example 8,
Since open incision tissue does not have barrier function, the most of lidocaine or totokaine in initial preparation can enter quickly
Incision tissue simultaneously enters systemic blood circulation, leads to very high lidocaine or totokaine peak plasma concentrations and very short analgesia
Duration.
Comparative example 2
By initial preparation used by each embodiment, 2% lidocaine hydrochloride injection, 2% lidocaine hydrochloride jelly,
1% lidocaine hydrochloride injection, 2% lidocaine carbonate injection, 1% lidocaine carbonate injection, hydrochloric acid benefit card
Because powder, 1% hydrochloric acid Kerocaine injection, hydrochloric acid Kerocaine powder, 1% tetracaine hydrochloride injection, 1% tetracaine hydrochloride are solidifying
Glue, tetracaine hydrochloride powder, 0.75% bupivacaine hydrochloride injection, bupivacaine HCl powder, are applied on healthy skin, this is first
Beginning preparation can not anaesthetize intact skin in 120 minutes, or even can not anaesthetize intact skin in 180 minutes.
Although specific embodiments of the present invention have been described above, it will be appreciated by those of skill in the art that these
It is merely illustrative of, protection scope of the present invention is defined by the appended claims.Those skilled in the art is not carrying on the back
Under the premise of from the principle and substance of the present invention, many changes and modifications may be made, but these are changed
Protection scope of the present invention is each fallen with modification.
Claims (28)
1. a kind of medical transformation formula, which is characterized in that the alkalinity of the transformation formula is higher than the solution that pH value is 10, and institute
Stating transformation formula includes water and alkaline matter.
2. transformation formula as described in claim 1, which is characterized in that it is 11 or 12 that the alkalinity of the transformation formula, which is higher than pH value,
Solution；The pH value of the transformation formula is preferably 11-14, is more preferably 12-13.
3. transformation formula as described in claim 1, which is characterized in that the water is pure water, preferably deionized water or steaming
Distilled water；
And/or the alkaline matter is one in sodium tripolyphosphate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide
Kind is a variety of；Preferably, the alkaline matter is sodium hydroxide and/or potassium hydroxide.
4. transformation formula as claimed in claim 3, which is characterized in that when the alkaline matter in the transformation formula is only
When sodium tripolyphosphate, mass percent of the alkaline matter in the transformation formula is 0.1wt%-6wt%, preferably
0.2wt%-4wt% is more preferably 0.3wt%-3wt%；
When the alkaline matter of the transformation formula is only sodium hydroxide and/or potassium hydroxide, the alkaline matter is in institute
Stating the mass percent in transformation formula is 0.05wt%-15wt%, preferably 0.05wt%-12wt%；More preferably it is
0.07wt%-6wt%；It is further more preferably 0.1wt%-2wt%；
When the alkaline matter in the transformation formula is only any one in sodium hydroxide, potassium hydroxide and lithium hydroxide
When, mass percent of the alkaline matter in the transformation formula is 0.05wt%-15wt%, preferably
0.05wt%-12wt% is more preferably 0.07wt%-6wt%, is further more preferably 0.1wt%-2wt%；
When the alkaline matter in the transformation formula is only sodium bicarbonate, the alkaline matter is in transformation formula
Mass percent be 0.1wt%-8wt%, preferably 0.2wt%-5wt%, be more preferably 0.3wt%-3wt%.
5. transformation formula as described in claim 1, which is characterized in that also contain thickener, the increasing in the transformation formula
Thick dose of dosage makes the viscosity of the transformation formula be 100-800000 centipoise；Preferably, the dosage of the thickener makes
The viscosity of the transformation formula is 1000-200000 centipoise；More preferably, the dosage of the thickener makes the transformation formula
Viscosity is 5000-10000 centipoise；
And/or the thickener is carbomer, polyvinyl alcohol, propyl cellulose, ethyl cellulose, hydroxyethyl cellulose and gathers
One of vinylpyrrolidone is a variety of；Preferably, mass percent of the thickener in the transformation formula is
0.5% or more, 0.5%-20%, 0.8%-20%, 2%-20%, 3%-12% or 4%-6%；
And/or the transformation formula also contains glycerol, preferably, mass percent of the glycerol in the transformation formula
For 5%-10%.
6. transformation formula as described in claim 1, which is characterized in that the transformation formula after mixing with initial preparation for obtaining
The end formulation for being 6.5-13 to pH value；
Wherein, the initial preparation is the preparation containing local anesthetic, the local anaesthesia in the preparation containing local anesthetic
Medicine is amides local anesthetic or esters local anesthetic, and the amides local anesthetic is lidocaine hydrochloride, carbonic acid
One of lidocaine, bupivacaine HCl, prilocaine hydrochloride, Ropivacaine HCL and hydrochloric acid levobupivacaine are more
Kind；The esters local anesthetic is hydrochloric acid Kerocaine and/or tetracaine hydrochloride；
Mass percent of the amides local anesthetic in the end formulation is 0.5% or more；The esters part
Mass percent of the arcotic in the end formulation is 0.1% or more.
7. transformation formula as claimed in claim 6, which is characterized in that the transformation formula with the initial preparation for mixing
The end formulation that pH value is 7-13 is obtained afterwards；Preferably, the transformation formula is for obtaining pH after mixing with the initial preparation
Value is the end formulation of 7-11,7-9.5,7-9 or 7.5-9.
8. transformation formula as claimed in claim 6, which is characterized in that the amides local anesthetic is in the end formulation
In mass percent be 0.5%-9.1%, 0.5%-5% or 0.5%-2%；The esters local anesthetic is described final
Mass percent in formula is 0.1%-9.1%, 0.1%-5% or 0.2%-2%.
9. such as the described in any item transformation formulas of claim 6-8, which is characterized in that the initial preparation is contained local anaesthesia
The preparation that medicine all dissolves and/or the pulvis containing local anesthetic；
Preferably, the initial preparation be the solution containing local anesthetic, the gel containing local anesthetic and contain local anesthetic
One of pulvis or a variety of；
More preferably, the initial preparation be the solution containing local anesthetic, the gel containing local anesthetic or contain local anesthetic
Pulvis；
Further more preferably, the solution containing local anesthetic, the gel containing local anesthetic and the fiber crops containing part
Local anesthetic in the pulvis of liquor-saturated medicine be lidocaine hydrochloride, lidocaine carbonate, tetracaine hydrochloride, hydrochloric acid Kerocaine or
Bupivacaine HCl；For example, mass percent of the local anesthetic in the solution containing local anesthetic is
0.75%-5%；Mass percent of the local anesthetic in the gel containing local anesthetic is 0.75%-5%；
Further more preferably, the solution containing local anesthetic is 2wt% lidocaine hydrochloride injection, 2wt% carbonic acid
Lidocaine injection, 1wt% lidocaine hydrochloride injection, 1wt% lidocaine carbonate injection, general sieve of 1wt% hydrochloric acid
Cacaine injection, 1wt% tetracaine hydrochloride injection or 0.75wt% bupivacaine hydrochloride injection；It is described to contain local anesthetic
Gel be 2wt% lidocaine hydrochloride jelly or 1wt% tetracaine hydrochloride gel；The pulvis containing local anesthetic is salt
Lidocaine hydrochloride powder, lidocaine carbonate powder, hydrochloric acid Kerocaine powder, tetracaine hydrochloride powder or bupivacaine HCl powder.
10. a kind of medical transformation formula, which is characterized in that the transformation formula includes water, alkaline matter and thickener, described
Mass percent of the thickener in the transformation formula is 0.5% or more, and the pH value of the transformation formula is 11 or more.
11. transformation formula as claimed in claim 10, which is characterized in that the transformation formula is by water, alkaline matter and thickening
Agent composition, mass percent of the thickener in the transformation formula is 0.5% or more, and the pH value of the transformation formula
It is 11 or more.
12. transformation formula as described in claim 10 or 11, which is characterized in that the water is deionized water or distilled water；
And/or the pH value of the transformation formula is 11-14 or 12-13；Preferably, the alkaline matter is sodium tripolyphosphate, carbon
One of sour hydrogen sodium, sodium hydroxide, potassium hydroxide and lithium hydroxide are a variety of；More preferably, the alkaline matter is hydroxide
Sodium and/or potassium hydroxide；
And/or mass percent of the thickener in the transformation formula is 0.5%-20%, 0.8%-20%, 2%-
20%, 3%-12% or 4%-6%；Preferably, the thickener is carbomer, polyvinyl alcohol, propyl cellulose, ethyl cellulose
One of element, hydroxyethyl cellulose and polyvinylpyrrolidone are a variety of.
13. a kind of kit, which is characterized in that the kit includes box body, and the box body is equipped with storage unit and mixing unit, institute
State storage unit for store such as claim 1-12 described in any item transformations formula, the mixing unit is for matching described change
Side is mixed with initial preparation defined in claim 6 or 9；
Wherein, it preferably, the storage unit is used as the mixing unit, is mixed for being formulated the transformation with the initial preparation
It closes；
Wherein, preferably, the storage unit stores the 2-500 milliliters of transformation formulas；More preferably, the storage unit stores
The 5-200 milliliters of transformation formulas；Further more preferably, the storage unit stores the 10-50 milliliters of transformation formulas.
14. a kind of kit, it is characterised in that: the kit has box body, and the volume of the box body is 10-200 milliliters, institute
It states in box body containing 5-180 milliliters such as the described in any item transformation formulas of claim 10-12.
15. a kind of method of converting that initial preparation is changed into transdermal absorption formulation or sustained release preparation, which is characterized in that described turn
Change method includes the following steps: that initial preparation is mixed with the described in any item transformation formulas of such as claim 1-12 up to finally matching
Side, the end formulation are used as transdermal absorption formulation or sustained release preparation；Wherein, the initial preparation is institute in claim 6 or 9
The initial preparation of definition；The dosage of the transformation formula makes the pH value of the end formulation be 6.5-13, and makes the acyl
Mass percent of the amine local anesthetic in the end formulation is 0.5% or more or makes the esters local anesthetic
Mass percent in the end formulation is 0.1% or more.
16. method of converting as claimed in claim 15, which is characterized in that when the initial preparation is the powder containing local anesthetic
When agent, first the initial preparation is dissolved in the water to form initial soln, then the initial soln and the transformation are formulated and mixed
It closes up to the end formulation.
17. method of converting as claimed in claim 15, which is characterized in that the dosage of the transformation formula described finally to match
The pH value of side is 7-11, preferably 7-9.5, is more preferably 7-9, is further more preferably 7.5-9.
18. method of converting as claimed in claim 15, which is characterized in that the amides local anesthetic is finally matched described
Mass percent in side is 0.5%-9.1%, 0.5%-5% or 0.5%-2%；The esters local anesthetic it is described most
The mass percent in formula is 0.1%-9.1%, 0.1%-5% or 0.2%-2% eventually.
19. such as the described in any item method of converting of claim 15-18, which is characterized in that the transformation is formulated contained thickener
Mass percent and it is described transformation formula dosage make the end formulation viscosity be 100-800000 centipoise, preferably
It is more preferably 3000-10000 centipoise or 6000-10000 centipoise for 1000-200000 centipoise.
20. such as the described in any item method of converting of claim 15-18, which is characterized in that when the initial preparation is wanted for right
It is described when seeking the gel described in solution and/or claim 9 containing local anesthetic described in 9 containing local anesthetic
The ratio of the volume of initial preparation and the quality of the transformation formula is 0.05-10, unit mL/g；Preferably 0.2-10,
Unit is mL/g；It is more preferably 0.5-5, unit mL/g；
When the initial preparation is the pulvis described in claim 9 containing local anesthetic, the quality of the initial preparation
Ratio with the quality of the transformation formula is 0.001-0.2；Preferably 0.002-0.02.
21. such as the described in any item method of converting of claim 15-18, which is characterized in that when the initial preparation is 2wt% salt
Lidocaine hydrochloride solution, 2wt% lidocaine carbonate solution, 2wt% lidocaine hydrochloride jelly or 2wt% lidocaine carbonate
When gel, the alkaline matter in the transformation formula is sodium hydroxide or potassium hydroxide, and the alkaline matter is in the transformation
Mass percent in formula is 0.2wt%-12wt%, the quality of the transformation formula used in every milliliter of initial preparation
It is 0.1-5 grams；Preferably, the alkaline matter it is described transformation formula in mass percent be 0.2wt%-3wt%, every 5
The quality of the transformation formula used in the milliliter initial preparation is 0.1-15 grams；
When the initial preparation is 1wt% lidocaine hydrochloride solution, 1wt% lidocaine carbonate solution, 1wt% hydrochloric acid benefit
When cacaine gel or 1wt% lidocaine carbonate gel, the alkaline matter in the transformation formula is sodium hydroxide or hydroxide
Potassium, and mass percent of the alkaline matter in the transformation formula is 0.1wt%-6wt%, every milliliter of initial system
The quality of the transformation formula used in agent is 0.1-5 grams；Preferably, quality of the alkaline matter in the transformation formula
Percentage is 0.1wt%-1.5wt%, and the quality of the transformation formula used in every 5 milliliters of initial preparations is 0.1-15
Gram；
Alkaline matter when the initial preparation is lidocaine hydrochloride powder or lidocaine carbonate powder, in the transformation formula
For sodium hydroxide or potassium hydroxide, and mass percent of the alkaline matter in the transformation formula is 0.1wt%-
8wt%, the quality of the transformation formula used in every 50 milligrams of initial preparations are 0.25-30 grams；Preferably, the alkalinity
Mass percent of the substance in the transformation formula is 0.1wt%-4wt%, the quality of the initial preparation and the transformation
The ratio of the quality of formula is 0.005-0.2；
When the initial preparation is 1wt% hydrochloric acid Kerocaine solution or 1wt% hydrochloric acid Kerocaine gel, the transformation is matched
Alkaline matter in side is sodium hydroxide or potassium hydroxide, and the alkaline matter is in the mass percent changed in formula
For 0.05wt%-5wt%, the quality of the transformation formula used in every 5 milliliters of initial preparations is 1-40 grams；Preferably,
Mass percent of the alkaline matter in the transformation formula is 0.05wt%-2wt%, every 5 milliliters of initial preparations
The quality of the transformation formula used is 0.25-40 grams；
When the initial preparation is hydrochloric acid Kerocaine powder, the alkaline matter in the transformation formula is sodium hydroxide or hydrogen-oxygen
Change potassium, and mass percent of the alkaline matter in the transformation formula is 0.05wt%-8wt%, described in every 50 milligrams
The quality of the transformation formula is 0.25-50 grams used in initial preparation；Preferably, the alkaline matter is in transformation formula
Mass percent be 0.05wt%-3wt%, the ratio of quality that the quality of the initial preparation and the transformation are formulated is
0.001-0.1；
When the initial preparation is 1wt% Tetracaine Hydrochloride Solution or 1wt% tetracaine hydrochloride gel, in the transformation formula
Alkaline matter be sodium hydroxide or potassium hydroxide, and the alkaline matter it is described transformation formula in mass percent be
0.05wt%-5wt%, the quality of the transformation formula used in every 5 milliliters of initial preparations are 1-40 grams；Preferably, institute
It states alkaline matter and changes the mass percent in being formulated for 0.1wt%-2wt%, used in every 5 milliliters of initial preparations described
The transformation formula quality be 0.25-40 grams；
When the initial preparation is tetracaine hydrochloride powder, the alkaline matter in the transformation formula is sodium hydroxide or hydroxide
Potassium, and mass percent of the alkaline matter in the transformation formula is 0.1wt%-8wt%, every 50 milligrams are described initial
The quality of the transformation formula used in preparation is 0.25-40 grams；Preferably, the alkaline matter is in transformation formula
Mass percent is 0.1wt%-3wt%, and the quality of the transformation formula used in every 50 milligrams of initial preparations is 1-40
Gram；
It is described when the initial preparation is 0.75wt% bupivacaine HCl solution or 0.75wt% bupivacaine HCl gel
Alkaline matter in transformation formula is sodium hydroxide or potassium hydroxide, and the alkaline matter is in the quality changed in formula
Percentage is 0.1wt%-4wt%, and the quality of the transformation formula used in every 5 milliliters of initial preparations is 0.5-10 grams；
Mass percent of the alkaline matter in the transformation formula is 0.1wt%-1.2wt%, every 5 milliliters of initial preparations
The quality of the transformation formula used is 2-8 grams；
When the initial preparation is bupivacaine HCl powder, the alkaline matter in the transformation formula is sodium hydroxide or hydrogen-oxygen
Change potassium, and alkaline matter mass percent in transformation formula is 0.1wt%-8wt%, every 50 milligrams described initial
The quality of the transformation formula is 0.25-30 grams used in preparation；Preferably, matter of the alkaline matter in the transformation formula
Amount percentage is 0.05wt%-3wt%, and the ratio for the quality that the quality of the initial preparation and the transformation are formulated is 0.001-
0.1。
22. such as the described in any item method of converting of claim 15-18, which is characterized in that the dosage of the transformation formula makes
50% or more local anesthetic exists in the form of undissolved in the end formulation；Preferably, the use of the transformation formula
Amount is so that 70% or more local anesthetic exists in the form of undissolved in the end formulation；More preferably, the transformation is matched
The dosage of side has the local anesthetic of 70%-99% in the end formulation in the form of undissolved.
23. a kind of method of converting that initial preparation is changed into transdermal absorption formulation or sustained release preparation, which is characterized in that initial system
Agent is mixed with the described in any item transformation formulas of such as claim 10-12 up to end formulation, and the end formulation is used as transdermal
Absorbable preparation or sustained release preparation；Wherein, the initial preparation is the solution containing local anesthetic defined in claim 9；
The dosage of the transformation formula makes the pH value of the end formulation be 7-11, and makes the amides local anesthetic in institute
The mass percent in end formulation is stated to be 0.5% or more or make the esters local anesthetic in the end formulation
Mass percent is 0.1% or more；The dosage of the transformation formula also makes in the end formulation 50% or more part fiber crops
Liquor-saturated medicine exists in the form of undissolved.
24. method of converting as claimed in claim 23, which is characterized in that the pH value of the end formulation is 7-9.5, preferably
It is more preferably 7.5-9 for 7-9；
And/or mass percent of the amides local anesthetic in the end formulation be 0.5%-9.1%,
0.5%-5% or 0.5%-2%；
And/or mass percent of the esters local anesthetic in the end formulation is 0.1%-9.1%, 0.1%-
5% or 0.2%-2%；
And/or the dosage of the transformation formula also makes the local anesthetic of 70%-99% in the end formulation with insoluble
Form exist.
25. method of converting as claimed in claim 23, which is characterized in that the end formulation can anaesthetize in 90 minutes
Whole non-facial skin；And/or the end formulation can anaesthetize complete facial skin in 30 minutes.
26. it is a kind of as the described in any item transformations of claim 1-12 be formulated by initial preparation be changed into transdermal absorption formulation or
Application in the method for converting of sustained release preparation, which is characterized in that the initial preparation is first defined in claim 6 or 9
Beginning preparation.
27. application as claimed in claim 26, which is characterized in that the transdermal absorption formulation is institute in claim 15 or 22
The end formulation of definition；The sustained release preparation is end formulation defined in claim 22.
28. application as claimed in claim 26, which is characterized in that the transdermal absorption formulation or the sustained release preparation can be
Complete non-facial skin is anaesthetized in 90 minutes；And/or the transdermal absorption formulation or the sustained release preparation can be in 30 minutes
Anaesthetize complete facial skin.
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| CN101069690A (en) * | 2005-03-11 | 2007-11-14 | 上海交通大学医学院附属第九人民医院 | Doxycyline Hyclate lipid gels and preparing method |
| CN101209250A (en) * | 2006-12-27 | 2008-07-02 | 上海复星医药（集团）股份有限公司 | Compound lignocaine emulsifiable paste and preparing technique |
| CN101792444A (en) * | 2009-02-02 | 2010-08-04 | 天津康鸿医药科技发展有限公司 | Sodium levofolinate and preparation method and drug combination thereof |
| WO2012064766A2 (en) * | 2010-11-09 | 2012-05-18 | Jie Zhang | Sheet and liquid combination systems for dermal drug delivery |
| US20150056296A1 (en) * | 2012-02-29 | 2015-02-26 | Medion Research Laboratories Inc. | Kit for preparing carbon-dioxide-containing composition |
| CN105579003A (en) * | 2013-07-10 | 2016-05-11 | 张洁 | A kit for sustained transdermal drug delivery using liquid or semisolid formulations and method of using the same |
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2018
- 2018-01-17 CN CN201810046186.2A patent/CN110051620A/en not_active Withdrawn
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101069690A (en) * | 2005-03-11 | 2007-11-14 | 上海交通大学医学院附属第九人民医院 | Doxycyline Hyclate lipid gels and preparing method |
| CN101209250A (en) * | 2006-12-27 | 2008-07-02 | 上海复星医药（集团）股份有限公司 | Compound lignocaine emulsifiable paste and preparing technique |
| CN101792444A (en) * | 2009-02-02 | 2010-08-04 | 天津康鸿医药科技发展有限公司 | Sodium levofolinate and preparation method and drug combination thereof |
| WO2012064766A2 (en) * | 2010-11-09 | 2012-05-18 | Jie Zhang | Sheet and liquid combination systems for dermal drug delivery |
| US20150056296A1 (en) * | 2012-02-29 | 2015-02-26 | Medion Research Laboratories Inc. | Kit for preparing carbon-dioxide-containing composition |
| CN105579003A (en) * | 2013-07-10 | 2016-05-11 | 张洁 | A kit for sustained transdermal drug delivery using liquid or semisolid formulations and method of using the same |
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