CN109528628A - A kind of Pharmaceutical composition and its preparation method and application comprising levocarnitine - Google Patents
A kind of Pharmaceutical composition and its preparation method and application comprising levocarnitine Download PDFInfo
- Publication number
- CN109528628A CN109528628A CN201811534006.1A CN201811534006A CN109528628A CN 109528628 A CN109528628 A CN 109528628A CN 201811534006 A CN201811534006 A CN 201811534006A CN 109528628 A CN109528628 A CN 109528628A
- Authority
- CN
- China
- Prior art keywords
- levocarnitine
- pharmaceutical composition
- water
- tackifier
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
-
- 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
- A61K47/06—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
-
- 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
-
- 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
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
Abstract
The invention belongs to technical field of medicine, are related to a kind of pharmaceutical composition comprising levocarnitine and its corresponding preparation method and medical usage.Specifically, pharmaceutical composition of the invention includes levocarnitine, gel-type vehicle, tackifier and water for pharmaceutical purposes, it is a kind of thermosensitive in situ gel preparation.Compared with common eye-drops preparations, thermosensitive in-situ gel preparation of the invention has a characteristic that 1) the hydrophily three-dimensional net structure with gelling agent and good histocompatbility；2) have many advantages, such as and mucous membrane tissue affinity is strong, the residence time is long, local drug concentration is high, bioavilability is high；3) it can avoid " paste view phenomenon " that common oil Eye ointments generates, reduce the irritation to eye；4) preparation is simple, easy to use, considerably increases the compliance of patient；5) dosage can accurately control, and reach the slow controlled-release effect of medicinal active ingredient.
Description
Technical field
The invention belongs to technical field of medicine, it is related to a kind of pharmaceutical composition comprising levocarnitine and its corresponding
Preparation method and medical usage.
Background technique
Xerophthalmia (Dry Eye Disease), also known as angle xerosis of conjunctiva (Keratoconjunctivitis Sicca),
Refer to the matter of the tear as caused by any reason or measure exception or dynamics exception, and then tear film stability is caused to decline, and
With the general name of a variety of diseases of the features such as ophthalmic uncomfortable and/or ocular lesion tissue, common sympton includes that eyes are dry and astringent, holds
Easy tired, eye itches, foreign body sensation, pain burning heat sensation, secretion are sticky, fear of wind, photophobia, sensitive etc. to environmental stimuli；More severe case, eye
Eyeball understands redness, hyperemia, keratinization, corneal epithelium broken skin and has filiform adherency, with the passing of time can then cause angle conjunctive disorder, and influence
Eyesight.In addition, the tear osmotic pressure of xerophthalmia patients significantly increases, osmotic pressure is (326 ± 22.1) mOsmol/L, normal person
Tear osmotic pressure is (302 ± 9.7) mOsmol/L.Use 316mOsmol/L as the diagnosis index of xerophthalmia, sensibility and spy
The opposite sex is better than any other diagnosis index.
Currently, the treatment method of xerophthalmia has tear alternative medicine, tear maintenance therapy, tear irritation therapy, anti-inflammatory treatment
Method, operative treatment, physical therapy etc. are (referring to Jones L.et al., TFOS DEWS II Management and Therapy
Report [J], Ocul.Surf., 2017,15 (3): 575-628), wherein with artificial tears' eye droppings for main treatment method,
But this method is palliative, and bioavilability is low；Tear alternative medicine (such as autoserum source) has great limitation
Property, preparation and preservation are inconvenient；Anti-inflammatory drug (such as glucocorticoid) prolonged application may lead intraocular pressure raising, cataract；
In addition, patient is low to the acceptance level of operative treatment, therefore select the crowd of operation seldom.
Carnitine (Carnitine, also known as carnitine) has left-handed (L-), dextrorotation (D-) and three kinds of optics of racemization (DL-) different
Structure body form, but only levocarnitine (abbreviation levocarnitine) has in vivo bioactivity.Levocarnitine (L-Carnitine,
Also known as L-carnitine, structure are as shown above), entitled (R) -3- hydroxyl -4- (trimethyl ammonium) the butyric acid inner salt of chemistry, molecular formula is
C7H15NO3, molecular weight 161.20 is a kind of white crystalline powder, have draw by force it is moist, it is readily soluble in water, ethyl alcohol, third
It is ketone, ether, almost insoluble in benzene.The chemical structure of levocarnitine is similar to choline, close but different from amino acid, is not used in
The synthesis of protein there is collaboration to make the absorption of liposoluble vitamin (such as vitamin E, A and D) and calcium, phosphorus microelement
With (referring to Zhu Hongming etc., the pharmacology and clinical application research of levocarnitine are in progress [J], Tianjin pharmacy, 2014,26 (04): 58-
63).In addition, levocarnitine can effectively remove free radical as a kind of antioxidant, lipid peroxidation is reduced, blocks oxygen certainly
The Apoptosis as caused by base, having protective effect in the stabilization for maintaining film, (referring to horse Jing etc., levocarnitine is in reproductive medicine
In application study be in progress [J], difficult disease magazine, 2017,16 (11): 1175-1178/1184).
Currently, levocarnitine is clinically mainly used for cardiovascular disease, kidney trouble, diabetic complication, liver disease
The treatment of the diseases such as disease, central nervous system degenerative disease and andrological diseases.In addition, levocarnitine also has anti-apoptotic, resists
Oxidation characteristic, for treating Eye disease, cornea tissue reparation and ophthalmologic operation etc., it is thin that anti-apoptotic characteristic can improve cutin
Born of the same parents, the cell migration of epithelial cell and endothelial cell, proliferation and adherency are conducive to the reparation of cornea (referring to Peluso G.et
al.,Carnitine:an osmolyte that plays a metabolic role[J],Journal of Cellular
Biochemistry,2000,80(1):1-10).For first hair style xerophthalmia or for xerophthalmia early stage, hypertonic is most allusion quotation
The course of disease and the cause of disease of type, and the osmotic pressure adjustment effect of levocarnitine can be effectively improved the hypertonic symptom of xerophthalmia.As one
Kind Compatible solute, levocarnitine protect cell by equilibrium osmotic pressure under extreme osmotic pressure, without influencing cell
Metabolism, osmotic protection effect depends on the amount and its retention time of ingestion of medicines, therefore international dry eyes treatment guidelines push away
Recommend as a kind of permeation protective agent come using.However, the domestic report in terms of L-carnitine in treatment xerophthalmia is seldom,
Huo Jian is prepared for levocarnitine eye drops, using om observation corneal epithelium form, corneal epithelium thickness measure, om observation
Conjunctival epithelium form, goblet cell count, scanning electron microscope observes the Histopathological methods such as corneal epithelium, further demonstrate,prove
The mouse dry eye model ocular that real levocarnitine induce hypertonic saline eye drip is with protective effect (referring to Huo Jian, Zuo Kani
The Primary Study [D] for the mouse dry eye model ocular protective effect that spit of fland induces hypertonic saline, Third Military Medical University, 2012).
There are some drawbacks when in use in traditional eye-drops preparations (such as eye drops, ointment).Since eyeball surface holds
Product is very limited, and the speed that is exhausted by nasolacrimal duct of tear is again quickly, causes drug short in the residence time of eye, drug wastage amount
Greatly, bioadhesive is poor, and bioavilability is low.In addition, needing frequent drug administration because of drug wastage again and will cause adverse drug and is anti-
Risk is answered to increase.Certain eye drops contain preservative, though micro preservative is to ocular damage and little, long-term excessive contact
Preservative may to eyes generate injury, cause normal tear film to be destroyed, corneal epithelial cell damages, easily it is secondary its
His eye disease.Although retention time of the Eye ointments in conjunctival sac is longer than eye drops, the disadvantage is that having greasy feeling, eyesight mould
Paste and eyelid flake, therefore generally can only night medication.The patient tolerability of intraocular inserting agent is poor.Although ophthalmically acceptable ordinary gel agent
Drug can be reduced in the loss of eye, bioavilability is improved, extend the residence time on cornea, reach slow releasing function,
But when being administered with gel form, dosage inaccuracy (difficult quantitation), viscosity is larger before being administered, and there is administration difficulty, patient tolerance
The problems such as property is poor, lacks good spreadability, limits it in the application of eye.Therefore, it is found for levocarnitine novel ophthalmically acceptable
Dosage form simultaneously develops patent medicine and seems particularly necessary.
Summary of the invention
Problems to be solved by the invention
For existing stagnant for preventing and/or treating eye existing for local application (ophthalmically acceptable) pharmaceutical preparation of xerophthalmia
The problems such as time is short, number of dropouts is big, bioavilability is low, patient tolerability is poor is stayed, includes Zuo Kani the present invention provides one kind
The pharmaceutical composition in spit of fland and its corresponding preparation method and medical usage.
The solution to the problem
On the one hand, the present invention provides a kind of pharmaceutical compositions comprising levocarnitine, and it includes levocarnitines, gel base
Matter, tackifier and water for pharmaceutical purposes.
Preferably, the pharmaceutical composition comprising levocarnitine is the temperature sensing in situ gel rubber comprising levocarnitine.
Further, in described pharmaceutical composition, the gel-type vehicle be selected from poloxamer, polysaccharide or derivatives thereof,
Poly- (methyl) acrylic acid or derivatives thereof, polyethylene glycol or derivatives thereof, polylactic acid or derivatives thereof, polyvinylpyrrolidone or
The mixture of any one or its arbitrary proportion in its derivative, polyvinyl alcohol or derivatives thereof, preferably poloxamer, it is more excellent
Select the mixture of poloxamer188 (P407), any one or its arbitrary proportion in PLURONICS F87 (P188).
Further, in described pharmaceutical composition, the tackifier are selected from carboxymethyl cellulose (CMC) or its salt, thoroughly
Bright matter sour (HA) or its salt, hydroxypropyl methyl cellulose (HPMC), hydroxypropyl guar gum (HP-guar), hydroxypropyl cellulose
(HPC), methylcellulose (MC), hydroxyethyl cellulose (HEC), polyethylene glycol (PEG), glucan (DEX), polyvinylpyrrolidine
Ketone (PVP), polyvinyl alcohol (PVA), any one or its arbitrary proportion in carbomer (Carbomer) mixture, preferred carboxylic
The mixture of any one or its arbitrary proportion in methylcellulose or its salt, hyaluronic acid or its salt, more preferable carboxymethyl
The mixture of any one or its arbitrary proportion in sodium cellulosate, Sodium Hyaluronate.
Further, in described pharmaceutical composition, the water for pharmaceutical purposes is selected from purified water, water for injection, sterile injection
With the mixture of any one or its arbitrary proportion in water.
Optionally, other than levocarnitine, gel-type vehicle, tackifier and water for pharmaceutical purposes, described pharmaceutical composition is also wrapped
Containing any one in osmotic pressure regulator, pH adjusting agent, antioxidant, Osmolyte regulator, electrolyte, preservative, cyclodextrin
Or the mixture of its arbitrary proportion.
Further, in described pharmaceutical composition, the osmotic pressure regulator be selected from sodium chloride, potassium chloride, glucose,
Mannitol, boric acid, any one or its arbitrary proportion in borax mixture.
Further, in described pharmaceutical composition, the pH adjusting agent is selected from citric acid and/or its salt (such as lemon
Acid-sodium citrate), phosphoric acid and/or its salt (such as sodium dihydrogen phosphate-disodium hydrogen phosphate), boric acid and/or its salt (such as boric acid-
Boratex) in any one or its arbitrary proportion mixture.
Further, in described pharmaceutical composition, the antioxidant is selected from sulphite (such as sodium sulfite, Asia
Sodium bisulfate), pyrosulfite (such as sodium pyrosulfite), thiosulfate (such as sodium thiosulfate), vitamin (such as ties up
Raw element C, vitamin E etc.), amino acid or derivatives thereof (such as acetylcysteine), protein (such as Selenoprotein P), flavones
(such as Quercetin), gallic acid or derivatives thereof (such as gallic acid, propylgallate, Catechin 3-gallate etc.)
In any one or its arbitrary proportion mixture.
Further, in described pharmaceutical composition, the Osmolyte regulator is selected from hyaluronic acid, glycine betaine, erythrose
The mixture of any one or its arbitrary proportion in alcohol, trehalose.
Further, in described pharmaceutical composition, the electrolyte is selected from hydrochloride (also known as chloride, such as chlorination
Sodium, potassium chloride, calcium chloride, magnesium chloride, zinc chloride etc.) class, phosphate (such as sodium phosphate) class, borate (such as Boratex)
The mixture of any one or its arbitrary proportion in class, carbonate (such as sodium bicarbonate) class.
Further, in described pharmaceutical composition, the preservative is selected from chlorite (such as sodium chlorite), quaternary ammonium
Salt (such as benzalkonium chloride, benzalkonium bromide etc.), polyquaternium (such as polyquaternium -1), paraben esters (such as methylparaben,
Ethylparaben, propylben etc.), organic mercury (such as phenylmercuric nitrate, thimerosal etc.), perborate (such as perboric acid
Sodium), anesin, any one or its arbitrary proportion in benzyl carbinol mixture.
Preferably, every 100mL described pharmaceutical composition includes following component: levocarnitine: 1g.
Preferably, every 100mL described pharmaceutical composition includes following component: gel-type vehicle: 0~45g, but is not 0.It is more excellent
Selection of land, every 100mL described pharmaceutical composition include following component: gel-type vehicle: 20~30g.Most preferably, described in every 100mL
Pharmaceutical composition includes following component: gel-type vehicle: 22~25g.
Preferably, every 100mL described pharmaceutical composition includes following component: tackifier: 0~1.3g, but is not 0.It is more excellent
Selection of land, every 100mL described pharmaceutical composition include following component: tackifier: 0~0.6g, but are not 0.Most preferably, often
100mL described pharmaceutical composition includes following component: tackifier: 0.1~0.2g.
Preferably, every 100mL described pharmaceutical composition includes following component: levocarnitine: 1g；Gel-type vehicle: 0~45g,
It but is not 0；Tackifier: 0~1.3g, but be not 0；Surplus is water for pharmaceutical purposes.It is highly preferred that every 100mL described pharmaceutical composition
Include following component: levocarnitine: 1g；Gel-type vehicle: 20~30g；Tackifier: 0~0.6g, but be not 0；Surplus is pharmaceutical purpose
Water.Most preferably, every 100mL described pharmaceutical composition includes following component: levocarnitine: 1g；Gel-type vehicle: 22~25g；Increase
Stick: 0.1~0.2g；Surplus is water for pharmaceutical purposes.
Further, in described pharmaceutical composition, the gel-type vehicle is poloxamer188 (P407) and poloxamer
The mixture of 188 (P188).Preferably, the weight ratio of the poloxamer188 and the PLURONICS F87 is 2:1~10:1,
It is preferred that 4:1~8:1, more preferable 6:1.
Further, in described pharmaceutical composition, the tackifier are sodium carboxymethylcellulose (CMC-Na) and transparent
The mixture of matter acid sodium (HA-Na).Preferably, the weight ratio of the sodium carboxymethylcellulose and the Sodium Hyaluronate is 3:1
~8:1, preferably 4:1~6:1, more preferable 5:1.
On the other hand, the present invention provides the preparation methods of the above-mentioned pharmaceutical composition comprising levocarnitine comprising under
Column step:
1) it prepares tackifier water solution: tackifier is added in a part of water for pharmaceutical purposes, make its dispersion, swelling at room temperature
And dissolve, obtain tackifier water solution；
2) it prepares blank temperature sensing in situ gel rubber: gel-type vehicle is added in tackifier water solution obtained in step 1),
It stirs evenly, is placed 24 hours or more at 4 DEG C, obtain blank temperature sensing in situ gel rubber；
3) preparation carries medicine temperature sensing in situ gel rubber: levocarnitine is added to blank temperature sensing in situ gel rubber obtained in step 2)
In, it places to room temperature, adds another part water for pharmaceutical purposes to full dose, stir evenly, obtain carrying medicine temperature sensing in situ gel rubber, as wrap
Pharmaceutical composition containing levocarnitine.
Further, in the preparation method, the water for pharmaceutical purposes is purified water.
Further, in the preparation method, a part of water for pharmaceutical purposes is the water for pharmaceutical purposes of total amount 70%.
Preferably, in the step 2) of the preparation method, gel-type vehicle and levocarnitine are added to step 1) simultaneously
Obtained in tackifier water solution, stir evenly, placed 24 hours or more at 4 DEG C, place to room temperature, add another part
Water for pharmaceutical purposes stirs evenly to full dose, obtains carrying medicine temperature sensing in situ gel rubber, as include the pharmaceutical composition of levocarnitine.
In another aspect, the present invention provides the above-mentioned pharmaceutical composition comprising levocarnitine preparation for prevent and/control
Treat the purposes in the drug of xerophthalmia.
Further, described on the way, the xerophthalmia is first hair style xerophthalmia.
The effect of invention
Compared with common eye-drops preparations, pharmaceutical composition (the ophthalmically acceptable temperature sensing in situ gel rubber comprising levocarnitine of the invention
Preparation) the gel-type vehicle formula based on optimization and there is unique solution-gel property of transition, thus make it have following spy
Point: (1) the hydrophily three-dimensional net structure with gelling agent and good histocompatbility；(2) have affine with mucous membrane tissue
The advantages that power is strong, the residence time is long, local drug concentration is high, bioavilability is high；(3) it can avoid common oil Eye ointments to produce
Raw " paste view phenomenon ", reduces the irritation to eye；(4) preparation is simple, easy to use, considerably increases complying with for patient
Property；(5) dosage can accurately control, and reach the slow controlled-release effect of medicinal active ingredient.
Detailed description of the invention
Fig. 1 is the extracorporeal releasing test result of levocarnitine temperature sensing in situ gel rubber (LCTISG).
Fig. 2 is the rabbit cornea permeability test result of levocarnitine temperature sensing in situ gel rubber (LCTISG).
Fig. 3 is the ocular residence time test result of levocarnitine temperature sensing in situ gel rubber (LCTISG).
Fig. 4 is the pharmacodynamic test result of levocarnitine temperature sensing in situ gel rubber (LCTISG).
Specific embodiment
Firstly, the present invention provides a kind of pharmaceutical compositions comprising levocarnitine.From formula composition, the drug
Composition mainly includes levocarnitine, gel-type vehicle, tackifier and water for pharmaceutical purposes.
In some embodiments of the present invention, the above-mentioned pharmaceutical composition comprising levocarnitine is to include levocarnitine
Temperature sensing in situ gel rubber.
Unless otherwise indicated, the term " levocarnitine " occurred in the context of the present invention refers to left-handed carnitine
(also known as L-carnitine) can both exist with free alkali form, can also with pharmaceutically acceptable inorganic acid or organic
The acid addition salt form thereof that acid is formed exists, can also be in the form of hydrate, solvate or prodrug (such as acetyl levocarnitine)
In the presence of.In addition, levocarnitine existing in the form of above-mentioned any one both can be amorphous substance, or crystal (including
Polymorph).Therefore, in the form of any one of the above existing for levocarnitine be included in protection scope of the present invention.
In some embodiments of the present invention, the levocarnitine in aforementioned pharmaceutical compositions is to exist with free alkali form
Levocarnitine.In some preferred embodiments, above-mentioned using levocarnitine existing for free alkali form as amorphous substance.
In some embodiments of the present invention, the levocarnitine in aforementioned pharmaceutical compositions is with pharmaceutically acceptable
The acid addition salt form thereof of inorganic acid exists.In some preferred embodiments, above-mentioned with pharmaceutically acceptable inorganic acid
Acid addition salt form thereof is levocarnitine hydrochlorate there are levocarnitine.In some further preferred embodiments, above-mentioned Zuo Kani
Spit of fland hydrochloride is amorphous substance.In other further preferred embodiments, above-mentioned levocarnitine hydrochlorate is crystalline powder.
In some embodiments of the present invention, the levocarnitine in aforementioned pharmaceutical compositions is with pharmaceutically acceptable
The acid addition salt form thereof of organic acid exists.In some preferred embodiments, above-mentioned with pharmaceutically acceptable organic acid
Acid addition salt form thereof is levocarnitine tartrate there are levocarnitine.In some further preferred embodiments, above-mentioned left card
Buddhist nun spit of fland tartrate is amorphous substance.In other further preferred embodiments, above-mentioned levocarnitine tartrate is crystallization
Property powder.
Unless otherwise indicated, the term " gel-type vehicle " occurred in the context of the present invention, which refers to, is used to form gel
Host material.
In some embodiments of the present invention, the gel-type vehicle in aforementioned pharmaceutical compositions is responsive to temperature type gel base
Matter, main component be temperature sensitive high molecular polymer, selected from poloxamer (also known as polyoxyethylene/polyoxypropylene block copolymers),
Polysaccharide or derivatives thereof (including xylan, glucan, xyloglucan etc.), poly- (methyl) acrylic acid or derivatives thereof, poly- second two
Alcohol or derivatives thereof, polylactic acid or derivatives thereof, polyvinylpyrrolidone (also known as povidone) or derivatives thereof, polyvinyl alcohol or
The mixture of any one or its arbitrary proportion in its derivative.In some preferred embodiments, said medicine combines
Gel-type vehicle in object is any one or its arbitrary proportion in poloxamer, such as poloxamer188, PLURONICS F87
Mixture.When temperature sensitive hydrogel medicine-feeding part apply after, temperature-sensitive polymers at application the variation of temperature due to it is rapid
The gel of non-chemical crosslinking is formed, specific mechanism depends primarily on the composed structure unit and crosslinking method of polymer.
Unless otherwise indicated, the term " tackifier " occurred in the context of the present invention refers to for adjusting gel rubber system
A kind of pharmaceutic adjuvant of adhesiveness between viscosity and gel and site of administration.
In some embodiments of the present invention, the tackifier in aforementioned pharmaceutical compositions be selected from carboxymethyl cellulose or its
Salt, hyaluronic acid or its salt, hydroxypropyl methyl cellulose, hydroxypropyl guar gum, hydroxypropyl cellulose, methylcellulose, hydroxyl second
Base cellulose, polyethylene glycol, glucan, polyvinylpyrrolidone, polyvinyl alcohol, any one or its in carbomer are any compares
The mixture of example.In some preferred embodiments, the tackifier in aforementioned pharmaceutical compositions be selected from carboxymethyl cellulose or
Any one in its salt (such as sodium carboxymethylcellulose), hyaluronic acid or its salt (such as Sodium Hyaluronate) or its any ratio
The mixture of example.In some further preferred embodiments, tackifier in aforementioned pharmaceutical compositions be carboxymethyl cellulose or
The mixture of any one or its arbitrary proportion in its salt, hyaluronic acid or its salt, such as sodium carboxymethylcellulose, hyalomitome
The mixture of any one or its arbitrary proportion in sour sodium.
Unless otherwise indicated, the term " water for pharmaceutical purposes " occurred in the context of the present invention refers to the life in pharmaceutical preparation
Water used in production. art mainly includes the different brackets such as drinking water, purified water, water for injection, sterilized water for injection.Wherein,
Term " drinking water " refers to can be without handling, directly feed the water that human body drinks；Term " purified water " refers to be made with drinking water
For raw water, through the way of distillation, ion-exchange, hyperfiltration or other refined water of suitable method, quality standard is high
In drinking water；Term " water for injection " refers to using purified water as raw water, specially designed distiller (such as multi-effect distilled water
Machine, vapour-pressure type distillation machine etc.) distillation, refined water is filtered through film again after condensation, quality standard is higher than purified water；Art
Language " sterilized water for injection " refers to that using water for injection as raw water, the sterilized refined water of processing, quality standard is higher than
Water for injection.
In some embodiments of the present invention, the water for pharmaceutical purposes in aforementioned pharmaceutical compositions is selected from purified water, injection
The mixture of any one or its arbitrary proportion in water, sterilized water for injection.In some preferred embodiments, above-mentioned medicine
Water for pharmaceutical purposes in compositions is purified water.Pharmacy in other preferred embodiments, in aforementioned pharmaceutical compositions
It is water for injection with water.
In order to further improve physicochemical property, other than levocarnitine, gel-type vehicle, tackifier and water for pharmaceutical purposes, on
Stating pharmaceutical composition also includes osmotic pressure regulator, pH adjusting agent, antioxidant, Osmolyte regulator, electrolyte, preservative, ring
The mixture of any one or its arbitrary proportion in dextrin.
Unless otherwise indicated, the term " osmotic pressure regulator " occurred in the context of the present invention refers to solidifying for adjusting
A kind of pharmaceutic adjuvant of colloid system osmotic pressure.In general, by with blood plasma or tear there is the solution of identical osmotic pressure to be known as waiting vadose solutions
Liquid (NaCl solution for being roughly equivalent to 0.9%), should be as far as possible with tear etc. for the osmotic pressure of the ophthalmically acceptable pharmaceutical preparation used
It seeps, because hypertonic solution is dehydrated ocular tissue and generates sense of discomfort in turn due to that can absorb moisture, and hypotonic solution then can
It expands cornea tissue and then causes pain.Osmotic pressure is too high or too low can to stimulate eyeball, affect the treatment.General ophthalmic preparation
In drug content it is lower, if being prepared with distilled water, the osmotic pressure of solution is equivalent to 0.5% NaCl solution (even more mostly
It is low), eyes can not be resistant to this hypotonic condition, and one of effective solution method is exactly to add osmotic pressure regulator thereto, with
It is in osmotic pressure in the range for being suitable for.
In some embodiments of the present invention, the osmotic pressure regulator in aforementioned pharmaceutical compositions is selected from sodium chloride, chlorine
Change the mixture of potassium, glucose, mannitol, boric acid, any one or its arbitrary proportion in borax.In some preferred implementations
In scheme, the osmotic pressure regulator in aforementioned pharmaceutical compositions is the mixture of sodium chloride and potassium chloride.The mixture can either
The osmotic pressure of gel rubber system is effectively adjusted, and is able to maintain the potassium-sodium balance inside and outside ocular cell.
Unless otherwise indicated, the term " pH adjusting agent " (also known as acidity regulator) occurred in the context of the present invention is
Refer to for adjusting gel rubber system pH value and keeping it in a kind of pharmaceutic adjuvant in particular range.As it is most sensitive and most vulnerable to
The organ stimulated to external environment, eyes are extremely fastidious for the pH value of ambient enviroment.Under normal circumstances, eyes can be with
The pH value of tolerance will generate apparent sense of discomfort, and alkaline condition less than 5.0 or greater than 11.0 between 5.0~9.0
More easily corneal damage.Optimum pH value is between 6.0~8.0, and eyes are without sense of discomfort within this range.
In some embodiments of the present invention, the pH adjusting agent in aforementioned pharmaceutical compositions be selected from citric acid and/or its
Salt (such as citric acid-sodium citrate), phosphoric acid and/or its salt (such as sodium dihydrogen phosphate-disodium hydrogen phosphate), boric acid and/or its
The mixture of any one or its arbitrary proportion in salt (such as boric acid-sodium borate).In some preferred embodiments, on
Stating the pH adjusting agent in pharmaceutical composition is phosphoric acid and/or its salt.Above-mentioned phosphoric acid and/or its salt are phosphoric acid, dihydric phosphate, phosphorus
At least any two kinds of combination in sour monohydric salt, phosphate, such as phosphoric acid/sodium dihydrogen phosphate (potassium), sodium dihydrogen phosphate (potassium)/
Disodium hydrogen phosphate (potassium), disodium hydrogen phosphate (potassium)/sodium phosphate (potassium) etc..In some preferred embodiments, said medicine group
Closing the pH adjusting agent in object is sodium dihydrogen phosphate (potassium)/disodium hydrogen phosphate (potassium).
Unless otherwise indicated, the term " antioxidant " occurred in the context of the present invention is to refer to prevent or delay
Active pharmaceutical ingredient is oxidized, to improve its stability and extend a kind of pharmaceutic adjuvant of its storage period.Utilize its oxidation electricity
The gesture attribute lower than main ingredient, antioxidant can preferentially with oxygen (or other substances with oxidability) effect in environment,
And the physicochemical property of drug is made to keep stablizing.
In some embodiments of the present invention, the antioxidant in aforementioned pharmaceutical compositions be selected from sulphite (such as
Na2SO3、NaHSO3), pyrosulfite (such as Na2S2O5), thiosulfate (such as Na2S2O3), vitamin (such as VC,
VE), amino acid or derivatives thereof (such as Ac-Cys-OH), protein (such as Selenoprotein P), flavones (such as Quercetin), no food
Any one or its in sub- acid or derivatives thereof (such as gallic acid, propylgallate, Catechin 3-gallate etc.)
The mixture of arbitrary proportion.In some preferred embodiments, the antioxidant in aforementioned pharmaceutical compositions is pyrosulfurous acid
Sodium.
Unless otherwise indicated, the term " Osmolyte regulator " occurred in the context of the present invention refers to for subject
Agents area generate osmotic adjustment effect a kind of pharmaceutic adjuvant.
In some embodiments of the present invention, the Osmolyte regulator in aforementioned pharmaceutical compositions is selected from hyaluronic acid, sweet tea
Dish alkali, antierythrite, any one or its arbitrary proportion in trehalose mixture.In some preferred embodiments,
Osmolyte regulator in aforementioned pharmaceutical compositions is hyaluronic acid.
Unless otherwise indicated, the term " electrolyte " occurred in the context of the present invention, which refers to, to be distributed widely in into the cell
Outside, multinomial metabolic activity in organism is participated in, and maintains a substance of normal activities.
In some embodiments of the present invention, the electrolyte in aforementioned pharmaceutical compositions be selected from chloride (such as NaCl,
KCl、CaCl2、MgCl2、ZnCl2Deng), phosphate (such as Na3PO4), borate (such as Na3BO3), carbonate (such as
NaHCO3) in any one or its arbitrary proportion mixture.In some preferred embodiments, aforementioned pharmaceutical compositions
In electrolyte be sodium chloride.
Unless otherwise indicated, the term " preservative " occurred in the context of the present invention refers to that being able to suppress microorganism lives
It is dynamic, and then prevent a kind of pharmaceutic adjuvant that pharmaceutical preparation is putrid and deteriorated, increases its stability.According to use habit, for solid,
It is known as preservative in semisolid preparation, in eye drops and injection also referred to as " bacteriostatic agent ".In eye-drops preparations, preservative
Safety, the potential danger of Long Term Contact and its brought adverse reaction are increasingly subject to the attention of eye doctor and pharmacist.
In some embodiments of the present invention, the preservative in aforementioned pharmaceutical compositions be selected from chlorite (such as
NaClO2), quaternary ammonium salt (such as BAC, BAB etc.), polyquaternium (such as PQ-1), paraben esters (such as MPB, EPB, PPB etc.),
Organic mercury (such as phenylmercuric nitrate, thimerosal etc.), perborate (such as NaBO3), it is anesin, any one in benzyl carbinol
The mixture of kind or its arbitrary proportion.In some preferred embodiments, the preservative in aforementioned pharmaceutical compositions is quaternary ammonium
Salt, such as benzalkonium chloride (BAC), benzalkonium bromide (BAB) etc..
Other than the particularity in formula composition, the dosage side of pharmaceutical composition of the invention each component in formula
Face also has particularity.
In some embodiments of the present invention, every 100mL pharmaceutical composition includes the levocarnitine of 1g.
In some embodiments of the present invention, every 100mL pharmaceutical composition includes 0~45g, but is not 0 gel
Matrix.In some preferred embodiments, every 100mL pharmaceutical composition includes the gel-type vehicle of 20~30g.It is some more
In preferred embodiment, every 100mL pharmaceutical composition includes the gel-type vehicle of 22~25g.
In some embodiments of the present invention, every 100mL pharmaceutical composition includes 0~1.3g, but is not 0 thickening
Agent.In some preferred embodiments, every 100mL pharmaceutical composition includes 0~0.6g, but is not 0 tackifier.One
In a little further preferred embodiments, every 100mL pharmaceutical composition includes the tackifier of 0.1~0.2g.
In some embodiments of the present invention, every 100mL pharmaceutical composition includes the levocarnitine of 1g；0~45g,
It but is not 0 gel-type vehicle；0~1.3g, but be not 0 tackifier；Surplus is water for pharmaceutical purposes.In some preferred embodiments
In, every 100mL pharmaceutical composition includes the levocarnitine of 1g；The gel-type vehicle of 20~30g；0~0.6g, but be not 0 increasing
Stick；Surplus is water for pharmaceutical purposes.In some further preferred embodiments, every 100mL pharmaceutical composition includes the left card of 1g
Ni Ting；The gel-type vehicle of 22~25g；The tackifier of 0.1~0.2g；Surplus is water for pharmaceutical purposes.
In some embodiments of the present invention, the gel-type vehicle in the pharmaceutical composition is the mixing of P407 and P188
Object.In some preferred embodiments, the weight ratio of P407 and P188 is 2:1~10:1.In some preferred embodiment party
In case, the weight ratio of P407 and P188 are 4:1~8:1.In some the most preferred embodiment, the weight ratio of P407 and P188
For 6:1.
In some embodiments of the present invention, the tackifier in the pharmaceutical composition are the mixing of CMC-Na and HA-Na
Object.In some preferred embodiments, the weight ratio of CMC-Na and HA-Na is 3:1~8:1.In some preferred implementations
In scheme, the weight ratio of CMC-Na and HA-Na are 4:1~6:1.In some the most preferred embodiment, CMC-Na and HA-Na
Weight ratio be 5:1.
Secondly, the present invention provides the preparation methods of the above-mentioned pharmaceutical composition comprising levocarnitine.The preparation method packet
Include the following steps:
1) it prepares tackifier water solution: tackifier is added in a part of water for pharmaceutical purposes, make its dispersion, swelling at room temperature
And dissolve, obtain tackifier water solution；
2) it prepares blank temperature sensing in situ gel rubber: gel-type vehicle is added in tackifier water solution obtained in step 1),
It stirs evenly, is placed 24 hours or more at 4 DEG C, obtain blank temperature sensing in situ gel rubber；
3) preparation carries medicine temperature sensing in situ gel rubber: levocarnitine is added to blank temperature sensing in situ gel rubber obtained in step 2)
In, it places to room temperature, adds another part water for pharmaceutical purposes to full dose, stir evenly, obtain carrying medicine temperature sensing in situ gel rubber, as wrap
Pharmaceutical composition containing levocarnitine.
In some embodiments of the present invention, the water for pharmaceutical purposes in the preparation method is purified water.
In some embodiments of the present invention, a part of water for pharmaceutical purposes in the step 1) of the preparation method is total amount
70% water for pharmaceutical purposes.It will be appreciated by persons skilled in the art that the purpose that a part of water for pharmaceutical purposes is added in the step exists
In dispersion, swelling and dissolve tackifier.Therefore, as long as can reach above-mentioned purpose, the additional amount of water for pharmaceutical purposes can take the circumstances into consideration
Adjustment, is not limited to this point value of total amount 70%.
In some preferred embodiments, gel-type vehicle and levocarnitine can be added to thickening simultaneously in step 2)
In agent aqueous solution.For example, gel-type vehicle and levocarnitine are added in tackifier water solution obtained in step 1) simultaneously, stir
It mixes uniformly, is placed 24 hours or more at 4 DEG C, placement is added another part water for pharmaceutical purposes to full dose, is stirred evenly to room temperature,
It obtains carrying medicine temperature sensing in situ gel rubber, as includes the pharmaceutical composition of levocarnitine.
Finally, the present invention provides the pharmaceutical applications of the above-mentioned pharmaceutical composition comprising levocarnitine.
In some embodiments of the present invention, which is that the above-mentioned pharmaceutical composition comprising levocarnitine is being made
The purposes being ready for use in the drug of prevention and/treatment xerophthalmia.In some preferred embodiments, the xerophthalmia is initial
Type xerophthalmia.
Unless otherwise indicated, the term " first hair style xerophthalmia " occurred in the context of the present invention refers to without serious
The xerophthalmia of keratoconjunctivitis sicca, the Etiological of the type xerophthalmia are that tear caused by a variety of causes is hypertonic, this is exactly Zuo Kani
The position in spit of fland.
Embodiment 1: the preparation of the pharmaceutical composition (LC thermosensitive in-situ gel preparation) comprising levocarnitine.
0.1g HA-Na and 0.3g CMC-Na is weighed, is added in 600mL purified water, makes HA-Na and CMC-Na at room temperature
Disperse, be swollen and dissolve, obtains tackifier water solution.0.1g P407 and 0.2g P188 are added to above-mentioned tackifier water solution
In, it stirs evenly, is put into 4 DEG C of refrigerators and refrigerates more than for 24 hours, clarified, finely dispersed blank temperature sensing in situ gel rubber.It will
10g levocarnitine (LC) is added in above-mentioned blank temperature sensing in situ gel rubber, is placed to room temperature, is added 400mL purified water to full dose
(1L), stirs evenly, and dissolves levocarnitine to get LC temperature sensing in situ gel rubber (including the pharmaceutical composition of levocarnitine).
Embodiment 2: the preparation of the pharmaceutical composition (LC thermosensitive in-situ gel preparation) comprising levocarnitine.
2.6g HA-Na and 10.4g CMC-Na is weighed, is added in 800mL purified water, makes HA-Na and CMC- at room temperature
Na dispersion is swollen and dissolves, and obtains tackifier water solution.It is water-soluble that 300g P407 and 150g P188 are added to above-mentioned tackifier
It in liquid, stirs evenly, is put into 4 DEG C of refrigerators and refrigerates more than for 24 hours, clarified, finely dispersed blank temperature sensing in situ gel rubber.It will
10g levocarnitine (LC) is added in above-mentioned blank temperature sensing in situ gel rubber, is placed to room temperature, is added 200mL purified water to full dose
(1L), stirs evenly, and dissolves levocarnitine to get LC temperature sensing in situ gel rubber (including the pharmaceutical composition of levocarnitine).
Embodiment 3: the preparation of the pharmaceutical composition (LC thermosensitive in-situ gel preparation) comprising levocarnitine.
0.1g HA-Na and 0.4g CMC-Na is weighed, is added in 700mL purified water, makes HA-Na and CMC-Na at room temperature
Disperse, be swollen and dissolve, obtains tackifier water solution.200g P407,50g P188 and 10g levocarnitine (LC) are added
It into above-mentioned tackifier water solution, stirs evenly, is put into 4 DEG C of refrigerators and refrigerates more than for 24 hours, place to room temperature, it is pure to add 300mL
Change water to full dose (1L), stirs evenly, dissolving levocarnitine to get LC temperature sensing in situ gel rubber (includes the medicine of levocarnitine
Compositions).
Embodiment 4: the preparation of the pharmaceutical composition (LC thermosensitive in-situ gel preparation) comprising levocarnitine.
1g HA-Na and 5g CMC-Na is weighed, is added in 700mL purified water, makes HA-Na and CMC-Na points at room temperature
It dissipates, be swollen and dissolve, obtain tackifier water solution.220g P407,80g P188 and 10g levocarnitine (LC) are added to
It in above-mentioned tackifier water solution, stirs evenly, is put into 4 DEG C of refrigerators and refrigerates more than for 24 hours, place to room temperature, add 300mL purifying
Water stirs evenly, dissolving levocarnitine to get LC temperature sensing in situ gel rubber (includes the drug of levocarnitine to full dose (1L)
Composition).
Embodiment 5: the preparation of the pharmaceutical composition (LC thermosensitive in-situ gel preparation) comprising levocarnitine.
0.2g HA-Na and 1g CMC-Na is weighed, is added in 700mL purified water, makes HA-Na and CMC-Na points at room temperature
It dissipates, be swollen and dissolve, obtain tackifier water solution.210g P407,35g P188 and 10g levocarnitine (LC) are added to
It in above-mentioned tackifier water solution, stirs evenly, is put into 4 DEG C of refrigerators and refrigerates more than for 24 hours, place to room temperature, add 300mL purifying
Water stirs evenly, dissolving levocarnitine to get LC temperature sensing in situ gel rubber (includes the drug of levocarnitine to full dose (1L)
Composition).
Experimental example 1: the extracorporeal releasing test of levocarnitine temperature sensing in situ gel rubber (LCTISG).
(1) preparation of levocarnitine eye drops (LCED):
Levocarnitine bulk pharmaceutical chemicals 1g is weighed, is added in 0.9% sodium chloride solution 100mL, stirs evenly, it is left to be made 1%
Carnitine eye drops (solution).
(2) preparation of manual simulation's tear (STF):
Sodium chloride 6.789g, calcium chloride dihydrate 0.0849g and potassium chloride 1.389g are weighed, is settled to using purified water
1000mL, oscillation, ultrasound, dissolves total material, and manual simulation's tear is made.
(3) extracorporeal releasing test (Bag filter method):
Precision pipettes each 5mL of LCTISG and LCED, is respectively placed in the bag filter (molecular cut off 3500) pre-processed,
It is sealed with clip at the both ends of bag filter；Bag filter is placed in the STF that 100mL bath temperature is 34 ± 0.5 DEG C, water bath with thermostatic control vibration
The cyclotron frequency for swinging device is set as 100rpm, pipettes respectively in 10,30,60,120,240,360,480,600 and 720min
Bag each 1mL of outer dissolution medium is analysed, and adds equivalent, synthermal STF, the sample of taking-up is crossed after 0.22 μm of miillpore filter through HPLC
Levocarnitine (LC) concentration is measured, Accumulation dissolution is calculated.
(4) test result analysis:
Accumulation dissolution as shown in Figure 1 is the results show that the levocarnitine in temperature sensing in situ gel rubber agent of the present invention substantially may be used
To discharge completely, Accumulation dissolution is substantially suitable with solution.In addition, phase, the rate of release of gelling agent are slightly below before releasing
Solution also embodies the release characteristics of hydrogel.
Experimental example 2: the Corneal trauma test of levocarnitine temperature sensing in situ gel rubber (LCTISG).
(1) the external permeability test of rabbit cornea:
34 DEG C of STF is added into reception tank, the LCED that precision pipettes in LCTISG and experimental example 1 in embodiment 5 is each
300 μ l, are separately added into sample cell, and it is 34 ± 0.5 DEG C that whole device, which is placed in bath temperature, and stirring rotor speed is 100rpm's
It is discharged in transdermal diffusion apparatus, is pipetted in reception tank in 10,30,60,120,240,360,480,600 and 720min respectively
Each 1ml of dissolution medium, and equivalent, synthermal STF are added, the sample of taking-up is crossed after 0.22 μm of miillpore filter and measures LC through HPLC
Concentration calculates accumulative releasing degree.
(2) test result analysis:
Accumulation dissolution as shown in Figure 2 is the results show that the levocarnitine in temperature sensing in situ gel rubber agent of the present invention can be fast
Speed penetrates cornea, and basic expressions are constant release within 200min, are conducive to drug in the constant absorption of ocular, favorably
In raising bioavilability.In addition, the cumulative maximum release of levocarnitine can reach 90% or so.
Experimental example 3: the ocular residence time test of levocarnitine temperature sensing in situ gel rubber (LCTISG).
(1) test method:
Suitable fluorescein sodium is added in the LCTISG into embodiment 5 and the LCED in experimental example 1 respectively, is contained
The LCTISG and LCED of 1% mass concentration fluorescein sodium.Healthy adult male rabbit 3 are taken, weight 2.5kg or so, slit-lamp is aobvious
It checks under micro mirror without eye illness.After rabbit intraperitoneal injection 10% chloraldurate solution (3.2mL/kg weight) is allowed to anesthesia, fixed family
Rabbit head, right and left eyes give 20 μ l drug eye drips respectively, and left eye gives fluorescein sodium LCTISG, and right eye gives fluorescein sodium
LCED makes lagophthalmos passively be closed 10s after administration, start timing, in 1min, 3min, 5min, 10min, 15min, 20min and
The time to be disappeared when 25min with slit lamp observation rabbit cornea surface continuous fluorescence layer, anterior corneal surface continuous fluorescence layer, it is denoted as eye
Portion's residence time.
(2) test result analysis:
It is as shown in Figure 3 the results show that ordinary eye drops disappear from ocular within 3min, and temperature sensitive original of the invention
Apparent fluorescence still can be observed when 20min in position gel, illustrates to be made after situ-gel, substantially prolongs drug in eye
The residence time of table is conducive to the absorption of drug and the performance of drug effect.
Experimental example 4: the foundation and pharmacodynamic test of dry eyes animal model.
(1) foundation of dry eyes corneal epithelial cell model:
Corneal epithelium (HCEC) cell of logarithmic growth phase, with 5 × 104The density of a/ml is inoculated into 96 orifice plates.Cell
After cultivating for 24 hours in the orifice plate, incline original culture medium, is incubated in the cell culture fluid containing 110mM sodium chloride hypertonic solution
For 24 hours, to establish the dry eyes cell model of hypertonic induction.
(2) evaluating drug effect:
The HCEC cell of logarithmic growth phase, with 5 × 104The density of a/mL is inoculated into 96 orifice plates.Cell is in 96 orifice plates
After culture for 24 hours, the cell of the LCTISG/LCED and 110mM sodium chloride hypertonic solution in the embodiment 5 containing various concentration is trained
It is incubated for for 24 hours in nutrient solution in 37 DEG C.Drug effect for 24 hours after, respectively with mtt assay detection cell survival rate (with normal cell culture fluid
The cell of incubation is as normal group, and the cell being incubated for using the hypertonic solution culture solution of sodium chloride containing 110mM is as model group, to contain
The cell that 110mM sodium chloride hypertonic solution and LCTISG/LCED culture solution are incubated for is as experimental group).
Cell survival rate (%) is calculated according to following equation:
Cell survival rate (LCTISG)=(LCTISG handles sample well-zeroing hole)/(the normal hole-zeroing hole of sample controls)
× 100%
Cell survival rate (LCED)=(LCED handles sample well-zeroing hole)/(the normal hole-zeroing hole of sample controls) ×
100%
Cell survival rate (model group)=(sample controls model hole-zeroing hole)/(the normal hole-zeroing hole of sample controls) ×
100%
Note: the control that cell-free culture fluid apertures (zeroing hole), the normal cell culture fluid without drug-treated are incubated for is thin
Cell hole (the sample controls model of the cell culture fluid incubation of hilum (the normal hole of sample controls), 110mM sodium chloride hypertonic solution
Hole), it is the cell hole (LCTISG handles sample well) of the LCTISG and 110mM sodium chloride hypertonic solution of various concentration processing, different
The cell hole of the LCED and 110mM sodium chloride hypertonic solution processing of concentration (LCED handles sample well).
(3) test result analysis:
Group of cells survival results are as shown in figure 4, compared with model group (M), ordinary eye drops group (LCED) He Benfa
The cell survival rate of bright temperature sensing in situ gel rubber group (LCTISG) is significantly raised, examines through T, P < 0.01, significant difference.It is above-mentioned
As a result illustrate, the damage of the different preparation corneal epithelial cells of levocarnitine all has good protective effect.Meanwhile
The survival rate of LCTISG group is slightly above LCED group, illustrates under Isodose, and temperature sensing in situ gel rubber group of the invention has no effect on
The effect of levocarnitine corneal epithelial cell, and drug itself may be reduced to thin due to the compatibility of gel-type vehicle
The stimulation of born of the same parents is more advantageous to the performance of drug effect.
Claims (10)
1. a kind of pharmaceutical composition comprising levocarnitine, it includes levocarnitine, gel-type vehicle, tackifier and water for pharmaceutical purposes.
2. the pharmaceutical composition according to claim 1 comprising levocarnitine, it is characterised in that:
Described pharmaceutical composition is the temperature sensing in situ gel rubber comprising levocarnitine.
3. the pharmaceutical composition according to claim 1 or 2 comprising levocarnitine, it is characterised in that:
The gel-type vehicle is selected from poloxamer, polysaccharide or derivatives thereof, poly- (methyl) acrylic acid or derivatives thereof, polyethylene glycol
Or derivatives thereof, polylactic acid or derivatives thereof, polyvinylpyrrolidone or derivatives thereof, appointing in polyvinyl alcohol or derivatives thereof
One kind of anticipating or the mixture of its arbitrary proportion；
The tackifier are selected from carboxymethyl cellulose or its salt, hyaluronic acid or its salt, hydroxypropyl methyl cellulose, hydroxypropyl melon
That glue, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, polyethylene glycol, glucan, polyvinylpyrrolidone, poly- second
The mixture of any one or its arbitrary proportion in enol, carbomer；
Any one or its arbitrary proportion of the water for pharmaceutical purposes in purified water, water for injection, sterilized water for injection it is mixed
Close object.
4. the pharmaceutical composition according to claim 1 or 2 comprising levocarnitine, it is characterised in that:
Described pharmaceutical composition also includes osmotic pressure regulator, pH adjusting agent, antioxidant, Osmolyte regulator, electrolyte, anti-corrosion
The mixture of any one or its arbitrary proportion in agent, cyclodextrin.
5. the pharmaceutical composition according to claim 1 or 2 comprising levocarnitine, it is characterised in that:
Every 100mL described pharmaceutical composition includes following component: levocarnitine: 1g；Gel-type vehicle: 0~45g, but be not 0；Increase
Stick: 0~1.3g, but be not 0；Surplus is water for pharmaceutical purposes.
6. the pharmaceutical composition according to claim 5 comprising levocarnitine, it is characterised in that:
The gel-type vehicle be poloxamer188 and PLURONICS F87 mixture, wherein the poloxamer188 with it is described
The weight ratio of PLURONICS F87 is 2:1~10:1.
7. the pharmaceutical composition according to claim 5 comprising levocarnitine, it is characterised in that:
The tackifier are the mixture of sodium carboxymethylcellulose and Sodium Hyaluronate, wherein the sodium carboxymethylcellulose and institute
The weight ratio for stating Sodium Hyaluronate is 3:1~8:1.
8. the preparation method of the pharmaceutical composition according to any one of claim 1 to 7 comprising levocarnitine comprising
The following steps:
1) it prepares tackifier water solution: tackifier is added in a part of water for pharmaceutical purposes, make its dispersion at room temperature, be swollen and is molten
Solution, obtains tackifier water solution；
2) it prepares blank temperature sensing in situ gel rubber: gel-type vehicle is added in tackifier water solution obtained in step 1), stir
Uniformly, it is placed 24 hours or more at 4 DEG C, obtains blank temperature sensing in situ gel rubber；
3) preparation carries medicine temperature sensing in situ gel rubber: levocarnitine is added in blank temperature sensing in situ gel rubber obtained in step 2),
It places to room temperature, adds another part water for pharmaceutical purposes to full dose, stir evenly, obtain carrying medicine temperature sensing in situ gel rubber, as include
The pharmaceutical composition of levocarnitine.
9. preparation method according to claim 8, it is characterised in that:
In step 2), gel-type vehicle and levocarnitine are added in tackifier water solution obtained in step 1) simultaneously, stirred
It mixes uniformly, is placed 24 hours or more at 4 DEG C, placement is added another part water for pharmaceutical purposes to full dose, is stirred evenly to room temperature,
It obtains carrying medicine temperature sensing in situ gel rubber, as includes the pharmaceutical composition of levocarnitine.
10. the pharmaceutical composition according to any one of claim 1 to 7 comprising levocarnitine is in preparation for preventing
With/xerophthalmia is treated, the purposes in the drug of especially first hair style xerophthalmia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811534006.1A CN109528628B (en) | 2018-12-14 | 2018-12-14 | Medicinal composition containing levocarnitine and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811534006.1A CN109528628B (en) | 2018-12-14 | 2018-12-14 | Medicinal composition containing levocarnitine and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109528628A true CN109528628A (en) | 2019-03-29 |
| CN109528628B CN109528628B (en) | 2022-02-08 |
Family
ID=65856127
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811534006.1A Active CN109528628B (en) | 2018-12-14 | 2018-12-14 | Medicinal composition containing levocarnitine and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109528628B (en) |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1377706A (en) * | 2002-04-22 | 2002-11-06 | 沈阳药科大学 | Ocular in-situ gel preparatino with proper phase conversion temperature |
| CN1964695A (en) * | 2003-03-28 | 2007-05-16 | 隆萨股份有限公司 | Topical l-carnitine compositions |
| CN101534794A (en) * | 2006-12-22 | 2009-09-16 | 希格马托制药工业公司 | Gel useful for the delivery of ophthalmic drugs |
| CN102018655A (en) * | 2009-09-17 | 2011-04-20 | 中国科学院理化技术研究所 | Transdermal medicament delivery combined preparation |
| WO2012019083A2 (en) * | 2010-08-06 | 2012-02-09 | Microchips, Inc. | Biosensor membrane composition, biosensor, and methods for making same |
| CN102697755A (en) * | 2012-06-15 | 2012-10-03 | 华东理工大学 | Novel levo-carnitine hydrogel patch and preparation method thereof |
| CN103458892A (en) * | 2010-12-09 | 2013-12-18 | 希格马托制药工业公司 | Composition for topical use for treating skin disorders |
| CN104706764A (en) * | 2015-03-24 | 2015-06-17 | 宁波高新区零零七工业设计有限公司 | Hydrogel patch and preparation method thereof |
| WO2016120796A1 (en) * | 2015-01-27 | 2016-08-04 | Professional Dietetics S.P.A. | Compositions comprising a) chitosan, b) glycolic acid, c) carnitine and/or n-acetyl cysteine for the dermal-epidermal peeling treatment |
| CN106237374A (en) * | 2016-08-17 | 2016-12-21 | 林春梅 | A kind of medical antibacterial aerogel dressing and preparation method thereof |
-
2018
- 2018-12-14 CN CN201811534006.1A patent/CN109528628B/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1377706A (en) * | 2002-04-22 | 2002-11-06 | 沈阳药科大学 | Ocular in-situ gel preparatino with proper phase conversion temperature |
| CN1964695A (en) * | 2003-03-28 | 2007-05-16 | 隆萨股份有限公司 | Topical l-carnitine compositions |
| CN101534794A (en) * | 2006-12-22 | 2009-09-16 | 希格马托制药工业公司 | Gel useful for the delivery of ophthalmic drugs |
| CN102018655A (en) * | 2009-09-17 | 2011-04-20 | 中国科学院理化技术研究所 | Transdermal medicament delivery combined preparation |
| WO2012019083A2 (en) * | 2010-08-06 | 2012-02-09 | Microchips, Inc. | Biosensor membrane composition, biosensor, and methods for making same |
| CN103458892A (en) * | 2010-12-09 | 2013-12-18 | 希格马托制药工业公司 | Composition for topical use for treating skin disorders |
| CN102697755A (en) * | 2012-06-15 | 2012-10-03 | 华东理工大学 | Novel levo-carnitine hydrogel patch and preparation method thereof |
| WO2016120796A1 (en) * | 2015-01-27 | 2016-08-04 | Professional Dietetics S.P.A. | Compositions comprising a) chitosan, b) glycolic acid, c) carnitine and/or n-acetyl cysteine for the dermal-epidermal peeling treatment |
| CN104706764A (en) * | 2015-03-24 | 2015-06-17 | 宁波高新区零零七工业设计有限公司 | Hydrogel patch and preparation method thereof |
| CN106237374A (en) * | 2016-08-17 | 2016-12-21 | 林春梅 | A kind of medical antibacterial aerogel dressing and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| BAORUI MA等: "Topical Delivery of Levocarnitine to the Cornea and Anterior Eye by Thermosensitive in-situ Gel for Dry Eye Disease", 《DRUG DESIGN, DEVELOPMENT AND THERAPY》 * |
| 敖惠等: "原位凝胶在中药靶向制剂中的研究进展", 《中国药师》 * |
| 黄平情等: "左卡尼汀温敏原位凝胶的制备及质量评价", 《药学学报》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109528628B (en) | 2022-02-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102811610B (en) | Nonirritant ophthalmology PVP-I composition | |
| US5888493A (en) | Ophthalmic aqueous gel formulation and related methods | |
| US5516808A (en) | Topical cellulose pharmaceutical formulation | |
| KR20090091769A (en) | Gel useful for the delivery of ophthalmic drugs | |
| Alase | Sustained ophthalmic delivery of gatifloxacin from in situ gelling system | |
| Tagami et al. | Lyophilized ophthalmologic patches as novel corneal drug formulations using a semi-solid extrusion 3D printer | |
| WO2011018800A2 (en) | A novel in-situ gel forming solution for ocular drug delivery | |
| CN105106107B (en) | A kind of Bendalysine eye gellan gum in-situ gel and preparation method thereof | |
| CN102066402B (en) | Peptide derivative and composition for promoting tear secretion comprising the same | |
| JPH0723325B2 (en) | Ophthalmic formulation | |
| ES2307754T3 (en) | PHARMACEUTICAL COMPOSITION BASED ON AZALIDOS FOR LOCAL APPLICATION IN OPHTHALMOLOGY. | |
| CN100362989C (en) | Ophthalmic composition containing N-acetyl-cysteine for treatment of dry-eye syndrome | |
| EP0517160A1 (en) | Extended-release ophthalmic preparations | |
| CN110090294A (en) | Ophthalmic composition with improved dry-run protection and reservation | |
| CN100562340C (en) | A kind of micro-emulsion type artificial tear | |
| CN1883469B (en) | An ocular microemulsion containing Vitamin A and Vitamin E and preparation method thereof | |
| CN105943500B (en) | A kind of antimycotic solution of ophthalmically acceptable nano-micelle containing Chinese mugwort Saperconazole | |
| CN106963730A (en) | Highly stable nepafenac medical composite for eye | |
| Gupta et al. | Enhancement of anti-glaucoma potential by novel ocular drug delivery system | |
| CN109528628A (en) | A kind of Pharmaceutical composition and its preparation method and application comprising levocarnitine | |
| KR102603837B1 (en) | Compositions providing improved eye comfort | |
| Simroth‐Loch et al. | Ophthalmic dosage forms | |
| CN105213418A (en) | Preoperative compound eye drops of a kind of ophthalmology and preparation method thereof | |
| CN109200016A (en) | A kind of Benzydalysine eye drop and preparation method thereof and purposes | |
| CN103860466A (en) | Loteprednol nano-micelle eyedrop |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |