CN114224822B - Eye sustained-release administration implant and manufacturing method thereof - Google Patents

Eye sustained-release administration implant and manufacturing method thereof Download PDF

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CN114224822B
CN114224822B CN202210107384.1A CN202210107384A CN114224822B CN 114224822 B CN114224822 B CN 114224822B CN 202210107384 A CN202210107384 A CN 202210107384A CN 114224822 B CN114224822 B CN 114224822B
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drug
release
implant
eye
micro
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CN114224822A (en
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孙建国
赵玉瑾
洪佳旭
徐建江
孙兴怀
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Eye and ENT Hospital of Fudan University
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Eye and ENT Hospital of Fudan University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F9/00—Methods or devices for treatment of the eyes; Devices for putting-in contact lenses; Devices to correct squinting; Apparatus to guide the blind; Protective devices for the eyes, carried on the body or in the hand
    • A61F9/0008—Introducing ophthalmic products into the ocular cavity or retaining products therein
    • A61F9/0017—Introducing ophthalmic products into the ocular cavity or retaining products therein implantable in, or in contact with, the eye, e.g. ocular inserts
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • 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
    • A61K9/0051—Ocular inserts, ocular implants
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • 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
    • 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
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/02—Local antiseptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2250/00—Special features of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2250/0058—Additional features; Implant or prostheses properties not otherwise provided for
    • A61F2250/0067—Means for introducing or releasing pharmaceutical products into the body
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides an eye slow-release drug delivery implant and a preparation method thereof, which belong to the technical field of medical equipment, and are arranged in conjunctival sac of human eyes and comprise a drug carrying matrix, a drug and a drug release control film; the medicine carrying matrix is annular and internally comprises a micro-channel and a functional group; the drug is loaded or released through the micro-channel by interaction with the functional group, and the drug release control film is used for maintaining the physical property stability of slow release drug administration implantation and the drug release stability. The eye slow-release administration implant can be directly placed in a conjunctival sac of a human eye, the annular structure of the eye slow-release administration implant can ensure long-term stable storage of the slow-release administration implant, and a patient can automatically replace the eye slow-release administration implant according to own illness conditions, so that the eye slow-release administration implant is simple and convenient. The sustained release implant can be administered to the ocular surface, lacrimal passage and intraocular.

Description

Eye sustained-release administration implant and manufacturing method thereof
Technical Field
The invention relates to the technical field of medical equipment, in particular to an eye sustained-release drug delivery implant and a manufacturing method thereof.
Background
The treatment of eye diseases is mainly carried out by locally dripping eyedrops, however, the bioavailability of the eyedrops is very limited, more than 95% of the medicines can not enter eyes, but flow into lacrimal passages and enter body circulation, and the medicines absorbed by non-target tissues cause certain adverse reactions, so that poorer and worse patient compliance is caused, and only 31-67% of patients can stay for 12 months, so that the treatment effect of the eye diseases is seriously affected. Treatment of ocular disorders, particularly chronic ocular disorders, often eventually enters a circulatory state of constant treatment, and constant recurrence. Thus, both bioavailability and patient compliance of eye drops are in need of improvement.
The eye slow release drug delivery provides a brand new idea for the effective treatment of chronic eye diseases. The sustained release preparation can obviously prolong the acting time of the medicine, reduce the administration times and maintain the stable medicine concentration, thereby not only ensuring the treatment requirement of eye diseases, but also avoiding the accumulated tissue toxicity of large-dose medicine to eyes, obviously reducing adverse reaction and improving the compliance of patients. A large number of researches show that the local slow release administration can well meet the long-term treatment of chronic eye diseases. However, the physiological structure of the eyes is special, the administration mode is limited, and certain supporting conditions are often needed for slow release administration of the eyes, for example, the slow release administration mode based on a corneal contact lens brings inconvenience to patients due to slightly complicated administration systems and administration methods. How to combine the maintenance of drug effectiveness and the convenience of drug administration and construct a convenient and effective eye sustained release drug delivery device is always a research hot spot.
There is currently a ring-shaped ocular surface drug delivery device to be marketed, developed by the company fosigmt vision5inc, us, see for details the patents WO 2014/066775Al, WO 2014/066775Al and WO 2014/16028 A1. The above patent reports a sustained release drug delivery device in which a silicone rubber matrix material is used to support and release the ocular hypotensive drug bemestrene, and a polypropylene core is used to reinforce the annular drug delivery device in order to obtain a suitable strength for ocular implantation. The annular drug delivery device achieves good therapeutic effects, but the annular drug delivery device still has the following defects: 1) The concentration of the released medicine is unstable, and linear release is difficult to realize; 2) The preparation process is complex, and the silicon rubber matrix material and the polypropylene inner core are assembled on the small size, so that the difficulty and the economic cost are high. In previous studies, an ocular surface sustained release drug delivery device was successfully developed and patented, see patent CN201710405482.2 for details. Then, the optimization work of the drug slow release speed and the immediate concentration of the drug is always carried out, and recently, an eye slow release drug delivery implant based on a surface modification technology is successfully developed, the biological safety and the effectiveness of the eye slow release drug delivery implant are fully verified, and the eye slow release drug delivery implant is described in detail in the patent.
Disclosure of Invention
The invention aims to provide an eye slow-release drug delivery implant and a manufacturing method thereof.
The technical scheme of the invention is realized as follows:
the invention provides an eye slow release drug delivery implant which is arranged in conjunctival sac of human eye and comprises a drug carrying matrix, a drug and a drug release control film; the medicine carrying matrix is annular and internally comprises a micro-channel and a functional group; the drug is loaded or released through the micro-channel by interaction with the functional group, and the drug release control film is used for maintaining the physical property stability of slow release drug administration implantation and the drug release stability.
As a further improvement of the present invention, the drug-carrying matrix material is an elastic thermosetting material, preferably a silicone rubber material, and the types thereof may be MED-4810, MED-4840, MED-4842, MEDl-4855, MED-4860, MED-4870, MED-4880, or a mixture thereof, with proper mechanical strength and elasticity being the best choice. The interior of the material contains a plurality of micro-channels and functional groups; the micro-channels and functional groups are prepared by surface modification technology. The micro-channels in the drug-carrying matrix and the surface are mutually communicated and allow substances to pass through in a molecular state, including the diffusion of water molecules into the matrix of the sustained release drug-delivery implant and the diffusion and discharge of drug molecules; the microchannel size and the type of surface functional groups depend on the physicochemical properties of the drug loaded and the dosing requirements; the physicochemical properties of the drug include molecular weight, water solubility, charge and permeability, etc., and for drug molecules with large molecular weight, poor water solubility, no charge and poor permeability, the micro-channels are required to be slightly larger, otherwise, the micro-channels are required to be slightly smaller.
As a further improvement of the invention, the cross section of the drug-carrying matrix material is round, fan-shaped, drop-shaped or drop-like; the water drop shape is a convex shape formed by surrounding a plurality of semi-circles and a triangle or a trapezoid, and two ends of the semi-circles are connected with two sides of the triangle or two waist sides of the trapezoid; the non-circular cross-section facilitates retention of the annular structure of the ocular sustained release delivery implant by mechanical features. The structure of the sustained release drug delivery implant is maintained to be reinforced by three aspects, namely, the geometric reinforcement is embodied as a certain cross section (similar to H-shaped steel or C-shaped steel mechanical reinforcement mechanism), the mechanical property of the drug-carrying matrix is enhanced to form a composite force through the stress difference of an inner ring and an outer ring, and the inner ring bears the force and the outer ring bears the tensile force; secondly, the filling expansion comes from the materials, and after the loose drug-carrying matrix material is loaded with the drug, the internal micropores are filled, so that the mechanical property of the drug-carrying matrix can be enhanced; thirdly, the drug loading of the drug-loading matrix material is completed at room temperature, when the drug-loading matrix material is implanted into a body, the temperature rises, the internal stress can be increased, and the macroscopic mechanical property can be enhanced. The structural reinforcement of the drug-carrying matrix material is an integral structure from microscopic to macroscopic, where the drug has the function of a reinforcing agent.
As a further improvement of the present invention, the functional groups include, but are not limited to, hydroxyl, carboxyl, amino, tartaric, malic, citric, etc., and the functional groups are selected to facilitate loading and sustained release of the drug of interest.
As a further improvement of the present invention, the drug release control film is a thermosetting material, or a thermoplastic material; the thermosetting material is polymethyl methacrylate, polyhydroxyethyl methacrylate, silicone rubber or a mixture thereof; the thermoplastic material is polyethylene, polypropylene, polyurethane, thermoplastic elastomer, or a mixture thereof. Research shows that the drug-carrying matrix can have obvious early burst release and unstable concentration characteristics on drug release; after the drug release control film is added, the drug release stability is greatly improved, because the drug release control film has constant diffusion resistance and can restrict the loaded drug from being released at a more constant speed; can stabilize early burst release, overcome the problem of insufficient release of the drug in the middle and later stages, and is favorable for maintaining stable drug concentration.
As a further improvement of the invention, the overall diameter of the drug-loaded implant ring structure may be 10-40mm; in particular, the overall diameter of the annular structure may be 20-30mm; more particularly, the annular structure may have a diameter of 22-25mm.
As a further improvement of the present invention, the sustained release ocular implant is obtained by loading the drug into a sustained release carrier by electrostatic adsorption and/or solvent evaporation forced loading.
As a further improvement of the present invention, the drug loaded by the slow release carrier may be at least one of the following drugs:
(1) Anti-glaucoma drug: beta-adrenergic receptor blockers (beta-receptor blockers) such as levobunolol (levobunolol), betaxolol (betaxolol), timolol (timolol) and carteolol (carteolol); alpha adrenergic receptor agonists (alpha-adrenoceptor agonists), such as brimonidine (brimonidine); carbonic anhydrase inhibitors (carbonic anhydrase inhibitor), such as brinzolamide and dorzolamide; prostaglandins (prostaglandin) and prostaglandin analogs (prostaglandin analog), such as travoprost, latanoprost (latanoprost), bimatoprost (bimatoprost), and tafluprost (tafluprost).
(2) Ophthalmic antibiotics and anti-inflammatory agents: quinolone antibiotics (quinolones) such as levofloxacin, ciprofloxacin, norfloxacin, ofloxacin, and lomefloxacin; aminoglycoside antibiotics (aminoglycosides) such as neomycin (neomycin), spectinomycin (spinomycin), streptomycin (streptomycin), kanamycin (kanamycin), tobramycin (tobramycin), gentamicin (genetamicin), sisomicin (sisomicin), micronomycin (microomin), amikacin (amikacin), netilmicin (netilimicin); tetracyclines such as tetracyclines (tetracyclines), doxycyclines (doxycyclines), metacyclines (metacyclines), chlortetracycline (chlorotetracyclines), oxytetracyclines (oxytetracyclines), doxycyclines (doxycyclines) and minocyclines (minocyclines); macrolide antibiotics (macrolides antibiotics), such as erythromycin and azithromycin; corticosteroids (corticosteroids) such as dexamethasone (dexamethasone), fluorometholone (fluorometholone), prednisone (prednisone), hydrocortisone (hydrocortisone) and loteprednol; antihistamines (anti-histamines); non-steroidal anti-inflammatory drugs (nonsteroidal anti-inflammatory drugs); non-penetrating steroids (non-pentaingsteroids); free acid sterols (free acid of steroid).
(3) Immunomodulating drugs: tacrolimus (tacrolimus), cyclosporine (cyclosporine a), small molecule integrin antagonists (small-molecule integrin antagonist), integrin antagonists (lifitegrast).
(4) Ophthalmic nutritional medicine: long chain fatty acids (long chain fatty acid), fatty alcohols (fatty alcohols), vitamins (vitamins), fatty acids (fatty acids), cetyl alcohol (cetyl alcohol), stearyl alcohol (stearyl alcohol).
As a further improvement of the invention, the loaded drug accounts for 0.1-30% of the total mass of the ocular sustained-release administration implant; in particular, the loaded drug accounts for 0.2-20% of the total mass of the ocular sustained-release administration implant; more particularly, the loaded drug accounts for 0.5-10% of the total mass of the ocular sustained release drug delivery implant; more particularly, the drug is loaded in an amount of 1-5% of the total mass of the ocular sustained release drug delivery implant.
The invention also provides a manufacturing method of the eye sustained-release drug delivery implant, which comprises the steps of constructing a micro-channel in the drug carrying matrix by a surface modification technology, grafting functional groups on the surface of the micro-channel, loading the drug into the drug carrying matrix by the functional groups, and then preparing a drug release control film on the surface of the drug carrying matrix to obtain the eye sustained-release drug delivery implant.
In the method for manufacturing the eye sustained-release drug delivery implant, the construction of the internal micro-channel is mainly realized by optimizing the internal structure of the matrix material, specifically, the covalent bond of the internal molecular chain of the drug-carrying matrix is partially cut off, and the polymer macromolecules which are cut off and are not firmly combined are extracted, so that the internal molecular chain structure is more loose, and the density of the drug-carrying matrix material is reduced. The method for cutting off the covalent bond of the inner part of the drug-carrying matrix material is a hydrolysis method, specifically an alkali etching method, and the alkali used is specifically sodium hydroxide solution.
In the method for manufacturing the eye sustained release drug delivery implant, the preparation of the functional groups on the surface of the internal micro-channel is completed by the interaction between the molecules containing the functional groups and the micro-channel surface of the drug carrying matrix; wherein the functional group-containing molecule comprises two or more functional groups, wherein at least one of the functional groups is capable of interacting with the drug-loaded matrix microchannel surface, the interaction comprising at least one of electrostatic adsorption, chemical reaction, and hydrogen bonding interaction.
In the preparation method of the eye sustained release drug delivery implant, before the functional group-containing molecule interacts with the surface of the drug-carrying matrix micro-channel, the surface of the drug-carrying matrix micro-channel needs to be subjected to silanization treatment, wherein the silane coupling agent used in the silanization treatment comprises amino silanization coupling agent, carboxyl silanization coupling agent, sulfhydryl silanization coupling agent, vinyl silanization coupling agent, acryl silanization coupling agent, methacryl silanization coupling agent, ethyl acryl silanization coupling agent, methoxy silanization coupling agent, bromopropyl silanization coupling agent, trimethoxy [3- (methylamino) propyl ] silane, diethoxymethyl [ (3-epoxymethoxy) methoxy) propyl ] silane, N- [3- (trimethoxysilyl) propyl ] aniline or a mixture thereof.
In the above method for manufacturing an ocular sustained-release drug delivery implant, one or more of the following drugs may be loaded into the drug-carrying matrix:
(1) Anti-glaucoma drug: beta-adrenergic receptor blockers (beta-receptor blockers) such as levobunolol, betaxolol, timolol, carteolol; alpha adrenergic receptor agonists (alpha-adrenoceptor agonists), such as brimonidine (brimonidine); carbonic anhydrase inhibitors (carbonic anhydrase inhibitor), such as brinzolamide and dorzolamide; prostaglandins (prostaglandin) and prostaglandin analogs (prostaglandin analog), such as travoprost, latanoprost (latanoprost), bimatoprost (bimatoprost), and tafluprost (tafluprost).
(2) Ophthalmic antibiotics and anti-inflammatory agents: quinolone antibiotics (quinolones) such as levofloxacin, ciprofloxacin, norfloxacin, ofloxacin, and lomefloxacin; aminoglycoside antibiotics (aminoglycosides) such as neomycin (neomycin), spectinomycin (spinomycin), streptomycin (streptomycin), kanamycin (kanamycin), tobramycin (tobramycin), gentamicin (genetamicin), sisomicin (sisomicin), micronomycin (microomin), amikacin (amikacin) and netilmicin (netilicin); tetracyclines such as tetracyclines (tetracyclines), doxycyclines (doxycyclines), metacyclines (metacyclines), chlortetracycline (chlorotetracyclines), oxytetracyclines (oxytetracyclines), doxycyclines (doxycyclines) and minocyclines (minocyclines); macrolide antibiotics (macrolides antibiotics), such as erythromycin and azithromycin; corticosteroids (corticosteroids) such as dexamethasone (dexamethasone), fluorometholone (fluorometholone), prednisone (prednisone), hydrocortisone (hydrocortisone) and loteprednol; antihistamines (antihistamines); non-steroidal anti-inflammatory drugs (nonsteroidal anti-inflammatory drugs); non-penetrating steroids (non-penetrating steroid); free acid sterols (free acid of steroid).
(3) Immunomodulating drugs: tacrolimus (tacrolimus), cyclosporine (cycloporine a), small molecule integrin antagonists (small-molecule integrin antagonist), integrin antagonists (lifitegrast).
(4) Ophthalmic nutritional medicine: long chain fatty acids (long chain fatty acid), fatty alcohols (fatty alcohols), vitamins (vitamin), fatty acids (fatty acids), cetyl alcohol (cetyl alcohol), stearyl alcohol (stearyl alcohol).
In the preparation method of the sustained release drug delivery implant, drug loading can be realized by a physical mixing method, an electrostatic adsorption method, a volatile solvent forced loading method and the like.
In the preparation method of the eye slow release drug delivery implant, the solid material is formed by further curing reaction of a monomer or a prepolymer, and the curing reaction can be thermal curing, ultraviolet curing or redox curing. The thermal curing reaction requires a thermal initiator and a heating process, the ultraviolet curing reaction requires ultraviolet initiator and ultraviolet irradiation, the redox curing reaction requires a redox initiator, and a crosslinking agent is added.
The invention has the following beneficial effects: the invention provides an eye sustained-release drug delivery implant which has a good drug sustained-release function, realizes the mechanical reinforcement of an annular structure by means of engineering mechanics principle and cohesive force, stabilizes early burst release of a drug by a drug release control film, improves the release rate of the drug in the middle and later stages, realizes the stable and sustained release of the drug, has the advantages of simple preparation method, wide raw material sources, low cost, realization of high-efficiency and stable drug release, and plays a long-acting release effect.
The eye slow-release administration implant can be directly placed in conjunctival sac of human eyes, the annular structure of the eye slow-release administration implant can ensure long-term stable storage of the slow-release administration implant, and a patient can automatically change the eye slow-release administration implant according to own illness conditions, so that the eye slow-release administration implant is simple and convenient. The sustained release implant can be administered to the ocular surface, lacrimal passage and intraocular.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described, it being obvious that the drawings in the following description are only some embodiments of the invention, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a view of a drop-like unmodified silicone rubber implant;
FIG. 2 is a cross-sectional view of a drop-like unmodified silicone rubber implant;
FIG. 3 is a diagram of a drug-loaded drop-like unmodified silicone rubber implant;
FIG. 4 is a view of a circular cross-section unmodified silicone rubber implant;
FIG. 5 is a view of a silicone rubber implant with a circular cross section without surface modification + drug loading;
FIG. 6 is a drug release profile of a silicone rubber implant of non-surface modified + drug loaded circular cross section;
FIG. 7 is a view of a surface modified silicone rubber implant of circular cross section;
FIG. 8 is a view of a silicone rubber implant with a circular cross-section of surface modified + drug loaded + TPU coating;
FIG. 9 is a method of making a surface modified + drug loaded + TPU coated silicone rubber implant of circular cross section;
FIG. 10 is a drug release profile of a surface modified + drug loaded + TPU (20%) coated silicone rubber implant of circular cross section;
FIG. 11 is a drug release profile of a surface modified + drug loaded + TPU (40%) coated silicone rubber implant of circular cross section;
FIG. 12 is a view of a circular cross-section of an ocular sustained release drug delivery implant at a conjunctival sac implantation site and drug delivery method;
FIG. 13 is a bar graph of in vivo drug concentration and concentration curve for a surface modified + drug loaded + TPU (20%) coated silicone rubber implant of circular cross section;
fig. 14 is a graph showing the short-term and long-term ocular hypotensive effects of a surface modified + drug loaded + TPU (20%) coated silicone rubber implant of circular cross section after implantation in rabbit eye conjunctival sac;
fig. 15 is a photograph of anterior ocular segment and tissue staining after implantation of a surface modified + drug loaded + TPU (20%) coated silicone rubber implant of circular cross section into rabbit eye conjunctival sac.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
The invention provides an eye sustained release drug delivery implant, which comprises a drug carrying matrix, a drug and a drug release control film, wherein the drug carrying matrix is annular, as shown in figure 1. Wherein the medicine carrying matrix is medical grade silicon rubber, the cross section area of the annular medicine carrying matrix is similar to a water drop shape, as shown in figure 2, the medicine is an immunosuppressant cyclosporine (cyclosporine A), the medicine release control film is not arranged temporarily, and the eye slow release medicine administration implant after medicine carrying is shown in figure 3. The external diameter of the eye slow-release drug delivery implant is 23.5mm, the drop-like cross section is formed by surrounding a plurality of semi-circles and an isosceles triangle, two ends of the semi-circle are connected with two sides of the triangle, and two ends of the semi-circle are tangent with two sides of the triangle, so that the natural smooth transition of the surface is formed. Wherein the diameter of the multi-semicircle is 1mm (the physical measurement is 0.93 mm), the length of the triangle extension structure is 1.5 times of the diameter of the cross section multi-semicircle, namely the total length of the cross section is 2mm (the physical measurement is 1.95 mm); the proportion of cyclosporine content in the total mass of the ocular sustained-release administration implant is 2.5%. In the preparation method of the eye sustained release drug delivery implant, the drug cyclosporine is loaded in a silicone rubber drug carrier matrix through a dichloromethane dissolution-immersion-volatilization method.
Example 2
The invention provides an eye slow release drug delivery implant, which comprises a drug carrying matrix, a drug and a drug release control film, wherein the drug carrying matrix is annular, the drug carrying matrix is medical grade silicon rubber, as shown in figure 4, wherein A is a macroscopic view photo; b is a section microscopic photograph; c is a surface scanning electron microscope photograph; d is a section scanning electron microscope photo; the annular medicine carrying matrix has circular cross section as shown in fig. 4A, and the side and cross section are shown in fig. 4B, 4C and 4D. The drug release control film is temporarily not provided. The medicine is brimonidine (brimonidine) which is an anti-glaucoma medicine, and the pictures of the front, the side and the section of the medicine carrying matrix after medicine carrying are shown in figure 5, wherein A is a macroscopic view picture; b is a section microscopic photograph; c is a surface scanning electron microscope photograph; d is a section scanning electron microscope photo. The external diameter of the eye slow release administration implant is 20.5mm, and the diameter of the circular section is 1.2mm; in the preparation method of the eye sustained-release administration implant, the carried drug brimonidine is loaded in a silicon rubber drug-carrying matrix by a dichloromethane dissolution-immersion-solvent volatilization method, and the content of brimonidine accounts for 0.85 percent of the total mass of the eye sustained-release administration implant; the drug release curve of the prepared ocular sustained-release drug delivery implant is shown in fig. 6, wherein A is an accumulated drug release curve, B is an instant drug concentration curve, and as shown in fig. 6A, the release of brimonidine from the ocular sustained-release drug delivery implant shows obvious burst effect, 32.1% is released at 1 hour, and 43.2% is released at 1 day; the late drug release was very slow, giving a total release of 62.5% over 35 days; and maintains a low immediate drug concentration (-12 μg/mL), as shown in figure 6B.
Example 3
The invention provides an eye sustained release drug delivery implant which comprises a drug carrying matrix, a drug and a drug release control film, wherein the drug carrying matrix is annular, the drug carrying matrix is medical-grade silicon rubber, the cross section of the annular drug carrying matrix is circular, as shown in fig. 4A, and the side surface and the section of the annular drug carrying matrix are shown in fig. 4B-4D. The interior of the silicon rubber drug-carrying matrix comprises a micro-channel and a functional group, wherein the micro-channel is realized by the alkaline catalytic hydrolysis of an internal O-Si-O bond of a sodium hydroxide solution, the amino silanization coupling agent is adopted to functionally modify the micro-channel in the silicon rubber drug-carrying matrix, and the photos of the front side, the side and the cross section of the surface modified drug-carrying matrix are shown in fig. 7, wherein A is a macroscopic view photo; b is a section microscopic photograph; c is a surface scanning electron microscope photograph; d is a section scanning electron microscope photo. The drug is brimonidine (brimonidine) which is an anti-glaucoma drug, a drug release control film is arranged on the surface of a drug-carrying matrix after drug carrying, the drug release control film is composed of thermoplastic elastomer (TPU), and the front, side and section photographs of the eye slow release drug administration implant after covering the drug release control film are shown in figure 8, wherein A is a macroscopic view photograph of the drug-carrying; b is a section microscopic photograph; c is a surface scanning electron microscope photograph; d is a section scanning electron microscope photo. The external diameter of the eye slow release administration implant is 22.5mm, and the diameter of the circular section is 1.5mm (the physical measurement is 1.53 mm). The preparation method of the eye sustained-release administration implant is shown in figure 9, the carried drug brimonidine is loaded in the silicon rubber drug-carrying matrix by a methylene dichloride dissolution-soaking-solvent volatilization method, and the content of brimonidine is 1.5 percent of the total mass of the eye sustained-release administration implant; the drug release control film is realized by soaking the drug-carrying matrix after drug carrying in tetrahydrofuran solution of TPU, then naturally airing, soaking again, and repeating for 4 times, wherein the concentration of TPU in the tetrahydrofuran solution of TPU is 20%. The drug release profile of the prepared ocular sustained release drug delivery implant is shown in fig. 10, wherein a is the cumulative drug release profile and B is the immediate drug concentration profile. Referring to fig. 10A, the surface modified + TPU coated silicone-loaded matrix was better able to inhibit early burst release with 1.1% release at 1 hour, 12.3% release at 1 day, 76.9% release at 14 days, and 93.2% cumulative release at 35 days, compared to the brimonidine ocular slow release drug delivery implant loaded in the non-surface modified silicone-loaded matrix; and maintain a high immediate drug concentration (-100 μg/mL), as shown in figure 10B.
Example 4
This example is substantially similar to example 3, and the sample characteristics are similar, except that the TPU concentration in the tetrahydrofuran solution of TPU is 40%, the outer diameter of the ocular slow release delivery implant is 24.5mm, the diameter of the circular cross section is 1.7mm, and the ratio of the brimonidine content to the total mass of the ocular slow release delivery implant is 4.3%. The drug release profile of the prepared ocular sustained release drug delivery implant is shown in fig. 11, wherein a is the cumulative drug release profile; b is an immediate drug concentration profile. As shown in fig. 11A, the early burst release of the brimonidine eye sustained release implant of the coated 40% TPU was further suppressed compared to the brimonidine eye sustained release implant of the coated 20% TPU, which released only 1.1% at 1 hour, 9.1% at 1 day, 55.5% at 14 days, and 65.1% cumulatively over 35 days; but its immediate drug concentration was only-70 μg/mL (as shown in figure 11B).
Example 5
This example is substantially similar to example 3, and the sample characteristics are similar, except that the ocular slow release drug delivery implant has an outer diameter of 22.5mm, a circular cross-sectional diameter of 1.6mm, and the ratio of brimonidine content to the total mass of the ocular slow release drug delivery implant is 2.3%. Drug release profiles of the prepared ocular release delivery implants are shown in fig. 10A and 10B. After the eye slow release administration implant is implanted into conjunctival sac of rabbit eye (shown in fig. 12, wherein (A) is a schematic diagram of the implantation position of conjunctival sac, (B) is a schematic diagram of drug delivery method), the concentration of brimonidine in aqueous humor of anterior chamber of eye is shown in fig. 13, wherein A is a histogram of in vivo drug concentration; b is a concentration curve, and eye drops are used as a control under the same conditions. As shown in fig. 13A, the eye sustained release implant significantly reduced the peak drug concentration (58.0 ng/mL vs.1040.2 ng/mL) at the initial stage of administration (1 hour), maintained a higher drug concentration (39.0 ng/mL vs.1.6 ng/mL) at 24 hours, and maintained a higher drug concentration (28.1-5.9 ng/mL) at 48 hours until day 8, which was above the effective drug concentration (2.9 ng/mL) as compared to commercial eye drops containing the same amount of drug. The above drug release profile is more clearly shown in fig. 13B, where about 5 hours is a critical point, before which the aqueous drug concentration of the eye drop group is higher than that of the eye slow release drug delivery implant group, after which the aqueous drug concentration of the eye slow release drug delivery implant group is significantly higher than that of the eye drop group. After the ocular slow-release administration implant is implanted into the ocular conjunctival sac, the ocular pressure of the rabbit eye can be obviously reduced; compared with the same dose of eye drops, the eye sustained release administration implant can maintain low intraocular pressure for a longer time (21 days vs.6 hours, 84 times, fig. 14 (a) is short term, and (B) is long term, and eye drops are used as a control and blank control is used as an intraocular pressure reference line under the same conditions). During implantation (28 day period), as shown in fig. 15, wherein a is a photograph of anterior ocular segment after rabbit eye and B is a photograph of histopathology; ocular sustained release administration implants did not cause significant inflammatory responses and adverse events (fig. 15A); after 28 days, rabbits were sacrificed and eyeballs were stained, and the pathological results showed (fig. 15B), that the ocular sustained-release administration implant did not cause significant inflammatory response, and had good biocompatibility.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.

Claims (10)

1. An eye slow release drug delivery implant which is arranged in conjunctival sac of human eye, and is characterized by comprising a drug carrying matrix, a drug and a drug release control film; the medicine carrying matrix is annular and internally comprises a micro-channel and a functional group; the drug is loaded or released through the micro-channel by interaction with the functional group, and the drug release control film is used for maintaining the physical property stability of slow release drug administration implantation and the drug release stability;
the drug-carrying matrix is silicon rubber, the functional group is at least one of hydroxyl, carboxyl, amino, tartaric acid group, malic acid group and citric acid group, and the drug release control film is a thermoplastic elastomer;
the preparation method of the eye sustained release administration implant comprises the following steps:
a micro-channel is constructed in the drug-carrying matrix by a surface modification technology, functional groups are grafted on the surface of the micro-channel, drugs are loaded in the drug-carrying matrix by the functional groups, and then a drug release control film is prepared on the surface of the drug-carrying matrix, so that the eye sustained-release drug-carrying implant is obtained;
the surface modification technology is an alkali etching method, and the grafting of functional groups on the surface of the micro-channel is completed through the interaction between molecules containing the functional groups and the surface of the micro-channel of the drug-carrying matrix; wherein the functional group-containing molecule comprises two or more functional groups, wherein at least one of the functional groups is capable of interacting with the drug-loaded matrix microchannel surface, the interaction comprising at least one of electrostatic adsorption, chemical reaction, and hydrogen bonding interaction; before the interaction between the molecule containing the functional group and the surface of the drug-carrying matrix micro-channel, the surface of the drug-carrying matrix micro-channel is subjected to silanization treatment.
2. The ocular slow release drug delivery implant of claim 1, wherein the silicone rubber is selected from at least one of MED-4810, MED-4840, MED-4842, MED-4855, MED-4860, MED-4810, MED-4880.
3. The ocular sustained-release drug delivery implant of claim 1, wherein the drug-carrying matrix is one of circular, fan-shaped, drop-like in cross section; the drop-like shape is a convex shape surrounded by a plurality of semi-circles and a triangle or a trapezoid, and two ends of the semi-circles are connected with two sides of the triangle or two waist sides of the trapezoid.
4. A method for preparing an ocular sustained-release drug delivery implant according to any one of claims 1 to 3, wherein a microchannel is constructed in a drug-carrying matrix by a surface modification technology, functional groups are grafted on the surface of the microchannel, a drug is loaded in the drug-carrying matrix by virtue of the functional groups, and then a drug release control film is prepared on the surface of the drug-carrying matrix to obtain the ocular sustained-release drug delivery implant; the surface modification technology is an alkali etching method, and the grafting of functional groups on the surface of the micro-channel is completed through the interaction between molecules containing the functional groups and the surface of the micro-channel of the drug-carrying matrix; wherein the functional group-containing molecule comprises two or more functional groups, wherein at least one of the functional groups is capable of interacting with the drug-loaded matrix microchannel surface, the interaction comprising at least one of electrostatic adsorption, chemical reaction, and hydrogen bonding interaction; before the interaction between the molecule containing the functional group and the surface of the drug-carrying matrix micro-channel, the surface of the drug-carrying matrix micro-channel is subjected to silanization treatment.
5. The method according to claim 4, wherein the alkali is sodium hydroxide.
6. The method according to claim 4, wherein the silane coupling agent used for the silylation is at least one member selected from the group consisting of an amino silylation coupling agent, a carboxyl silylation coupling agent, a mercapto silylation coupling agent, a vinyl silylation coupling agent, an acryl silylation coupling agent, a methacryl silylation coupling agent, an ethyl acryl silylation coupling agent, a methoxy silylation coupling agent, and a bromopropyl silylation coupling agent.
7. The process according to claim 4, wherein the silane coupling agent used for the silylation treatment is at least one member selected from the group consisting of trimethoxy [3- (methylamino) propyl ] silane, diethoxymethyl [ (3-oxiranylmethoxy) propyl ] silane and N- [3- (trimethoxysilyl) propyl ] aniline.
8. The method of claim 4, wherein the method of loading the drug into the drug-carrying matrix comprises electrostatic adsorption and/or solvent evaporation forced loading, and the content of the drug is 0.1-30wt%.
9. The method of claim 8, wherein the drug is present in an amount of 0.2 to 20wt%.
10. The method of claim 9, wherein the drug is selected from at least one of an anti-glaucoma drug, an ophthalmic antibiotic, an anti-inflammatory drug, an immunomodulating drug, an ophthalmic nutritional drug.
CN202210107384.1A 2022-01-28 2022-01-28 Eye sustained-release administration implant and manufacturing method thereof Active CN114224822B (en)

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