CN112107561B - Medicinal preparation containing chitosan, medicinal transdermal patch and preparation method thereof - Google Patents

Medicinal preparation containing chitosan, medicinal transdermal patch and preparation method thereof Download PDF

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CN112107561B
CN112107561B CN202011191501.4A CN202011191501A CN112107561B CN 112107561 B CN112107561 B CN 112107561B CN 202011191501 A CN202011191501 A CN 202011191501A CN 112107561 B CN112107561 B CN 112107561B
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transdermal
transdermal patch
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CN112107561A (en
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全丹毅
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Nanjing Demeng Biotechnology Co ltd
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Jiangsu Yiquan Pharmaceutical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
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  • Psychiatry (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Medicinal Preparation (AREA)
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Abstract

The invention relates to the field of medicines, in particular to a pharmaceutical preparation, a pharmaceutical transdermal patch containing the pharmaceutical preparation and a preparation method thereof. The drug preparation comprises a coated drug and an uncoated drug, the coated drug comprises a drug A and an inclusion material for coating the drug A, and the inclusion material contains chitosan and/or derivatives thereof; the non-encapsulated drug is drug B; the drug A is the same as or different from the drug B. The medicine preparation and the medicine transdermal patch can release effective dose of medicine for a long time (up to 7 days) and stably, and have stronger controllability so as to meet the medicine requirements of patients with different degrees.

Description

Medicinal preparation containing chitosan, medicinal transdermal patch and preparation method thereof
Technical Field
The invention relates to the field of medicines, in particular to a pharmaceutical preparation, a pharmaceutical transdermal patch containing the pharmaceutical preparation and a preparation method thereof.
Background
The external treatment method is a common clinical mode, is mostly in the form of Chinese herbal medicine plaster in the early stage, is used for applying to acupuncture points or injuring local parts to achieve the treatment effect, and has the advantages of simple and easy operation and high patient acceptance.
In addition, for the traditional western medicines which mostly adopt an oral administration or injection mode, a transdermal patch is also appeared in recent years to replace the oral administration or injection mode, and the mode can be continuously delivered into a human body, so that the action time of the medicine is prolonged, and the acceptance of a patient can be increased. However, the release of effective dose of drug through the stratum corneum of the skin is still difficult, and the permeation dose, stability and duration are not ideal. In this regard, the prior art has been largely investigated in the direction of finding more suitable absorption promoters and additives. However, the existing transdermal patches still have difficulty in achieving effective release with a long duration (up to 5-7 days), and new absorption enhancers may pose new risks to the human body.
Therefore, it is very important to develop a new transdermal patch of a drug which is safer to human body and can be released stably for a long time.
Disclosure of Invention
The present invention aims at overcoming the problems in the prior art and providing a medicine preparation, a medicine transdermal patch containing the medicine preparation and a preparation method of the medicine transdermal patch. The medicine preparation and the medicine transdermal patch can release effective dose of medicine for a long time (up to 7 days) and stably, and have stronger controllability so as to meet the medicine requirements of patients with different degrees.
The invention provides a pharmaceutical preparation, which comprises a wrapped type medicament and an unwrapped type medicament, wherein the wrapped type medicament comprises a medicament A and an inclusion material wrapping the medicament A, and the inclusion material contains chitosan and/or derivatives thereof; the non-encapsulated drug is drug B; the drug A is the same as or different from the drug B.
In the present invention, the drug a and the drug B may be the same or different. When identical, the term "drug a" and the term "drug B" are used only to distinguish different states of wrapped and unwrapped.
The inventor of the present invention finds that by wrapping part of the drug, the speed, concentration and duration of the drug release can be effectively adjusted; when the medicine A is the same as the medicine B, the comprehensive performance of good controllability, durability and effectiveness can be realized; when the drug A is different from the drug B, the mutual cooperation of the drug effects can be realized by utilizing the time difference of the drug effects of the drug A and the drug B, and the method has important significance in clinical application.
In the present invention, the ratio of the encapsulated drug to the unencapsulated drug can be set according to the specific dosage form and the requirement for the release period.
According to one embodiment of the present invention, when the pharmaceutical preparation is in the form of a transdermal patch and is released for 1 to 7 days, the weight ratio of the drug a to the drug B is preferably (0.1 to 10): 1, preferably (0.1-5): 1; specifically, the method comprises the following steps:
when a release period of 1 to 3 days is desired, preferably, the weight ratio of the drug a to the drug B is preferably (0.1 to 0.8): 1;
when a release period of 3 to 5 days is required, preferably, the weight ratio of the drug a to the drug B is (0.5 to 2): 1;
when a release period of 6 to 7 days is desired, preferably, the weight ratio of the drug a to the drug B is (1 to 5): 1.
through the above specific embodiments, the present invention can make the transdermal patch containing the drug preparation controllably and stably release for a set number of days by adjusting the ratio of the drug A to the drug B; although the above-mentioned days are exemplified as 7 days, the stable release can be achieved for a longer period of time in this embodiment of the present invention, but it is usually preferably set to 3 to 7 days in consideration of some skin irritation reaction caused by a long period of time.
In the present invention, said drug a and said drug B are the same or different and are selected according to the specific clinical situation and treatment regimen, in most clinical situations said drug a and said drug B are the same. The specific selection of the drug a and the drug B is not particularly limited, for example, the drug a and the drug B are each independently selected from one or more of hypnotic sedatives, anxiolytics, antidepressants, analgesic anesthetics, neurodegenerative drugs, preferably, the drug a and the drug B are each independently selected from one or more of escitalopram, lorazepam, alprazolam, and olanzapine; most preferably olanzapine, and thus can exert a better synergistic effect with the inclusion material of the invention.
In the present invention, the drug A and the drug B may be present in various therapeutically effective forms or derivatives thereof known to those skilled in the art to be suitable for the respective dosage forms. For example, when used in a transdermal patch, the drug a and the drug B may be the free acids or the free bases of the respective drugs. The free acid or free base is obtained commercially or may be prepared in a manner conventional in the art.
According to one embodiment of the present invention, when the pharmaceutical preparation is in the form of a transdermal patch and is released for 1 to 7 days, the weight ratio of the drug A to the inclusion material is preferably 1: (0.5-10), preferably 1: (1-6); specifically, the method comprises the following steps:
when the desired release period is 1 to 3 days, preferably the weight ratio of drug a to the inclusion material is 1: (0.8-2.5), more preferably 1: (1-2);
when the desired release period is 3-5 days, preferably the weight ratio of drug a to the inclusion material is 1: (1.5-4), more preferably 1: (1.8-2.5);
when the desired release period is 6-7 days, preferably the weight ratio of drug a to the inclusion material is 1: (2-6), more preferably 1: (2.2-3.5).
Through the specific implementation mode, the invention can further improve the release stability and controllability of the transdermal patch containing the drug preparation by further matching the proportion of the drug A and the inclusion material.
The inventors of the present invention have found that an inclusion material containing chitosan can exert a good effect of slowly releasing a drug encapsulated therein in a pharmaceutical preparation, particularly when used in a transdermal patch. Preferably, the inclusion material comprises chitosan and/or a derivative thereof in an amount of 51 to 100 wt%, more preferably 70 to 100 wt%, and still more preferably 90 to 100 wt%.
In the present invention, the chitosan is a concept that is conventional in the art, i.e., a compound having a structure represented by formula (1),
Figure BDA0002752921060000041
preferably, the chitosan or derivative thereof has a molecular weight of 1 to 50 ten thousand, more preferably 10 to 25 ten thousand. The molecular weight of the chitosan is more preferably 15 to 20 ten thousand.
In the present invention, the derivative of chitosan is a derivative in various forms recognized in the art, for example, a derivative obtained by functional group modification, graft modification, crosslinking modification, and the like.
Preferably, the derivative of chitosan is a derivative obtained by modifying a functional group, for example, a derivative obtained by acylation, alkylation, etherification, esterification, or oxidation.
More preferably, the derivative of chitosan is modified by acylation. Preferably, the chitosan derivative obtained by the acylation modification has a structure shown in formula (1'),
Figure BDA0002752921060000042
wherein, in the substitution site represented by the formula (1'), one or more of X1 to X8 is/are OCOR1Substituted, R1The structures at different positions are the same or different and are selected from saturated alkyl groups of C1-C4; one or more of X9-X11 is NHCOR2Substituted, R2The structures at different positions are the same or different and are selected from saturated alkyl groups of C1-C4.
More preferably, the acylation degree of the chitosan derivative obtained by the acylation modification is 0.8 to 2.4, more preferably 1 to 2.
According to the specific embodiment of the invention, the chitosan derivative obtained by acylation modification is shown as a formula (2), a formula (3) or a formula (4),
Figure BDA0002752921060000051
according to a particular embodiment of the invention, the inclusion material comprises chitosan and does not comprise the chitosan derivative.
According to another embodiment of the invention, the inclusion material comprises the chitosan derivative and does not comprise chitosan.
According to still another embodiment of the present invention, the inclusion material comprises the chitosan and the chitosan derivative.
In this case, preferably, the weight ratio of the chitosan to the chitosan derivative is 1: (0.2-1.5), more preferably 1: (0.3-0.8).
The inclusion material of the encapsulated medicament has good biocompatibility with skin, is adhered with stratum corneum to form an occlusion effect, improves the bioavailability of insoluble medicaments, can reduce the irritation of the medicament to the skin and reduce adverse reactions.
Preferably, the average particle size of the encapsulated drug is 1 to 1000nm, more preferably 20 to 500 nm. In the present invention, the average particle diameter of the particles is measured by a malvern laser particle sizer (malvern, Mastersizer 3000).
In the invention, the wrapped type medicine is not strictly limited to a core-shell structure, and the term "wrapping" is not limited to a form of "the medicine A is in the center, and the inclusion material forms a spherical shell on the outer layer"; rather, all references to "particles formed by the inclusion material together with drug A" are intended to be within the scope of the invention, both in terms of "entrapped" and "entrapped drug".
Through the technical scheme of wrapping by the inclusion material, the medicinal preparation disclosed by the invention can realize the following performances: the permeability of the drug is increased, the sustained and controlled release effect is realized, the stability of the drug is enhanced, the toxic and side effect is reduced, and a more proper oil-water distribution coefficient is realized.
The encapsulated drug can be obtained by various conventional encapsulation and granulation methods, for example, the encapsulated drug can be prepared by one or more of emulsion crosslinking, freeze drying and spray drying.
According to a specific embodiment of the present invention, the encapsulated drug is prepared by a freeze-drying method. Preferably, the freeze-drying method comprises: adding the drug A, the chitosan and/or the derivative thereof (and possible auxiliary materials which are conventional in the field) into a solvent, fully mixing, and then freeze-drying to obtain the encapsulated drug.
According to a specific embodiment of the present invention, the encapsulated drug is prepared by a spray drying method. Preferably, the spray drying method comprises: adding the drug A, the chitosan and/or the derivative thereof (and possible auxiliary materials which are conventional in the field) into a solvent, fully mixing, and then spray-drying to obtain the encapsulated drug.
According to a specific embodiment of the invention, the encapsulated drug is prepared by an emulsion crosslinking method. Preferably, the emulsion crosslinking method comprises: adding the aqueous solution containing the drug A and the chitosan and/or the derivatives thereof into an oil phase containing an emulsifier, carrying out ultrasonic treatment to form a W/O type emulsion, then adding a cross-linking agent to carry out chemical cross-linking, centrifuging, taking out the precipitate, and drying to obtain the encapsulated drug.
The method can obtain the encapsulated drug with better effect, and the inventor of the invention finds that the emulsion crosslinking method can obtain the encapsulated drug with better effect.
Preferably, the emulsifier is present in the oil phase in an amount of 1 to 10% by weight.
Preferably, the emulsifier is selected from one or more of poloxamers (including but not limited to poloxamer 188, poloxamer 407, poloxamer 182, poloxamer 908, poloxamer 85), lecithin, soy lecithin, sodium cholate, sodium deoxycholate, sodium taurocholate, sodium lauryl sulfate, polyvinyl alcohol (e.g., polyvinyl alcohol 124), tweens (e.g., tween 80), polyethylene glycols (e.g., polyethylene glycol 400), brij, and mazel, and synthetic phospholipids, including but not limited to: egg yolk lecithin (EPC), sphingomyelin (ESM), soybean lecithin (Soy PC), hydrogenated soybean lecithin (HSPC), Distearoylphosphatidylcholine (DSPC), Dioleoylphosphatidylcholine (DOPC), Dimyristoylphosphatidylcholine (DMPC), palmitoylphosphatidylcholine (POPC), egg yolk phosphatidylglycerol (EPG), Distearoylphosphatidylglycerol (DSPG), Dipalmitoylphosphatidylglycerol (DPPG), Dimyristoylphosphatidylglycerol (DMPG), and phosphatidylethanolamine (mPEG-DSPE).
Preferably, the organic solvent in the oil phase is selected from one or more of liquid paraffin, toluene and petroleum ether.
Preferably, the water-oil weight ratio of the aqueous solution to the oil phase is 1: (5-20), more preferably 1: (10-15).
Preferably, the cross-linking agent is formaldehyde and/or glutaraldehyde.
In the present invention, the term "chitosan and/or a derivative thereof" refers to "chitosan" when only chitosan is present, refers to "a derivative of chitosan" when only a derivative of chitosan is present, and refers to "chitosan and a derivative thereof" when both are present, according to the circumstances in the specific embodiment.
In a second aspect, the present invention provides a transdermal drug delivery patch comprising a drug-loaded layer containing the drug formulation according to the first aspect of the present invention.
The drug transdermal patch can be any transdermal patch with various structures and forms in the field, and the drug-loaded layer of the drug transdermal patch contains the drug preparation of the first aspect of the invention, so long as the drug transdermal patch belongs to the protection scope of the invention.
The drug-loaded layer of the present invention may also contain ingredients other than the pharmaceutical formulation, and may be carried out in a manner conventional in the art.
For example, the drug-loaded layer further contains a percutaneous absorption enhancer. Preferably, the percutaneous absorption enhancer is contained in an amount of 50 to 300 parts by weight, more preferably 80 to 250 parts by weight, still more preferably 100 to 250 parts by weight, relative to 100 parts by weight of the sum of the drug A and the drug B.
In the present invention, the transdermal absorption enhancer may be a transdermal absorption enhancer conventionally used in a drug-loaded layer of a transdermal patch in the art, and may be, for example, one or more selected from alcohols, sulfoxides, terpenes, amines, amides, fatty acids and esters, amino acids and esters thereof, and phospholipid compounds; preferably, the percutaneous absorption enhancer is selected from one or more of span 80, tween 80, span 20, oleic acid, menthol, N-methylpyrrolidone and isopropyl myristate.
For example, the drug-loaded layer further comprises a drug-loaded matrix. Preferably, the drug-loaded matrix is contained in an amount of 500-900 parts by weight, more preferably 600-900 parts by weight, relative to 100 parts by weight of the drug preparation.
In the present invention, the drug-loaded matrix may be a drug-loaded matrix conventionally used in drug-loaded layers of transdermal patches in the art, such as a pressure sensitive adhesive, for example, selected from one or more of acrylic adhesives, vinyl acetate adhesives, natural or synthetic rubbers, ethylene-vinyl acetate copolymers, polysiloxanes, polyacrylates, polyurethanes, plasticized polyether block amide copolymers and plasticized styrene-rubber block copolymers.
The pressure-sensitive adhesive used as the drug-carrying matrix can be divided into three types, namely a pressure-sensitive adhesive with a carboxyl functional group, a pressure-sensitive adhesive with a hydroxyl functional group and a pressure-sensitive adhesive without a functional group (the non-functional group means that the pressure-sensitive adhesive does not contain a carboxyl group and/or a hydroxyl functional group), and the three types can be classified according to the properties of the compound per se and can also be obtained by performing functional group modification on the compound. The inventor of the invention finds that when the three types of pressure-sensitive adhesives are used in a specific ratio, the balance of three properties of solubility, release property and stability of the medicine can be further improved, so that the comprehensive performance is improved. Specifically, the inventors of the present invention have found that when a pressure-sensitive adhesive having a carboxyl functional group is used in combination with a pressure-sensitive adhesive having a hydroxyl functional group and/or a pressure-sensitive adhesive having no functional group, the overall performance of the resulting agent can be improved.
According to a preferred embodiment, the drug-loaded matrix is a pressure sensitive adhesive with carboxyl functional groups.
According to another preferred embodiment, the drug-carrying matrix is a combination of a pressure-sensitive adhesive with carboxyl groups and a pressure-sensitive adhesive with hydroxyl groups and/or a pressure-sensitive adhesive without functional groups, preferably, the content of the pressure-sensitive adhesive with carboxyl groups is 50-95 wt%, the content of the pressure-sensitive adhesive with hydroxyl groups is 0-50 wt%, and the content of the pressure-sensitive adhesive without functional groups is 0-50 wt%; more preferably, based on the total weight of the drug-carrying matrix, the content of the pressure-sensitive adhesive with carboxyl functional groups is 60-80 wt%, the content of the pressure-sensitive adhesive with hydroxyl functional groups is 0-40 wt%, and the content of the pressure-sensitive adhesive without functional groups is 0-40 wt%. According to a preferred embodiment, the content of the pressure-sensitive adhesive with carboxyl functional groups is 60-80 wt%, the content of the pressure-sensitive adhesive with hydroxyl functional groups is 5-25 wt%, and the content of the pressure-sensitive adhesive without functional groups is 5-25 wt%, based on the total weight of the drug-carrying matrix.
In the present invention, the drug transdermal patch may have a structure conventional in the art, for example, the drug transdermal patch further includes a protective layer and a backing layer respectively disposed at both sides of the drug-loaded layer.
The material of the protective layer may be a material conventionally used in the art, and according to a preferred embodiment, the protective layer is a release film. The thickness of the protective layer may be as conventional in the art, for example, 0.5 to 10 μm.
The material of the backing layer may be any material conventionally used in the art, and according to a preferred embodiment, the backing layer is polyurethane, polyethylene or EVA. The thickness of the backing layer may be as conventional in the art, e.g. 0.5-10 μm.
The pharmaceutical preparation and the pharmaceutical transdermal patch according to the present invention can realize a suitable transdermal flux that is long-lasting and stable in a small administration area; preferably, the thickness of the drug-loaded layer is 10-300 μm and the administration area of the drug transdermal patch is 3-100cm2(ii) a More preferably, the thickness of the drug-carrying layer is 15-250 μm and the administration area of the drug transdermal patch is 5-80cm2。
The pharmaceutical formulations and transdermal patches of the present invention may also contain other pharmaceutically acceptable materials or additives such as diluents, skin irritation reducing agents, carriers or vehicles, excipients, plasticizers, emollients or other additives and mixtures thereof, provided that such additives do not materially affect the basic and unique characteristics of the principal component.
In a third aspect, the present invention provides a method for preparing the transdermal drug delivery patch of the second aspect, comprising the steps of:
(II1) mixing the pharmaceutical preparation of the first aspect with a percutaneous absorption enhancer and a drug-loaded matrix to obtain a drug-loaded layer material;
(II2) placing the drug-loaded layer material between a protective layer and a backing layer.
In the step (II1), both the encapsulated drug and the unencapsulated drug in the drug preparation are in a free state, so that the drug preparation can be sufficiently mixed with the percutaneous absorption enhancer and uniformly dispersed in the drug-carrying matrix. The encapsulated drug may be obtained by the method described in the first aspect of the invention.
In step (II1), the unencapsulated drug may be dissolved in a solvent and then mixed with the encapsulated drug, the percutaneous absorption enhancer, and the drug-loaded matrix; the solvent may be selected, for example, from one or more of methanol, ethanol, propylene glycol, butylene glycol or n-butanol. The amount of the solvent is preferably 0.5 to 5 times the weight of the unencapsulated drug.
In step (II2), preferably, the drug-loaded layer material is coated on the protective layer and covered with the backing layer after drying, and preferably, the drying conditions include: drying at 60-90 deg.C for 5-30 min; more preferably, the drying conditions include: the drying temperature is 65-75 deg.C, and the drying time is 10-20 min.
The material obtained after covering with the backing layer is punched to obtain the transdermal drug patch of the invention.
Through the technical scheme, compared with the prior art, the invention at least has the following advantages:
(1) the drug transdermal patch of the invention can realize long-term (can reach 5-7 days) continuous administration at a therapeutically effective transdermal permeation rate;
(2) the pharmaceutical preparation and the transdermal patch can realize sustained release of the drug, reduce the absorption rate of the drug entering an organism and further have better treatment effect; the controlled release of the medicine is realized, and the medicine is released outwards at regular time, quantity and uniform speed, so that the blood concentration is constant, and the curative effect is better exerted;
(3) the drug transdermal patch can reduce the drug administration times of a patient and prevent the skin from being damaged due to overlong contact time between the skin and the patch, thereby obviously improving the drug administration compliance of the patient;
(4) the transdermal drug patch adopts a single-layer patch, has simple structure, controllable quality and simple process, and is beneficial to industrial production.
The pharmaceutical preparation and transdermal patch of the present invention can be used for various indications of corresponding drugs.
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
Detailed Description
The present invention will be described in detail below by way of examples. The described embodiments of the invention are only some, but not all embodiments of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Before the present disclosure and description are made, it is to be understood that this invention is not limited to the particular process and materials disclosed herein but, on the contrary, extends to equivalent processes and materials recognized by those skilled in the relevant art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention.
The singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a transdermal penetration enhancer" includes reference to one or more transdermal penetration enhancers and reference to "an adhesive" includes reference to one or more such adhesives.
The term "encapsulation" as used herein means that the drug is physically or chemically bound in one or more materials in a single molecule, multiple molecules, crystalline micronized or amorphous form, such as "encapsulation", "inclusion", "encapsulation", "adsorption", "dispersion", etc., to form a composition, thereby changing the physical or chemical properties of the drug itself.
The term "therapeutically effective" refers to the amount of a drug or the rate of administration required to produce the desired therapeutic result.
The term "bioavailability" as used herein refers to the degree to which an active ingredient or active moiety is absorbed from a pharmaceutical product and becomes available at the site of action. The extent is determined by pharmacokinetic parameters such as the area under the plasma drug concentration-time curve (AUC) of the drug.
An "effective amount" of a drug or osmotic agent refers to a non-toxic but sufficient amount of the compound to provide the desired local or systemic effect. As used herein, an "effective amount" of a permeation enhancer refers to an amount selected to provide a desired increase in membrane permeability and, correspondingly, a desired depth of penetration, rate of administration, and amount of drug.
As used herein, "transdermal" or "transdermal" delivery refers to delivery of a drug by entering and through skin or mucosal tissue. Thus, the terms "transdermal" and "transmucosal" are used interchangeably unless specifically indicated otherwise. Likewise, the terms "skin", "dermis", "epidermis", "mucosa", etc. should be used interchangeably unless otherwise indicated.
The term "component" as used herein refers to an ingredient within the drug-loaded layer, including, but not limited to, drugs, additives, penetration enhancers, stabilizers, dyes, diluents, plasticizers, viscosity increasing agents, pigments, carriers, inert fillers, antioxidants, excipients, gelling agents, anti-irritants, vasoconstrictors, and the like, as defined above.
The terms "matrix", "matrix system" or "matrix patch" are meant to encompass an active osmotic agent or drug dissolved or suspended in a biocompatible polymer phase, preferably a pressure sensitive adhesive, which may also contain other ingredients. This definition includes embodiments where such a polymer phase may be laminated to a pressure sensitive adhesive or used with a coverlay adhesive. The matrix system typically and preferably includes an adhesive layer having an impermeable film backing laminated to its distal surface and a release liner on the proximal surface of the adhesive prior to transdermal application. The film backing protects the polymer phase of the matrix patch and prevents the release of the drug and/or enhancer into the environment. The release liner functions similarly to an impermeable backing, but is removed from the matrix patch prior to application of the patch to the application site. Matrix patches are known in the art of transdermal drug delivery to conventionally comprise such backing and release liner components, and matrix patches according to the present invention should be considered to comprise such backing and release liner or functional equivalents thereof.
As used herein, "application site" refers to a site suitable for topical application, with or without mechanical sustained release devices, e.g., behind the ears, arms, back, chest, abdomen, legs, instep, etc.
The starting materials and reagents not specifically described in the following examples are commercially available standard substances.
The following group a examples illustrate the drug formulations and transdermal patches of the present invention with olanzapine only as an example, and exemplary validation of other drugs will be shown in the subsequent group B examples. The references to "olanzapine" in the following examples and comparative examples refer to olanzapine free base. The drug-loaded matrix used in the following examples is an acrylic adhesive available from Henkel (Bridgewater, New Jersey) under the trademark DURO-TAK, wherein designations 235A and 2852 are carboxyl-group-containing pressure sensitive adhesives, 2287 and 2516 are hydroxyl-group-containing pressure sensitive adhesives, and 4098 is a nonfunctional pressure sensitive adhesive.
Example A1
(1) Preparation of packaged medicine
Dissolving 0.28g of olanzapine in an aqueous solution containing 0.41g of chitosan represented by formula (1) (having a molecular weight of 18 ten thousand) and 0.21g of a chitosan derivative represented by formula (2) (having a molecular weight of 15 ten thousand and an acylation degree of 1) to obtain an aqueous phase; adding the obtained water phase into 15 times of oil phase (containing 0.2g of emulsifier Tween-80 and petroleum ether as the rest, and the same below), performing ultrasonic treatment for 30min to form W/O emulsion, adding cross-linking agent glutaraldehyde for chemical cross-linking, centrifuging, separating, and drying to obtain olanzapine chitosan clathrate with average particle size of 387 nm.
(2) Ingredients
The packaged medicine is as follows: the preparation of the embodiment is carried out;
non-encapsulated drugs: olanzapine, 0.1 g;
percutaneous absorption enhancers: isopropyl myristate 0.57 g;
drug-loaded matrix: 7.17g in total, wherein the pressure-sensitive adhesive (containing carboxyl) with the mark of 2852 is 5.02g, the pressure-sensitive adhesive (containing hydroxyl) with the mark of 2287 is 1.4g, and the pressure-sensitive adhesive (without functional group) with the mark of 4098 is 0.75 g;
solvent: propylene glycol, 0.4 g.
(3) Preparing a pharmaceutical transdermal patch
Mixing and dissolving the non-encapsulated drug prepared in the embodiment with a solvent, fully mixing the non-encapsulated drug with the encapsulated drug, a percutaneous absorption enhancer and a drug-loaded substrate to obtain a drug-loaded layer material, uniformly coating the drug-loaded layer material on a release film (3M, the same below), drying the drug-loaded layer material at 70 ℃ for 15min, then covering the drug-loaded layer material with polyurethane (3M, the same below) as a backing material, and punching the drug-loaded layer material into a patch; the thickness was made 250 μm and the area was made 5cm2The same applies hereinafter.
The resulting patch was designated as a 1.
Example A2
(1) Preparation of packaged medicine
Dissolving 0.25g of olanzapine in an aqueous solution containing 0.46g of chitosan represented by formula (1) (molecular weight: 15 ten thousand) and 0.19g of chitosan derivative represented by formula (3) (molecular weight: 20 ten thousand, acylation degree: 1) to obtain an aqueous phase; and adding the obtained water phase into the oil phase with the weight being 12 times that of the water phase, performing ultrasonic treatment for 30min to form a W/O type emulsion, adding a cross-linking agent glutaraldehyde for chemical cross-linking, performing centrifugal separation on the obtained material, and drying to obtain an olanzapine chitosan wrap with the average particle size of 354 nm.
(2) Ingredients
The packaged medicine is as follows: the preparation of the embodiment is carried out;
non-encapsulated drugs: olanzapine, 0.1 g;
percutaneous absorption enhancers: isopropyl myristate 0.42 g;
drug-loaded matrix: 7.5g in total, wherein the pressure-sensitive adhesive (containing carboxyl) with the mark of 235A is 6.00g, the pressure-sensitive adhesive (containing hydroxyl) with the mark of 2516 is 0.75g, and the pressure-sensitive adhesive (without functional group) with the mark of 4098 is 0.75 g;
solvent: butanediol, 0.3 g.
(3) Preparing a pharmaceutical transdermal patch
The non-encapsulated drug prepared in the embodiment is mixed with a solvent for dissolving, then is fully mixed with the encapsulated drug, a percutaneous absorption enhancer and a drug-loaded matrix to obtain a drug-loaded layer material, is uniformly coated on a release film, is dried for 15min at 70 ℃, is covered by polyurethane serving as a backing material, and is punched into a patch.
The resulting patch was designated as a 2.
Example A3
Dissolving 0.22g of olanzapine in an aqueous solution containing 0.41g of chitosan represented by formula (1) (molecular weight: 20 ten thousand) and 0.25g of chitosan derivative represented by formula (4) (molecular weight: 18 ten thousand, acylation degree: 2) to obtain an aqueous phase; and adding the obtained water phase into the oil phase with the weight being 10 times that of the water phase, performing ultrasonic treatment for 30min to form a W/O type emulsion, adding a cross-linking agent glutaraldehyde for chemical cross-linking, performing centrifugal separation on the obtained material, and drying to obtain an olanzapine chitosan wrap with the average particle size of 436 nm.
(2) Ingredients
The packaged medicine is as follows: the preparation of the embodiment is carried out;
non-encapsulated drugs: olanzapine, 0.1 g;
percutaneous absorption enhancers: span 20, 0.7 g;
drug-loaded matrix: 7.64g in total, wherein the pressure-sensitive adhesive (containing carboxyl) with the mark of 2852 is 4.59g, and the pressure-sensitive adhesive (containing hydroxyl) with the mark of 2516 is 3.06 g;
solvent: n-butanol, 0.5 g.
(3) Preparing a pharmaceutical transdermal patch
The non-encapsulated drug prepared in the embodiment is mixed with a solvent for dissolving, then is fully mixed with the encapsulated drug, a percutaneous absorption enhancer and a drug-loaded matrix to obtain a drug-loaded layer material, is uniformly coated on a release film, is dried for 15min at 70 ℃, is covered by polyurethane serving as a backing material, and is punched into a patch.
The resulting patch was designated as a 3.
Example A4
Reference is made to example A1, except that the chitosan of formula (1) and the chitosan derivative of formula (2) are replaced by the same weight of chitosan of formula (1).
The final patch was designated a 4.
Example A5
Reference was made to example A1, except that the weight ratio of the chitosan of formula (1) and the chitosan derivative of formula (2) was changed while keeping the total weight constant, specifically, the chitosan of formula (1) was 0.21g and the chitosan derivative of formula (2) was 0.41 g.
The final patch was designated a 5.
Example A6
Reference is made to example A1, except that the chitosan derivative of formula (2) is replaced by the same weight of chitosan derivative (formula (1'), the substituent R1And R2Both methyl groups, degree of acylation of 3).
The final patch was designated a 6.
Comparative example AD1
Reference is made to example a1, except that instead of coating drug a, in particular step (1), the weight of unencapsulated olanzapine is adjusted to 0.38g in step (2) in the same amount as used in example 1.
The final patch was designated AD 1.
Comparative example AD2
Reference is made to example A1, except that the inclusion material does not encapsulate or granulate drug A, but is mixed directly. Specifically, the method comprises the following steps:
(1) ingredients
Medicine preparation: olanzapine, 0.38 g;
the chitosan shown in the formula (1) is 041 g;
0.21g of the chitosan derivative represented by the formula (2);
percutaneous absorption enhancers: isopropyl myristate 0.57 g;
drug-loaded matrix: 7.17g in total, wherein the pressure-sensitive adhesive (containing carboxyl) with the mark of 2852 is 5.02g, the pressure-sensitive adhesive (containing hydroxyl) with the mark of 2287 is 1.4g, and the pressure-sensitive adhesive (without functional group) with the mark of 4098 is 0.75 g;
solvent: propylene glycol, 0.4 g.
(3) Preparing a pharmaceutical transdermal patch
Mixing the medicine with solvent, dissolving, mixing with other materials to obtain medicine-carrying layer material, uniformly coating on release film, drying at 70 deg.C for 15min, covering with polyurethane as backing material, and die-cutting into patch.
The resulting patch was designated AD 2.
Test example A
This group of test examples the patches obtained in the above group a examples and comparative examples were each subjected to the following tests:
(1) transdermal flux (ug/cm)2Day)
The adopted external penetration absorption device is a horizontal diffusion pool, the effective area is 1.77 square centimeters, the used skin is the skin of a hair-removed pig, the patch is attached to one side of the horny layer of the skin in the experimental process, one side of the corium layer faces to the receiving pool, the volume of the receiving pool is 7.0ml, continuous magnetic stirring is carried out in the permeation process, the stirring speed is 800rpm, and the temperature of the receiving pool is maintained to be 32 ℃ by using peripheral circulating water bath.
The unit transdermal permeability (ug/cm) per day was measured by high performance liquid chromatography2Day), 10 tests per day were averaged and the results are reported in table 1; and 5-balance mean reduction (equal to (day 1 transdermal transmission-day 5 transdermal transmission) ÷ 5) and 7-balance mean reduction (equal to (day 1 transdermal transmission-day 7 transdermal transmission) ÷ 7) were calculated, the smaller the mean reduction, indicating more stable drug release, indicating greater stability.
TABLE 1
Figure BDA0002752921060000171
Figure BDA0002752921060000181
As can be seen from table 1, the transdermal patch prepared from the pharmaceutical formulation of the present invention can stably release a desired dose of drug, and can last for up to 7 days, with very excellent durability, stability and effectiveness. In contrast, the comparative example using the prior art method released erratic, short duration, and low release.
(2) Stability test
The obtained patches were placed under accelerated conditions (40 ℃. + -. 2 ℃ and RH 75%. + -. 5%) for 6 months, and then the precipitation of the crystal form was observed.
The test finds that: the transdermal patches of AD1 and AD2 showed a significant decrease in sample permeation after accelerated stability testing, with partial crystallization; in contrast, the transdermal patch of the example of the present invention showed no significant change in the permeation amount after the placement, and no partial crystallization was observed.
The following group B examples are presented to illustrate the use of the pharmaceutical formulations and transdermal patches of the present invention with other drugs.
Examples B2-B4 each replaced the agent of example a1 with another agent of the same mass, as shown in table 2.
Test example B
The patches obtained in group B were tested in this group of test examples, and the specific test procedure was performed with reference to test example a. The drugs used hereinafter are all referred to as the free base of the drug.
(1) Transdermal flux (ug/cm)2Day) are shown in table 2.
TABLE 2
Figure BDA0002752921060000191
As can be seen from table 1, the patch of the present invention can also achieve good durability, stability and effectiveness when used with other drugs.
(2) The results of the stability test were:
after the patches obtained above were placed under accelerated conditions (40 ℃ C. + -. 2 ℃ C., RH 75%. + -. 5%) for 6 months, no significant change in the permeation amount was observed, and no partial crystallization was observed.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.

Claims (20)

1. A drug transdermal patch is characterized by comprising a drug-loaded layer, wherein the drug-loaded layer comprises a wrapped drug and an unwrapped drug, the wrapped drug comprises a drug A and an inclusion material wrapping the drug A, and the inclusion material contains chitosan and derivatives thereof; the non-encapsulated drug is drug B; the drug a is the same or different from the drug B;
the chitosan derivative is obtained by acylation modification, and the acylation degree is 0.8-2.4;
the weight ratio of the chitosan to the chitosan derivative is 1: (0.2-1.5).
2. The drug transdermal patch of claim 1, wherein the weight ratio of drug a to drug B is (0.1-10): 1.
3. the drug transdermal patch of claim 2, wherein the weight ratio of drug a to drug B is (0.1-5): 1.
4. the pharmaceutical transdermal patch of claim 1, wherein drug a and drug B are each independently selected from one or more of escitalopram, lorazepam, alprazolam, and olanzapine.
5. The drug transdermal patch of claim 1, wherein the weight ratio of drug a to the inclusion material is 1: (0.5-10).
6. The drug transdermal patch of claim 5, wherein the weight ratio of drug A to the inclusion material is 1: (1-6).
7. The drug transdermal patch of claim 1, wherein the chitosan or derivative thereof has a molecular weight of 1 to 50 ten thousand.
8. The pharmaceutical transdermal patch of any one of claims 1 to 7, wherein when a desired release period of time of 3 to 5 days is reached, the weight ratio of drug A to drug B is (0.5 to 2): 1, and/or the weight ratio of the drug A to the inclusion material is 1: (1.8-2.5);
when the desired release period is 6-7 days, the weight ratio of the drug A to the drug B is (1-5): 1, and/or the weight ratio of the drug A to the inclusion material is 1: (2.2-3.5).
9. The transdermal drug patch of any one of claims 1 to 7, wherein the encapsulated drug is prepared by an emulsion crosslinking method comprising: adding the aqueous solution containing the drug A and the chitosan and/or the derivatives thereof into an oil phase containing an emulsifier, carrying out ultrasonic treatment to form a W/O type emulsion, then adding a cross-linking agent to carry out chemical cross-linking, centrifuging, taking out the precipitate, and drying to obtain the encapsulated drug.
10. The drug transdermal patch of claim 9, wherein the water-oil weight ratio of the aqueous solution and the oil phase is 1: (5-20).
11. The pharmaceutical transdermal patch of claim 9, wherein the cross-linking agent is formaldehyde and/or glutaraldehyde.
12. The drug transdermal patch according to claim 1, wherein the drug-loaded layer further comprises a drug-loaded matrix, and the drug-loaded matrix is contained in an amount of 500-900 parts by weight relative to 100 parts by weight of the drug transdermal patch.
13. The drug transdermal patch according to claim 1, wherein the drug-loaded layer further comprises a drug-loaded matrix, and the drug-loaded matrix is contained in an amount of 600 parts by weight and 900 parts by weight relative to 100 parts by weight of the drug transdermal patch.
14. The transdermal drug delivery patch of claim 12, wherein the drug-loaded matrix is a combination of a pressure-sensitive adhesive with carboxyl functional groups and a pressure-sensitive adhesive with hydroxyl functional groups and/or a pressure-sensitive adhesive without functional groups, and the pressure-sensitive adhesive with carboxyl functional groups accounts for 50-95 wt%, the pressure-sensitive adhesive with hydroxyl functional groups accounts for 0-50 wt%, and the pressure-sensitive adhesive without functional groups accounts for 0-50 wt%, based on the total weight of the drug-loaded matrix.
15. The transdermal drug delivery patch according to claim 12, wherein the pressure sensitive adhesive with carboxyl functional groups is contained in an amount of 60 to 80 wt%, the pressure sensitive adhesive with hydroxyl functional groups is contained in an amount of 5 to 25 wt%, and the pressure sensitive adhesive without functional groups is contained in an amount of 5 to 25 wt%, based on the total weight of the drug-carrying matrix.
16. The pharmaceutical transdermal patch according to claim 1, wherein the drug-carrying layer further comprises a percutaneous absorption enhancer in an amount of 80 to 250 parts by weight relative to 100 parts by weight of the sum of the drug a and the drug B.
17. The transdermal drug patch according to claim 16, wherein the transdermal absorption enhancer is one or more selected from the group consisting of alcohols, sulfoxides, terpenes, amines, amides, fatty acids and esters, amino acids and esters thereof, and phospholipid compounds.
18. The transdermal drug patch of claim 1, wherein the drug-loaded layer has a thickness of 10 to 300 μm and an administration area of 3 to 100cm2。
19. The transdermal drug patch of claim 1, further comprising a protective layer and a backing layer respectively disposed on both sides of the drug-loaded layer, wherein the protective layer is a release film, and the backing layer is polyurethane, polyethylene or EVA.
20. A method of making a pharmaceutical transdermal patch according to any one of claims 1 to 19 comprising the steps of:
(II1) mixing the drug transdermal patch with a percutaneous absorption enhancer and a drug-loaded matrix to obtain a drug-loaded layer material;
(II2) placing the drug-loaded layer material between a protective layer and a backing layer.
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