Pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention provides a pharmaceutical composition as well as a preparation method and application thereof. The pharmaceutical composition provided by the invention utilizes the synergistic effect of the first penetration enhancer and the second penetration enhancer to improve the transdermal rate of AD16. By externally applying the pharmaceutical composition provided by the invention, the compliance of a patient can be improved, and the regularity of medication can be ensured.

Description

Technical Field

[0001] This disclosure relates to the field of pharmaceutical preparations, specifically to a pharmaceutical composition, its preparation method, and its use. Background Technology

[0002] Neurodegenerative diseases are neuronal dysfunctions caused by the loss of neurons and their myelin sheaths. Depending on the affected brain regions, they manifest as motor dysfunction, cognitive decline, and dementia. For example, Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disease clinically characterized by continuously deteriorating cognitive and memory functions, progressive decline in daily living abilities, and various neuropsychiatric symptoms and behavioral disorders. Blocking neuroinflammation is one of the important strategies for improving the course of neurodegenerative diseases. Pyridazine-3-formylpiperazine compounds, such as (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone (AD16), can effectively treat or prevent neurodegenerative diseases as neuroinflammation inhibitors.

[0003] Conventional oral administration often leads to missed doses or discontinuation of medication in patients with neurodegenerative diseases due to the tendency to forget the frequency or dosage. Injection administration can cause pain, resulting in poor patient compliance. Given these drawbacks, topical administration is a better option for patients, preventing them from forgetting the frequency and dosage and improving compliance. However, pyridazine-3-formylpiperazine compounds have poor transdermal penetration. Therefore, there is an urgent need to develop topical compositions suitable for pyridazine-3-formylpiperazine compounds. Summary of the Invention

[0004] To address any of the aforementioned technical problems, this disclosure provides a pharmaceutical composition. The pharmaceutical composition provided by this disclosure utilizes the synergistic effect of a first penetration enhancer and a second penetration enhancer to improve the transdermal permeability of AD16. Topical application of the pharmaceutical composition provided by this disclosure helps improve patient compliance and ensure regular medication use.

[0005] In a first aspect, this disclosure provides a pharmaceutical composition comprising a pharmaceutically active ingredient, a matrix, and a penetration enhancer; wherein, The active pharmaceutical ingredient includes (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone; The penetration enhancer includes a first penetration enhancer and a second penetration enhancer. The first penetration enhancer includes at least one of diethylene glycol monoethyl ether and diethylene glycol monomethyl ether. The second penetration enhancer includes at least one of polyethylene glycol glycerol octanoate and propylene glycol octanoate.

[0006] The pharmaceutical composition disclosed herein utilizes the synergistic effect of a first penetration enhancer and a second penetration enhancer to improve the transdermal permeability of AD16. The synergistic effect of the first penetration enhancer and the second penetration enhancer also contributes to improving the stability of the composition disclosed herein.

[0007] In a second aspect, this disclosure provides a method for preparing a pharmaceutical composition according to the first aspect of this disclosure, comprising mixing raw materials uniformly to obtain a pharmaceutical composition, wherein the raw materials include a pharmaceutical active ingredient, a matrix, a first penetration enhancer and a second penetration enhancer; optionally, the raw materials further include at least one of a crosslinking agent, a humectant, a pH adjuster, a crosslinking regulator, a solvent or a third penetration enhancer; optionally, the raw materials further include at least one of an adhesive or an anti-adhesion agent.

[0008] Thirdly, this disclosure provides a patch comprising a backing layer, a drug storage layer, and an anti-adhesive layer disposed sequentially, wherein the drug storage layer comprises a pharmaceutical composition as described in the first aspect of this disclosure or a pharmaceutical composition prepared according to the preparation method of the second aspect of this disclosure.

[0009] Fourthly, this disclosure provides the use of the pharmaceutical composition of the first aspect of this disclosure and / or the patch of the third aspect of this disclosure in the preparation of a medicament for the prevention, treatment and / or relief of diseases, symptoms and / or disorders; optionally, the diseases, symptoms or disorders include neurodegenerative diseases, psychosis, epilepsy, seizures, stroke and pain; more preferably, neurodegenerative diseases include Alzheimer's disease, Parkinson's disease and cognitive impairment, and the pain includes chronic inflammatory pain.

[0010] It should be understood that the description in this section is not intended to identify key or essential features of the embodiments of this application, nor is it intended to limit the scope of this application. Other features of this application will become readily apparent from the following description. Attached Figure Description

[0011] Figure 1 The chemical structure of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone is shown.

[0012] Figure 2 The images shown are photographs of the prescriptions in Examples 1-2 under a polarizing microscope.

[0013] Figure 3 The images shown are photographs of the prescriptions in Examples 1-3 under a polarizing microscope. Detailed Implementation

[0014] Unless otherwise stated, the terminology used herein has the common meaning understood by one of ordinary skill in the art. It may vary for those skilled in the art depending on the desired properties and effects sought through this application, and each numerical parameter should be interpreted according to the number of significant figures and conventional rounding methods or as understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the experimental procedures in organic chemistry, medicinal chemistry, and biology described herein are well-known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains. Where multiple definitions exist for terms used herein, the definitions in this section shall prevail unless otherwise stated.

[0015] Unless otherwise stated, all figures used in this specification and claims to indicate content, concentration, proportion, weight, particle size, percentage, technical effect, etc., shall in any event be understood to be modified by the terms “about” or “approximately”. Therefore, unless indicated to the contrary, the numerical parameters listed in the following specification and appended claims are approximate values. “About” or “approximately” can be understood to mean a range of plus or minus 10%, 20%, 30%, 40%, or 50% of the indicated values.

[0016] When used in this document, the expression “A and / or B” includes three cases: (1) A; (2) B; and (3) A and B. The expression “A, B and / or C” includes seven cases: (1) A; (2) B; (3) C; (4) A and B; (5) A and C; (6) B and C; and (7) A, B and C. The meanings of similar expressions can be deduced by analogy.

[0017] When used in this document, the terms “including,” “contains,” or “comprising” mean that other elements are not excluded in addition to the elements listed.

[0018] When used herein, the terms “optional” or “optionally” mean that the event or circumstances described below may, but not necessarily, occur, including the circumstances in which the event or circumstances may or may not occur.

[0019] As used in this article, the term "matrix" refers to a carrier that retains the active ingredient of a drug.

[0020] As used herein, the term "crosslinker" refers to a compound that can react with a matrix polymer to form a three-dimensional network structure, which can enable the matrix to achieve more suitable strength.

[0021] As used herein, the term "crosslinking regulator" refers to a substance that can regulate the rate of crosslinking and affect the composition, such as a gel, or the formation of a product.

[0022] As used herein, the term "humectant" refers to a substance used to retain moisture in a composition.

[0023] As used herein, the term "pH adjuster" refers to a substance that can adjust the pH value of a composition.

[0024] As used herein, the term "adhesive" refers to a substance that increases the viscosity of a composition.

[0025] As used herein, the term "anti-stick agent" refers to a substance that increases lubrication and prevents the composition from becoming too sticky.

[0026] Pharmaceutical Composition In a first aspect, this disclosure provides a pharmaceutical composition comprising a pharmaceutically active ingredient, a matrix, and a penetration enhancer; wherein, The active pharmaceutical ingredient includes (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone; The penetration enhancer includes a first penetration enhancer and a second penetration enhancer. The first penetration enhancer includes at least one of diethylene glycol monoethyl ether and diethylene glycol monomethyl ether. The second penetration enhancer includes at least one of polyethylene glycol glycerol octanoate and propylene glycol octanoate.

[0027] The pharmaceutical composition disclosed herein utilizes the synergistic effect of a first penetration enhancer and a second penetration enhancer to improve the transdermal permeability of AD16. The structure of AD16 is as follows: Figure 1 As shown. The synergistic effect of the first and second penetration enhancers also contributes to improving the stability of the compositions disclosed herein.

[0028] In some embodiments, the matrix includes at least one selected from sodium polyacrylate, polyvinyl alcohol, carbomer, and gelatin. In some embodiments, the matrix includes sodium polyacrylate.

[0029] In some embodiments, the first penetration enhancer includes diethylene glycol monoethyl ether.

[0030] In some embodiments, the second penetration enhancer includes polyethylene glycol glycerol octanoate-capric acid.

[0031] In some embodiments, the pharmaceutical composition includes (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone, sodium polyacrylate, diethylene glycol monoethyl ether, and polyethylene glycol glycerol octanoate-decanoate.

[0032] In some embodiments, the compositions of this disclosure are in the form of a paste. In some embodiments, the compositions of this disclosure are in the form of a gel.

[0033] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.01-2 parts of the active pharmaceutical ingredient, 50-90 parts of the matrix, 20-70 parts of a first penetration enhancer, and 20-70 parts of a second penetration enhancer.

[0034] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.05-1.5 parts of the active pharmaceutical ingredient, 60-80 parts of the matrix, 30-60 parts of a first penetration enhancer, and 20-40 parts of a second penetration enhancer.

[0035] In some embodiments, the pharmaceutical composition comprises 0.05 parts, 1 part, 1.5 parts, 2 parts, or any two of the above-mentioned parts by weight, or a value within the range of the composition.

[0036] In some embodiments, the pharmaceutical composition comprises a matrix of 50 parts, 55 parts, 60 parts, 65 parts, 70 parts, 75 parts, 80 parts, 85 parts, or 90 parts, or any two of the above weight parts, or a value within the range of the composition.

[0037] In some embodiments, the pharmaceutical composition includes 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, or 70 parts, or any two of the above weight parts, or a value within the range of the composition.

[0038] In some embodiments, the pharmaceutical composition includes 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, 55 parts, 60 parts, 65 parts, or 70 parts, or any two of the above weight parts, or a value within the range of the composition.

[0039] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 1 part of the active pharmaceutical ingredient, 70 parts of the matrix, 50 parts of a first penetration enhancer, and 30 parts of a second penetration enhancer.

[0040] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 1 part of (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine), 70 parts of sodium polyacrylate, 50 parts of diethylene glycol monoethyl ether, and 30 parts of polyethylene glycol glycerol octanoate.

[0041] In some embodiments, the pharmaceutical composition further includes at least one selected from the group consisting of a crosslinking agent, a humectant, a third penetration enhancer, a pH adjuster, a crosslinking regulator, or a solvent. In some embodiments, the pharmaceutical composition further includes a crosslinking agent, a humectant, a third penetration enhancer, a pH adjuster, a crosslinking regulator, and a solvent.

[0042] In some embodiments, a crosslinking agent may or may not be used, depending on actual needs. In some embodiments, any type of crosslinking agent in the art may be used, depending on the actual situation. In some embodiments, the crosslinking agent includes at least one of aluminum hydroxyl, aluminum chloride, and aluminum hydroxide. In some embodiments, the crosslinking agent is selected from aluminum hydroxyl.

[0043] In some embodiments, a moisturizer may or may not be used, depending on actual needs. In some embodiments, any form of moisturizer in the art may be used, depending on the actual situation. In some embodiments, the moisturizer includes at least one of glycerin, polyethylene glycol, and propylene glycol. In some embodiments, the moisturizer is selected from glycerin.

[0044] In some embodiments, a third penetration enhancer may or may not be used, depending on actual needs. In some embodiments, the third penetration enhancer includes at least one selected from propylene glycol, menthol, laurocapram, isopropyl myristate, and polysorbates. In some embodiments, the third penetration enhancer is selected from propylene glycol.

[0045] In some embodiments, a pH adjuster may or may not be used, depending on actual needs. In some embodiments, a pH adjuster of any form in the art may be used, depending on the actual situation. In some embodiments, the pH adjuster includes at least one selected from L-tartaric acid, citric acid, lactic acid, oleic acid, phosphoric acid, fumaric acid, malic acid, and ethylenediaminetetraacetic acid. In some embodiments, the pH adjuster is selected from L-tartaric acid.

[0046] In some embodiments, a crosslinking regulator may or may not be used, depending on actual needs. In some embodiments, any type of crosslinking regulator in the art may be used, depending on the specific circumstances. In some embodiments, the crosslinking regulator is selected from disodium ethylenediaminetetraacetate.

[0047] In some embodiments, a solvent may or may not be used, depending on actual needs. In some embodiments, any solvent of the art may be used, depending on the specific circumstances. In some embodiments, the solvent includes water. In some embodiments, the solvent is selected from water.

[0048] In some embodiments, the pharmaceutical composition includes (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone, sodium polyacrylate, diethylene glycol monoethyl ether, PEG-glycerol caprylate, aluminum hydroxyl, glycerol, propylene glycol, L-tartaric acid, disodium EDTA, and water.

[0049] In some embodiments, the pharmaceutical composition further includes the following components in parts by weight: 0.5-6 parts of a crosslinking agent, 200-300 parts of a humectant, 20-80 parts of a third penetration enhancer, 10-50 parts of a pH adjuster, 0.5-4 parts of a crosslinking regulator, and 400-650 parts of a solvent.

[0050] In some embodiments, the pharmaceutical composition further includes the following components in parts by weight: 2-4 parts of a crosslinking agent, 220-280 parts of a humectant, 30-70 parts of a third penetration enhancer, 15-35 parts of a pH adjuster, 0.5-2 parts of a crosslinking regulator, and 450-550 parts of a solvent.

[0051] In some embodiments, the pharmaceutical composition further includes 0.5 parts, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 4 parts, 5 parts, 6 parts, or any two of the above weight parts or values ​​within the range of the composition.

[0052] In some embodiments, the pharmaceutical composition further includes 200 parts, 210 parts, 220 parts, 230 parts, 240 parts, 250 parts, 260 parts, 270 parts, 280 parts, 290 parts, 300 parts, or any two of the above-mentioned parts by weight, or values ​​within the range of the composition.

[0053] In some embodiments, the pharmaceutical composition further includes a third penetration enhancer in the form of 20 parts, 30 parts, 40 parts, 50 parts, 60 parts, 70 parts, or 80 parts, or any two of the above-mentioned parts by weight, or a value within the range of the composition.

[0054] In some embodiments, the pharmaceutical composition further includes 10 parts, 20 parts, 30 parts, 40 parts, or 50 parts, or any two of the above-mentioned parts by weight, or a value within the range of the composition.

[0055] In some embodiments, the pharmaceutical composition further includes 0.5 parts, 1 part, 1.5 parts, 2 parts, 2.5 parts, 3 parts, 4 parts, or any two of the above weight parts, or a value within the range of the composition.

[0056] In some embodiments, the pharmaceutical composition further includes 400 parts, 425 parts, 450 parts, 475 parts, 500 parts, 510 parts, 520 parts, 525 parts, 530 parts, 535 parts, 540 parts, 545 parts, 550 parts, 575 parts, 600 parts, 625 parts, 650 parts, or any two of the above parts by weight ranges or values ​​within the range of the composition.

[0057] In some embodiments, the pharmaceutical composition further includes the following components in parts by weight: 2-3 parts of a crosslinking agent, 230 parts of a humectant, 50 parts of a third penetration enhancer, 20 parts of a pH adjuster, 1 part of a crosslinking regulator, and 500-550 parts of a solvent.

[0058] In some embodiments, the pharmaceutical composition further includes at least one of an adhesive or an anti-adhesive.

[0059] Adhesives are beneficial for further improving the transdermal permeability of the active pharmaceutical ingredient of this disclosure. Appropriate viscosity, i.e., the combined use of adhesives and anti-adhesives, helps to further improve the transdermal permeability of the active pharmaceutical ingredient of this disclosure while maintaining good stability.

[0060] In some embodiments, the binder includes at least one selected from cellulose derivatives, chitosan, carbomer, xanthan gum, gelatin, and sodium alginate. In some embodiments, the binder includes at least one selected from sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. In some embodiments, the binder includes sodium carboxymethyl cellulose.

[0061] In some embodiments, the anti-sticking agent includes at least one of talc and titanium dioxide. In some embodiments, the anti-sticking agent includes talc.

[0062] In some embodiments, the pharmaceutical composition further includes sodium carboxymethyl cellulose and talc.

[0063] In some embodiments, the pharmaceutical composition further includes 5-65 parts by weight of a binder. In some embodiments, the pharmaceutical composition further includes 10-30 parts by weight of a binder. In some embodiments, the pharmaceutical composition further includes 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, or 65 parts by weight, or any two of the above-mentioned parts by weight ranges, or values ​​within the range of the composition. In some embodiments, the pharmaceutical composition further includes 10 parts by weight of the binder.

[0064] In some embodiments, the pharmaceutical composition further includes 5-55 parts by weight of an anti-adhesive agent. In some embodiments, the pharmaceutical composition further includes 10-30 parts by weight of an anti-adhesive agent. In some embodiments, the pharmaceutical composition further includes 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, or 55 parts by weight, or any two of the above-mentioned parts by weight ranges, or values ​​within the range of the composition. In some embodiments, the pharmaceutical composition further includes 20 parts by weight of an anti-adhesive agent.

[0065] In some embodiments, the pharmaceutical composition further includes the following components in parts by weight: 10 parts of an adhesive and 20 parts of an anti-adhesive agent.

[0066] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.01-2 parts of the active pharmaceutical ingredient, 50-90 parts of the matrix, 0.5-6 parts of the crosslinking agent, 200-300 parts of the humectant, 20-80 parts of the third penetration enhancer, 20-70 parts of the first penetration enhancer, 20-70 parts of the second penetration enhancer, 10-50 parts of the pH adjuster, 0.5-4 parts of the crosslinking regulator, and 400-650 parts of the solvent.

[0067] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.05-1.5 parts of the active pharmaceutical ingredient, 60-80 parts of the matrix, 30-60 parts of a first penetration enhancer and 20-40 parts of a second penetration enhancer, 2-4 parts of a crosslinking agent, 220-280 parts of a humectant, 30-70 parts of a third penetration enhancer, 15-35 parts of a pH adjuster, 0.5-2 parts of a crosslinking regulator, and 450-550 parts of a solvent.

[0068] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 1 part of the active pharmaceutical ingredient, 70 parts of the matrix, 2-3 parts of the crosslinking agent, 230 parts of the humectant, 50 parts of the third penetration enhancer, 50 parts of the first penetration enhancer, 30 parts of the second penetration enhancer, 20 parts of the pH adjuster, 1 part of the crosslinking regulator, and 500-550 parts of the solvent.

[0069] In some embodiments, the pharmaceutical composition further includes the following components in parts by weight: 2-3 parts of aluminum hydroxyl, 230 parts of glycerol, 50 parts of propylene glycol, 20 parts of L-tartaric acid, 1 part of disodium EDTA, and 500-550 parts of water.

[0070] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.01-2 parts of the active pharmaceutical ingredient, 50-90 parts of the matrix, 0.5-6 parts of the crosslinking agent, 200-300 parts of the humectant, 20-80 parts of the third penetration enhancer, 20-70 parts of the first penetration enhancer, 20-70 parts of the second penetration enhancer, 10-50 parts of the pH adjuster, 0.5-4 parts of the crosslinking regulator, 400-650 parts of the solvent, and 6-65 parts of the binder.

[0071] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.05-1.5 parts of the active pharmaceutical ingredient, 60-80 parts of the matrix, 30-60 parts of a first penetration enhancer and 20-40 parts of a second penetration enhancer, 2-4 parts of a crosslinking agent, 220-280 parts of a humectant, 30-70 parts of a third penetration enhancer, 15-35 parts of a pH adjuster, 0.5-2 parts of a crosslinking regulator, 450-550 parts of a solvent, and 10-30 parts of a binder.

[0072] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 1 part of the active pharmaceutical ingredient, 70 parts of the matrix, 2-3 parts of the crosslinking agent, 230 parts of the humectant, 50 parts of the third penetration enhancer, 50 parts of the first penetration enhancer, 30 parts of the second penetration enhancer, 20 parts of the pH adjuster, 1 part of the crosslinking regulator, 500-550 parts of the solvent, and 10 parts of the binder.

[0073] In some embodiments, the pharmaceutical composition further includes the following components in parts by weight: 2-3 parts of aluminum hydroxyl, 230 parts of glycerol, 50 parts of propylene glycol, 20 parts of L-tartaric acid, 1 part of disodium EDTA, 500-550 parts of water, and 10 parts of sodium carboxymethyl cellulose.

[0074] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.01-2 parts of the active pharmaceutical ingredient, 50-90 parts of the matrix, 0.5-6 parts of the crosslinking agent, 200-300 parts of the humectant, 20-80 parts of the third penetration enhancer, 20-70 parts of the first penetration enhancer, 20-70 parts of the second penetration enhancer, 10-50 parts of the pH adjuster, 0.5-4 parts of the crosslinking regulator, 400-650 parts of the solvent, and 5-55 parts of the anti-adhesion agent.

[0075] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.05-1.5 parts of the active pharmaceutical ingredient, 60-80 parts of the matrix, 30-60 parts of a first penetration enhancer and 20-40 parts of a second penetration enhancer, 2-4 parts of a crosslinking agent, 220-280 parts of a humectant, 30-70 parts of a third penetration enhancer, 15-35 parts of a pH adjuster, 0.5-2 parts of a crosslinking regulator, 450-550 parts of a solvent, and 10-30 parts of an anti-adhesion agent.

[0076] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 1 part of the active pharmaceutical ingredient, 70 parts of the matrix, 2-3 parts of the crosslinking agent, 230 parts of the humectant, 50 parts of the third penetration enhancer, 50 parts of the first penetration enhancer, 30 parts of the second penetration enhancer, 20 parts of the pH adjuster, 1 part of the crosslinking regulator, 500-550 parts of the solvent, and 20 parts of the anti-adhesion agent.

[0077] In some embodiments, the pharmaceutical composition further includes the following components in parts by weight: 2-3 parts of aluminum hydroxyl, 230 parts of glycerol, 50 parts of propylene glycol, 20 parts of L-tartaric acid, 1 part of disodium EDTA, 500-550 parts of water, and 20 parts of talc.

[0078] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.01-2 parts of the active pharmaceutical ingredient, 50-90 parts of the matrix, 0.5-6 parts of the crosslinking agent, 200-300 parts of the humectant, 20-80 parts of the third penetration enhancer, 20-70 parts of the first penetration enhancer, 20-70 parts of the second penetration enhancer, 10-50 parts of the pH adjuster, 0.5-4 parts of the crosslinking regulator, 400-650 parts of the solvent, 5-65 parts of the binder, and 5-55 parts of the anti-sticking agent.

[0079] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 0.05-1.5 parts of the active pharmaceutical ingredient, 60-80 parts of the matrix, 30-60 parts of a first penetration enhancer and 20-40 parts of a second penetration enhancer, 2-4 parts of a crosslinking agent, 220-280 parts of a humectant, 30-70 parts of a third penetration enhancer, 15-35 parts of a pH adjuster, 0.5-2 parts of a crosslinking regulator, 450-550 parts of a solvent, 10-30 parts of a binder, and 10-30 parts of an anti-sticking agent.

[0080] In some embodiments, the pharmaceutical composition comprises the following components in parts by weight: 1 part of the active pharmaceutical ingredient, 70 parts of the matrix, 2-3 parts of the crosslinking agent, 230 parts of the humectant, 50 parts of the third penetration enhancer, 50 parts of the first penetration enhancer, 30 parts of the second penetration enhancer, 20 parts of the pH adjuster, 1 part of the crosslinking regulator, 500-550 parts of the solvent, 10 parts of the binder, and 20 parts of the anti-adhesion agent.

[0081] In some embodiments, the pharmaceutical composition further includes the following components in parts by weight: 2-3 parts of aluminum hydroxyl, 230 parts of glycerol, 50 parts of propylene glycol, 20 parts of L-tartaric acid, 1 part of disodium EDTA, 500-550 parts of water, 10 parts of sodium carboxymethyl cellulose, and 20 parts of talc.

[0082] Preparation method Secondly, this disclosure provides a method for preparing a pharmaceutical composition according to the first aspect of this disclosure, comprising mixing raw materials uniformly to obtain a pharmaceutical composition, wherein the raw materials include a pharmaceutically active ingredient, a matrix, a first penetration enhancer, and a second penetration enhancer. In some embodiments, the raw materials further include at least one selected from a crosslinking agent, a humectant, a pH adjuster, a crosslinking regulator, a solvent, or a third penetration enhancer. In some embodiments, the raw materials further include at least one selected from a binder or an anti-adhesion agent.

[0083] plaster Thirdly, this disclosure provides a patch comprising a backing layer, a drug storage layer, and an anti-adhesive layer disposed sequentially, wherein the drug storage layer comprises a pharmaceutical composition as described in the first aspect of this disclosure or a pharmaceutical composition prepared according to the preparation method of the second aspect of this disclosure.

[0084] In some embodiments, the patch disclosed herein is a gel patch.

[0085] In some implementations, the backing layer comprises a nonwoven fabric.

[0086] In some embodiments, the non-stick layer includes a release film, such as polyethylene terephthalate (PET) film.

[0087] In some embodiments, the method for preparing the plaster disclosed herein includes the following steps: The composition disclosed herein is coated onto a backing layer to form a drug storage layer; an anti-adhesive layer is then laminated onto the drug storage layer to obtain a plaster.

[0088] use Fourthly, this disclosure provides the use of the pharmaceutical compositions of the first aspect of this disclosure and / or the patches of the third aspect of this disclosure in the preparation of medicaments for the prevention, treatment, and / or relief of diseases, symptoms, and / or disorders. In some embodiments, diseases, symptoms, or disorders include neurodegenerative diseases, psychosis, epilepsy, seizures, stroke, and pain. In some embodiments, neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, and cognitive impairment, and pain includes chronic inflammatory pain.

[0089] In some implementations, chronic inflammatory pain includes mechanical pain and thermal pain.

[0090] As used herein, “relief” and “treatment” and their synonyms refer to improvement of a disease, symptom, and / or condition. “Relief” and “treatment” can be an improvement in at least one measurable physical parameter, which is not necessarily identifiable by the patient. “Relief” and “treatment” can also be physical (e.g., stabilizing identifiable symptoms), physiological (e.g., stabilizing physical parameters), or both, suppression of the progression of a disease, symptom, and / or condition. “Relief” and “treatment” can also be the slowing of or reversal of the progression of a disease, symptom, and / or condition.

[0091] When used herein, the term “prevention” means a method implemented to block, reduce, inhibit, prevent and / or delay the occurrence of a disease or condition or symptom (e.g., cancer, metastatic cancer cells, respiratory diseases and symptoms, infections or autoimmune diseases) in a subject, or a method to reduce the incidence of infectious diseases in said subject.

[0092] Treatment Fifthly, this disclosure provides a method for preventing, treating, and / or alleviating diseases, symptoms, and / or disorders, the method comprising administering to a subject in need an effective dose of a pharmaceutical composition of the first aspect of this disclosure and / or a patch of the third aspect of this disclosure.

[0093] As used herein, the term "effective dose" means an amount sufficient to achieve, or at least partially achieve, the desired effect. For example, the term "therapeutic effective dose" means, as used herein, an amount that results in benefit or treatment of a disease compared to a corresponding subject who did not receive that amount, but which is sufficiently low, within the range of reasonable medical judgment, to avoid serious side effects. The therapeutic effective dose of a drug will vary depending on the chosen drug, pharmaceutical composition, combination of drugs, drug conjugates; route of administration; severity of the disease being treated; age, body type, weight, and physical condition of the patient being treated; the patient's medical history; duration of treatment; nature of concurrent treatments; desired therapeutic effect, etc., but can still be determined by those skilled in the art in a conventional manner.

[0094] When used in this document, the term “subject” includes animals such as vertebrates, preferably mammals such as dogs, cats, pigs, cattle, sheep, horses, rodents (e.g., mice, rats, or guinea pigs) or primates (e.g., gorillas, chimpanzees, and humans).

[0095] In some implementations, the disease, symptom, or disorder includes neurodegenerative diseases, psychosis, epilepsy, seizures, stroke, and pain.

[0096] In some implementations, neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, and cognitive impairment, and pain includes chronic inflammatory pain.

[0097] In some implementations, chronic inflammatory pain includes mechanical pain and thermal pain.

[0098] The following description, in conjunction with the accompanying drawings, illustrates exemplary embodiments of this application, including various details of these embodiments to aid understanding. It should be understood that these are merely exemplary and are in no way intended to limit the scope of protection of this application. The scope of protection of this application is defined only by the claims. Therefore, those skilled in the art will recognize that various changes and modifications can be made to the embodiments described herein without departing from the scope of this application. Similarly, for clarity and brevity, descriptions of well-known functions and structures are omitted in the following description.

[0099] Example Unless otherwise specified, the experimental methods used in the following examples are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.

[0100] Materials and Instruments AD16 (Guangzhou Shenyuan Huikang Biomedical Technology Co., Ltd., ENBH240355-011), Sodium polyacrylate (Alpha High-Tech, AG39240601), Caprylic / Capric acid glyceride (Tianrun Pharmaceutical, 190913), Diethylene glycol monoethyl ether (GATTRTOSSE SAS, 190975), Aluminum hydroxyl (Hunan Jiudian Hongyang, TF128230902), Propylene glycol (Weier Pharmaceutical, 20230603), Polarizing microscope (PLM) (Shanghai Changfang, XPV-203E), High performance liquid chromatography (Agilent, Agilent1260), Transdermal diffusion instrument (Hanson Research).

[0101] Example 1: Preparation of the pharmaceutical composition The preparation method is as follows: Weigh out the prescribed amount of AD16, add propylene glycol, diethylene glycol monoethyl ether, caprylic / capric acid, and polyethylene glycol glycerol, and stir. Separately, dissolve sodium polyacrylate and aluminum hydroxyacetate in glycerol and mix with the drug phase. Add sodium carboxymethyl cellulose, talc, tartaric acid, and disodium EDTA to the aqueous phase and mix with the drug phase to obtain the final product.

[0102] The compositions with different formulations are shown in the table below.

[0103]

[0104]

[0105] Example 2: Mixing Uniformity Experiment The above-mentioned drug composition was dispersed in a medium (silicone oil), and the images were observed and recorded using a polarizing microscope (PLM): observation was performed using a 10X eyepiece (or 5X eyepiece) and a 10X objective lens, and the images were recorded using a camera computer system.

[0106] Polarizing microscope images of the compositions formulated in Examples 1-2 are shown below. Figure 2 As shown, polarized light microscope images of the combinations of formulations from Examples 1-3 are as follows. Figure 3 As shown, according to Figure 2 and Figure 3 It can be seen that the drugs were mixed evenly and no precipitation occurred.

[0107] Example 3: Transdermal Transfusion Rate Experiment The methods for detecting the in vitro release content of the composition are shown in the table below.

[0108]

[0109] Table 1: Transdermal permeability of active pharmaceutical ingredients in drug compositions with different component ratios

[0110] According to Table 1, a comparison of Examples 1-1, 1-3, and 1-4 with Comparative Example 1-3 shows that, compared with the use of diethylene glycol monoethyl ether or caprylic / capric acid glyceride alone, the combined use of the two is beneficial to improving the transdermal permeability of the active pharmaceutical ingredient disclosed herein.

[0111] Specifically, in Comparative Example 1, 5g of diethylene glycol monoethyl ether (Transcutol P) was added, and the active pharmaceutical ingredient existed in suspension within the matrix. The in vitro transdermal delivery of the drug exhibited a time lag of approximately 2 hours; the 24-hour in vitro transdermal delivery percentage was 2.41%, and the 24-hour drug release rate was 1.01 ± 0.04 µg / h. In Comparative Example 2, 8g of diethylene glycol monoethyl ether was added, and the 24-hour in vitro transdermal delivery percentage was 4.65%, with a 24-hour drug release rate of 1.94 ± 0.34 µg / h. In Comparative Example 3, 8g of polyethylene glycol glycerol caprylate / capric acid was added, and the 24-hour in vitro transdermal delivery percentage was 8.55%, with a 24-hour drug release rate of 3.56 ± 0.69 µg / h.

[0112] In Example 1-1, 3g of polyethylene glycol glyceride (caprylic / capric acid) was added, which had a synergistic effect with diethylene glycol monoethyl ether (5g), significantly improving the in vitro transdermal rate of the drug. The 24h in vitro transdermal percentage increased to 17.56%, and the 24h drug release rate increased to 7.32±0.92 µg / h. Compared to Comparative Example 1, the addition of 3g of polyethylene glycol glycerol caprylate in Example 1-1 increased the 24-hour in vitro transdermal percentage and drug release rate by 7.3 times; compared to Comparative Example 2 (8g diethylene glycol monoethyl ether), Example 1-1 (5g diethylene glycol monoethyl ether, 3g polyethylene glycol glycerol caprylate) increased the 24-hour in vitro transdermal percentage and drug release rate by 3.8 times; compared to Comparative Example 3 (8g polyethylene glycol glycerol caprylate), Example 1-1 (5g diethylene glycol monoethyl ether, 3g polyethylene glycol glycerol caprylate) increased the 24-hour in vitro transdermal percentage and drug release rate by 2.1 times; the combined use of diethylene glycol monoethyl ether and polyethylene glycol glycerol caprylate is beneficial to improving the transdermal rate and drug release rate of the pharmaceutical composition disclosed herein. Compared to Examples 1-1, the formulations of Examples 1-3 further incorporated sodium carboxymethyl cellulose, further increasing the 24-hour in vitro transdermal penetration rate to 23.67% and the 24-hour drug release rate to 9.86 ± 0.55 µg / h. Compared to Examples 1-1, Examples 1-4 further incorporated sodium carboxymethyl cellulose and talc, further increasing the 24-hour in vitro transdermal penetration rate to 20.26% and the 24-hour drug release rate to 8.44 ± 0.07 µg / h.

[0113] Example 4: Stability Experiment The pharmaceutical compositions of Examples 1-1 to 1-4 and Comparative Examples 1-3 were placed at 25°C for 30 days, while the pharmaceutical compositions of Examples 1-3 to 1-4 were placed at 40°C for 30 days. After the placement period, the properties and related substances of the pharmaceutical compositions were examined.

[0114] The relevant substance detection parameters are shown in the table below.

[0115]

[0116] Table 2: Stability of pharmaceutical compositions with different component ratios

[0117] As shown in the table above, no drug precipitation was observed in any of the pharmaceutical compositions of Examples 1-1 to 1-4 at day 0. The pharmaceutical compositions of Comparative Examples 1 to 3 and Examples 1-1 to 1-4, after being placed at 25°C for 30 days, showed that the related substances increased to 0.26%, 0.16%, 0.24%, 0.16%, 0.22%, 0.35%, and 0.41%, respectively. The pharmaceutical compositions of this disclosure exhibit good stability. Among them, the formulations of Comparative Example 2 and Example 1-1 are relatively more stable, but the drug release rate and transdermal penetration rate of Comparative Example 2 are not good. Comparative Examples 2, 3, 1-3, and 1-4, after being placed at 40°C for 30 days, changed from orange-yellow to yellow (pigment color change), and the related substances increased to 1.1%, 1.7%, 2.52%, and 0.64%, respectively. Compared with Comparative Examples 2, 3, and 1-3, Example 1-4, which added talc, showed better high-temperature stability.

[0118] It should be noted that the above are merely preferred embodiments of this disclosure and are not intended to limit the scope of this disclosure. Various modifications and variations are possible for those skilled in the art. Although specific implementations have been described, alternatives, modifications, variations, improvements, and substantial equivalents of the above implementations may exist or be unforeseeable to the applicant or other persons skilled in the art. Therefore, the appended claims and any possible amendments to the claims are intended to cover all such alternatives, modifications, variations, improvements, and substantial equivalents. Importantly, as technology evolves, many elements described herein can be replaced by equivalent elements that appear after this disclosure.

Claims

1. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises a pharmaceutically active ingredient, a matrix, and a penetration enhancer; wherein... The active pharmaceutical ingredient includes (2-pyrimidinoperazinyl)(4-methyl-6-phenylpyridazine) methyl ketone; The penetration enhancer includes a first penetration enhancer and a second penetration enhancer. The first penetration enhancer includes at least one of diethylene glycol monoethyl ether and diethylene glycol monomethyl ether. The second penetration enhancer includes at least one of polyethylene glycol glycerol caprylate and propylene glycol caprylate.

2. The pharmaceutical composition according to claim 1, characterized in that, The matrix comprises at least one of sodium polyacrylate, polyvinyl alcohol, carbomer, and gelatin; optionally, the matrix comprises sodium polyacrylate; and / or, The first penetration enhancer comprises diethylene glycol monoethyl ether; and / or, The second penetration enhancer includes polyethylene glycol glycerol ester (PEG-C-C).

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, The pharmaceutical composition comprises the following components in parts by weight: 0.01-2 parts of the active pharmaceutical ingredient, 50-90 parts of the matrix, 20-70 parts of the first penetration enhancer and 20-70 parts of the second penetration enhancer; Optionally, the pharmaceutical composition comprises the following components in parts by weight: 0.05-1.5 parts of the active pharmaceutical ingredient, 60-80 parts of the matrix, 30-60 parts of the first penetration enhancer and 20-40 parts of the second penetration enhancer; Alternatively, the pharmaceutical composition comprises the following components in parts by weight: 1 part of the active pharmaceutical ingredient, 70 parts of the matrix, 50 parts of the first penetration enhancer, and 30 parts of the second penetration enhancer.

4. The pharmaceutical composition according to any one of claims 1-3, characterized in that, The pharmaceutical composition further includes at least one of a crosslinking agent, a humectant, a third penetration enhancer, a pH adjuster, a crosslinking regulator, or a solvent.

5. The pharmaceutical composition according to claim 4, characterized in that, The crosslinking agent includes at least one of aluminum hydroxyl, aluminum chloride, and aluminum hydroxide; and / or, The moisturizer includes at least one of glycerin, polyethylene glycol, and propylene glycol; and / or, The third penetration enhancer includes at least one of propylene glycol, menthol, laurocapram, isopropyl myristate, and polysorbates; and / or, The pH adjuster includes at least one selected from L-tartaric acid, citric acid, lactic acid, oleic acid, phosphoric acid, fumaric acid, malic acid, and ethylenediaminetetraacetic acid; and / or, The crosslinking regulator includes at least one of disodium ethylenediaminetetraacetate; and / or, The solvent includes water.

6. The pharmaceutical composition according to claim 4 or 5, characterized in that, The crosslinking agent is selected from aluminum hydroxide; and / or, The humectant is selected from glycerin; and / or, The third penetration enhancer is selected from propylene glycol; and / or, The pH adjuster is selected from L-tartaric acid; and / or, The crosslinking regulator is selected from disodium ethylenediaminetetraacetate; and / or, The solvent is selected from water.

7. The pharmaceutical composition according to any one of claims 4-6, characterized in that, The pharmaceutical composition further comprises the following components in parts by weight: 0.5-6 parts of the crosslinking agent, 200-300 parts of the moisturizer, 20-80 parts of the third penetration enhancer, 10-50 parts of the pH adjuster, 0.5-4 parts of the crosslinking regulator, and 400-650 parts of the solvent; Optionally, the pharmaceutical composition further comprises the following components in parts by weight: 2-4 parts of the crosslinking agent, 220-280 parts of the humectant, 30-70 parts of the third penetration enhancer, 15-35 parts of the pH adjuster, 0.5-2 parts of the crosslinking regulator, and 450-550 parts of the solvent; More preferably, the pharmaceutical composition further comprises the following components in parts by weight: 2-3 parts of the crosslinking agent, 230 parts of the humectant, 50 parts of the third penetration enhancer, 20 parts of the pH adjuster, 1 part of the crosslinking regulator, and 500-550 parts of the solvent.

8. The pharmaceutical composition according to any one of claims 1-7, characterized in that, The pharmaceutical composition further includes at least one of an adhesive or an anti-adhesive.

9. The pharmaceutical composition according to claim 8, characterized in that, The adhesive comprises at least one of cellulose derivatives, chitosan, carbomer, xanthan gum, gelatin, and sodium alginate; optionally, the adhesive comprises at least one of sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose; and / or, The anti-sticking agent includes at least one of talc and titanium dioxide.

10. The pharmaceutical composition according to claim 8 or 9, characterized in that, The pharmaceutical composition further comprises the following components in parts by weight: 5-65 parts of the adhesive, and / or 5-55 parts of the anti-adhesion agent; Optionally, the pharmaceutical composition further includes the following components in parts by weight: 10-30 parts of the adhesive, and / or 10-30 parts of the anti-adhesive; Alternatively, the pharmaceutical composition may further include the following components in parts by weight: 10 parts of the adhesive and / or 20 parts of the anti-adhesive.

11. The pharmaceutical composition according to any one of claims 1-10, characterized in that, The pharmaceutical composition comprises the following components in parts by weight: 0.01-2 parts of the active pharmaceutical ingredient, 50-90 parts of the matrix, 0.5-6 parts of the crosslinking agent, 200-300 parts of the humectant, 20-80 parts of the third penetration enhancer, 20-70 parts of the first penetration enhancer, 20-70 parts of the second penetration enhancer, 10-50 parts of the pH adjuster, 0.5-4 parts of the crosslinking regulator, and 400-650 parts of the solvent; Optionally, the pharmaceutical composition further includes 5-65 parts of the binder; and / or, Optionally, the pharmaceutical composition further includes 5-55 parts of an anti-adhesion agent.

12. A method for preparing the pharmaceutical composition according to any one of claims 1-11, characterized in that, The preparation method includes mixing raw materials uniformly to obtain the pharmaceutical composition, wherein the raw materials include a pharmaceutical active ingredient, a matrix, a first penetration enhancer, and a second penetration enhancer; optionally, the raw materials further include at least one of a crosslinking agent, a humectant, a pH adjuster, a crosslinking regulator, a solvent, or a third penetration enhancer; more preferably, the raw materials further include at least one of an adhesive or an anti-adhesion agent.

13. A plaster, characterized in that, The plaster comprises a backing layer, a drug storage layer, and an anti-adhesion layer arranged sequentially, wherein the drug storage layer comprises a drug composition as described in any one of claims 1-11 or a drug composition prepared by the preparation method according to claim 12.

14. Use of the pharmaceutical composition of any one of claims 1-11 and / or the patch of claim 13 in the preparation of a medicament for the prevention, treatment and / or relief of diseases, symptoms and / or disorders; Optionally, the diseases, symptoms, or disorders include neurodegenerative diseases, psychosis, epilepsy, seizures, stroke, and pain; Alternatively, the neurodegenerative disease includes Alzheimer's disease, Parkinson's disease, and cognitive impairment, and the pain includes chronic inflammatory pain.

Images