Ropinirole transdermal pharmaceutical composition as well as preparation method and application thereof

Abstract

The invention discloses a ropinirole transdermal pharmaceutical composition as well as a preparation method and application thereof, and belongs to the technical field of veterinary drugs. The composition comprises, by weight, 1%-30% of ropinirole or pharmaceutically acceptable salt of ropinirole as an active component, and at least one transdermal promoting solvent, and can be prepared into a transdermal non-aqueous solution, a transdermal ointment, a transdermal gel preparation or a transdermal patch and other dosage forms.

Description

Technical Field

[0001] This invention belongs to the field of veterinary drug technology, specifically relating to a transdermal pharmaceutical composition of ropinirole and its pharmaceutically acceptable salts, as well as a method for preparing the composition and its application. This composition can be formulated into various transdermal dosage forms for inducing vomiting in animals, especially pets (such as dogs and cats), when they have ingested toxic substances or foreign objects. Background Technology

[0002] Ropinirone, a non-ergot alkaloid dopamine receptor agonist, is used in veterinary medicine to induce vomiting in companion animals such as dogs and cats in cases of accidental ingestion of toxic substances or foreign objects. Currently, ropinirone is mainly administered orally in tablets and capsules, but this method has significant limitations. Oral administration is susceptible to the first-pass effect, resulting in low bioavailability, and animal compliance with oral administration is poor, especially in cases of ingestion of foreign objects, making administration difficult for pet owners.

[0003] Transdermal drug delivery systems, as a non-invasive route of administration, offer advantages such as avoiding the first-pass effect, rapid absorption, and convenient administration. Especially in the veterinary field, transdermal formulations can be easily applied to animal skin, avoiding stress reactions caused by oral administration difficulties or injection resistance. However, existing technologies lack highly efficient, stable, and easy-to-use ropinirole transdermal drug compositions. Therefore, developing a ropinirole transdermal drug composition that overcomes these shortcomings is of significant practical importance. Summary of the Invention

[0004] The present invention aims to provide a transdermal pharmaceutical composition of ropinirole and its pharmaceutically acceptable salts, which exhibits high transdermal efficiency, good stability, and broad applicability, and can be formulated into various transdermal dosage forms. Another object of the present invention is to provide a method for preparing this composition, which is simple in process and easy to industrialize. A further object of the present invention is to provide an application of this composition, namely, for the preparation of a drug to induce vomiting in animals, especially pets (such as dogs and cats), in response to the accidental ingestion of toxic substances or foreign objects.

[0005] To achieve the above objectives, the present invention adopts the following technical solution: A ropinirole transdermal pharmaceutical composition comprising ropinirole or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient, and at least one transdermal-enhancing solvent; wherein the active pharmaceutical ingredient comprises 1% to 30% by weight in the composition; and wherein the composition is in the form of a transdermal non-aqueous solution, a transdermal ointment, a transdermal gel, or a transdermal patch.

[0006] Furthermore, when the composition is a transdermal non-aqueous solution, its solvent is selected from one or more of medium-chain glycerides, polyisobutylene, polybutene, propylene glycol diacetate, ethanol, and propylene carbonate.

[0007] Furthermore, when the composition is a transdermal non-aqueous solution, it also contains a co-solvent selected from one or more of methanol, benzyl alcohol, dimethyl sulfoxide, and ethylene glycol.

[0008] Furthermore, the transdermal promoting solvent is selected from one or more of polyethylene glycol 400, ethanol, isopropyl myristate, oleic acid, and azone.

[0009] Furthermore, when the composition is a transdermal non-aqueous solution, it also contains an antioxidant, which is one or both of butylated hydroxyanisole and butylated hydroxytoluene.

[0010] Furthermore, when the composition is a transdermal gel formulation, it also comprises a gel matrix selected from one or more of carbomer, hydroxypropyl cellulose, sodium alginate, and xanthan gum.

[0011] Furthermore, when the composition is a transdermal patch, it also includes a backing layer, a drug reservoir layer, and an adhesive layer; the drug reservoir layer includes ropinirole or a pharmaceutically acceptable salt thereof and a transdermal-enhancing solvent.

[0012] The present invention discloses a method for preparing a ropinirole transdermal pharmaceutical composition. When the composition is a transdermal non-aqueous solution, the method includes the following steps: dissolving ropinirole or its pharmaceutically acceptable salt in a co-solvent, adding it to a mixture containing an appropriate amount of solvent, antioxidant, and transdermal promoting solvent, stirring evenly, and finally adjusting the volume with solvent to obtain the final product.

[0013] Furthermore, when the composition is a transdermal gel formulation, it includes the following steps: dispersing the gel matrix in water, swelling it, adding ropinirole or its pharmaceutically acceptable salt dissolved in a solvent and a transdermal promoting solvent, and stirring until homogeneous; adding a humectant, stirring until homogeneous, and finally adding water to the set total amount to obtain the final product.

[0014] The present invention relates to the use of a ropinirole transdermal pharmaceutical composition in the preparation of a drug for inducing vomiting in animals, wherein the animals are pets, including dogs and cats; the vomiting induction is used in cases where the animals have ingested toxic substances or foreign objects.

[0015] The present invention has the following beneficial effects: Improving transdermal efficiency and bioavailability: Through an optimized combination of various transdermal enhancement solvents, which work synergistically on the stratum corneum, the transdermal rate and permeation of ropinirole or its pharmaceutically acceptable salts are significantly enhanced. In vitro transdermal experiments show that the permeation is increased by more than 30%, thereby improving the bioavailability of the drug and ensuring the full exertion of its efficacy.

[0016] Avoiding the first-pass effect: Transdermal drug delivery allows drugs to enter the bloodstream directly through the skin, avoiding the first-pass effect that occurs when drugs pass through the gastrointestinal tract and liver as with oral administration. This reduces drug degradation and loss, and improves drug utilization efficiency.

[0017] Improving medication compliance: The variety of dosage forms (transdermal non-aqueous solutions, transdermal ointments, transdermal gels, and transdermal patches) caters to the operational needs of different pet owners and the acceptance levels of their pets. Transdermal drug delivery eliminates the need for pets to take oral medication, especially in cases of ingestion of poisons or foreign objects, reducing stress responses in pets and making the drug delivery process more convenient and smooth, thus improving medication compliance in affected animals.

[0018] High stability: The addition of antioxidants to the transdermal non-aqueous solution effectively prevents the oxidative degradation of the drug; the matrix and solvent components selected for each dosage form have good compatibility with the drug, ensuring the stability of the composition during storage and use. Accelerated tests show that after 6 months of storage at 40°C and 75%RH, the drug content decreases by <5%, which meets the stability requirements for veterinary drugs.

[0019] The preparation process is simple: the preparation method of the present invention has few steps, is easy to operate, and does not require complex equipment and process conditions, which is conducive to large-scale industrial production and reduces production costs.

[0020] Low side effects: Compared to oral tablets and capsules, transdermal administration allows for rapid absorption and induces vomiting, avoiding the gastrointestinal irritation and other side effects that may be caused by slow absorption of oral medications, thus improving the safety of medication use. Detailed Implementation

[0022] This invention provides a ropinirole transdermal pharmaceutical composition comprising ropinirole or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient, and at least one transdermal promoting solvent; the active pharmaceutical ingredient constitutes 1% to 30% by weight in the composition; the composition is available in the form of a transdermal non-aqueous solution, a transdermal ointment, a transdermal gel, or a transdermal patch. The active pharmaceutical ingredient, ropinirole or a pharmaceutically acceptable salt thereof, is the core therapeutic component of this composition, acting by binding to dopamine receptors in animals to induce a vomiting response. The 1% to 30% weight percentage range is chosen because concentrations below 1% result in insufficient drug dosage, making it difficult to effectively induce vomiting; while concentrations above 30% may increase the drug's toxic side effects and hinder stable dispersion of the drug in the composition. This concentration range ensures both efficacy and safety.

[0023] Furthermore, when the composition is a transdermal non-aqueous solution, its solvent is selected from one or more of medium-chain glycerides, polyisobutylene, polybutene, propylene glycol diacetate, ethanol, and propylene carbonate.

[0024] Further preferably, the cosolvent for the transdermal non-aqueous solution is selected from one or more of methanol, benzyl alcohol, dimethyl sulfoxide, and ethylene glycol. Cosolvents can increase the solubility of ropinirole or its pharmaceutically acceptable salts in the solvent, ensuring sufficient drug dissolution, preventing drug precipitation, and thus guaranteeing the effective concentration and stability of the drug. For example, benzyl alcohol not only increases drug solubility but also has a certain antibacterial effect, helping to extend the shelf life of the composition.

[0025] Further preferred, the solvent for the transdermal non-aqueous solution is selected from one or more of medium-chain triglycerides, polyisobutylene, polybutene, and propylene carbonate. Its main function is to serve as a dispersion medium for the drug and other components, enabling them to mix uniformly and form a stable solution. Medium-chain triglycerides and other solvents possess good solubility and compatibility, ensuring the complete dissolution of ropinirole or its pharmaceutically acceptable salts, as well as transdermal promoting solvents. Simultaneously, their own properties are stable, making them less prone to reacting with other components, which helps maintain the stability of the composition.

[0026] Furthermore, the transdermal penetration enhancer solvent is selected from one or more of polyethylene glycol 400, ethanol, isopropyl myristate, oleic acid, and azone. More preferably, the transdermal penetration enhancer solvent is selected from one or more of polyethylene glycol 400, isopropyl myristate, oleic acid, and azone. Its function is to enhance the transdermal effect of the drug through multiple mechanisms. For example, polyethylene glycol can alter the lipid structure of the stratum corneum, increase hydration of the stratum corneum, and weaken the skin's barrier function; isopropyl myristate and oleic acid can penetrate into the stratum corneum, dissolve lipids, and widen the channels between skin cells; azone can reduce the surface tension of the stratum corneum and promote the diffusion of drug molecules. These transdermal penetration enhancers work synergistically to significantly increase the rate and amount of ropinirole or its pharmaceutically acceptable salts passing through the skin, thereby improving the bioavailability of the drug.

[0027] Furthermore, when the composition is a transdermal non-aqueous solution, it also contains an antioxidant, which is one or two of butylated hydroxyanisole (BHT), butylated hydroxytoluene (BHT), and di-tert-butyl-p-benzophenol (BHT). Its function is to prevent ropinirole or its pharmaceutically acceptable salts, as well as other components, from oxidation during storage and use, thereby improving the stability of the composition. Butylated hydroxyanisole (BHT) and butylated hydroxytoluene (BHT) can scavenge free radicals, prevent oxidation reactions, and reduce the degradation of the active pharmaceutical ingredient.

[0028] Furthermore, when the composition is a transdermal gel formulation, it also comprises a gel matrix selected from one or more of carbomer, hydroxypropyl cellulose, sodium alginate, and xanthan gum. The gel matrix enables the composition to form a gel-like structure with a certain viscosity and elasticity, facilitating application to the animal skin surface and enabling rapid drug release. Carbomer and similar matrices exhibit good biocompatibility and stability, can mix well with drugs and other components, and the resulting gel has a certain moisturizing property, which is beneficial for drug absorption through the skin.

[0029] Furthermore, when the composition is a transdermal patch, it also includes a backing layer, a drug reservoir layer, and an adhesive layer; the drug reservoir layer contains ropinirole or a pharmaceutically acceptable salt thereof, as well as a transdermal-enhancing solvent. Specifically, the transdermal patch comprises a backing layer, a drug reservoir layer, and an adhesive layer. The backing layer functions to prevent drug leakage from the back of the patch and protect the drug reservoir layer; it is typically made of materials such as polyester film, which has good barrier properties. The drug reservoir layer, containing ropinirole or a pharmaceutically acceptable salt thereof, as well as a transdermal-enhancing solvent, is the source of drug release, enabling continuous and stable release of the drug into the skin. The adhesive layer's function is to fix the patch to the animal's skin surface; it typically uses medical-grade acrylic pressure-sensitive adhesive, which has good adhesion and skin compatibility, preventing the patch from falling off and ensuring continuous drug delivery.

[0030] Furthermore, when the composition is a transdermal non-aqueous solution, it includes the following steps: dissolving ropinirole or its pharmaceutically acceptable salt in a co-solvent, adding it to a mixture containing an appropriate amount of solvent, antioxidant, and transdermal promoting solvent, stirring evenly, and finally adjusting the volume with solvent to obtain the final product.

[0031] Furthermore, when the composition is a transdermal gel formulation, it includes the following steps: dispersing the gel matrix in water, swelling it, adding ropinirole or its pharmaceutically acceptable salt dissolved in a solvent and a transdermal promoting solvent, stirring until homogeneous, adding a humectant, stirring until homogeneous, and finally adding solvent to the set total amount to obtain the final product.

[0032] In this invention, the ropinirole transdermal pharmaceutical composition is used in the preparation of a drug for inducing vomiting in animals, wherein the animals are pets, including dogs and cats; the vomiting induction is used in cases where the animals have ingested toxic substances or foreign objects.

[0033] In this invention, the active pharmaceutical ingredient ropinirole or its pharmaceutically acceptable salt is the basis for its vomiting-inducing effect, while the transdermal promoting solvent helps it cross the skin barrier and improves bioavailability. In transdermal non-aqueous formulations, the solvent provides a dispersion environment for each component, the solubilizer increases the drug's solubility, and the antioxidant ensures the drug's stability in this environment. The synergistic effect of these four components enables the transdermal non-aqueous formulation to function stably and effectively. In transdermal gel formulations, the gel matrix encapsulates the drug, transdermal promoting solvent, and other components, forming a gel form that is easy to use. At the same time, the properties of the gel matrix synergistically work with the transdermal promoting solvent to ensure both rapid drug release and promote transdermal absorption. In transdermal patches, the backing layer, drug reservoir layer, and adhesive layer work together. The backing layer protects the drug, the drug reservoir layer provides the drug and absorption-promoting components, and the adhesive layer ensures close contact between the patch and the skin, enabling continuous and stable transdermal absorption of the drug.

[0034] In this invention, the preparation of the transdermal non-aqueous solution is as follows: Ropinirole or its pharmaceutically acceptable salt is first added to a mixture containing a solubilizer, followed by a mixture containing an appropriate amount of solvent, antioxidant, and transdermal promoting solvent. The mixture is stirred until homogeneous, and finally the solvent is added. The mixture is stirred until homogeneous again and then brought to the set total volume. The solution is then dispensed. For example, to prepare 100g of the transdermal non-aqueous solution containing 5g ropinirole hydrochloride, 20g benzyl alcohol, 5g oleic acid, 5g azone, 0.5g butylated hydroxytoluene, and the remainder being medium-chain triglycerides, 5g ropinirole hydrochloride is first completely dissolved in 20g benzyl alcohol. This solution is then added to a mixture of 5g oleic acid, 5g azone, 0.5g butylated hydroxytoluene, and 30g medium-chain triglycerides. The mixture is stirred until homogeneous, and finally the medium-chain triglycerides are added to a final volume of 100g. The mixture is stirred until homogeneous.

[0035] In this invention, the preparation of the transdermal gel formulation is as follows: according to the formula amount, the gel matrix is ​​dispersed in an appropriate amount of water and left to swell fully for a period of time; at the same time, ropinirole or its pharmaceutically acceptable salt is dissolved in a solvent, and a transdermal promoting solvent is added and stirred evenly; the above drug mixture is added to the swollen gel matrix and stirred evenly; then the humectant propylene glycol is added and stirred evenly; finally, the solvent is added to the set total amount to obtain the final product. For example, to prepare a 100g transdermal gel formulation containing 10.0g ropinirole hydrochloride, 0.5g carbomer 940, 5.0g propylene glycol, 10.0g PEG400, and 3.0g azone, with water added to a final volume of 100.0g, first disperse 0.5g carbomer 940 in an appropriate amount of water until it swells. Then add 10.0g ropinirole hydrochloride dissolved in water and stir until homogeneous. Next, add 10g PEG400 and 3.0g azone and stir until homogeneous. Finally, add 5.0g propylene glycol and stir until homogeneous. The final volume of water is 100.0g, and the mixture is stirred until homogeneous.

[0036] The transdermal ointment is prepared by mixing an appropriate amount of transdermal promoting solvent and an oily matrix (such as petrolatum) and heating to melt. Then, ropinirole or its pharmaceutically acceptable salt is added after dissolution. The mixture is stirred evenly and cooled to room temperature.

[0037] The transdermal patch is prepared by dissolving ropinirole or its pharmaceutically acceptable salt in a mixture containing a transdermal penetration enhancer, adding a matrix material (such as ethylene-vinyl acetate copolymer), and stirring until homogeneous to form a drug reservoir layer material. This material is then coated onto a backing layer, dried, and an adhesive layer material (such as medical acrylic pressure-sensitive adhesive) is applied to its surface. After drying, the patch is cut into patches of the required size. For example, to prepare a transdermal patch containing 8.0g of ropinirole, where the drug reservoir layer also contains 10g of isopropyl myristate, 20g of benzyl alcohol, and an appropriate amount of ethylene-vinyl acetate copolymer, 8.0g of ropinirole is dissolved in a mixture of 10g of isopropyl myristate and 20g of benzyl alcohol. An appropriate amount of ethylene-vinyl acetate copolymer is added, stirred until homogeneous, coated onto a polyester film backing layer, dried, coated with medical acrylic pressure-sensitive adhesive as an adhesive layer, and then cut to obtain the patch.

[0038] The present invention will be described in detail below through embodiments, but the present invention is not limited to these embodiments.

[0039] Example 1: Preparation of Ropiniron transdermal non-aqueous solution formula: ropinirole: 5g Ethyl acetate: 20g Oleic acid: 5g Azone: 5g Butylated hydroxytoluene (antioxidant): 0.5g Medium-chain triglycerides: Add to 100g Preparation method: Add ropinirole hydrochloride to benzyl alcohol and stir until completely dissolved; add it to a mixture of 5g oleic acid, 5g azone, 0.5g butylated hydroxytoluene and 30g medium-chain triglycerides, stir evenly, and finally add medium-chain triglycerides to 100g, continue stirring evenly, and use blow-fill-seal (BSF) technology to dispense into plastic packaging to obtain transdermal non-aqueous solution.

[0040] Example 2: Preparation of Ropiniron transdermal gel formula: Ropinirone hydrochloride: 10.0g Carbomer 940: 0.5g Propylene glycol: 5.0g PEG400: 10.0g Azone: 3.0g Water: Add to 100.0g Preparation method: Disperse carbomer 940 in an appropriate amount of water and let it swell; dissolve ropinirole hydrochloride in water and add it to the swollen gel, and stir evenly; add PEG400 and azone to it and stir evenly; add propylene glycol and stir evenly; finally add water to 100.0g to obtain the final product.

[0041] Example 3: Preparation of Ropinirole Transdermal Patch Formulation (drug storage layer): Ropinirole: 8.0g Isopropyl myristate: 10.0g Benzyl alcohol: 20.0g Azone: 3.0g Antioxidant: Di-tert-butyl-p-benzophenol (BHT) 0.5g Ethylene-vinyl acetate copolymer (EVA): Appropriate amount (as matrix) Backing layer: Polyester film Adhesion layer: Medical-grade acrylic pressure-sensitive adhesive Preparation method: Dissolve ropinirole in benzyl alcohol, add it to a mixed solvent containing isopropyl myristate and ethyl bHT, add ethylene-vinyl acetate copolymer, and stir until uniform; coat the mixture onto a polyester film backing layer and dry; coat the dried drug reservoir layer surface with medical acrylic pressure-sensitive adhesive as an adhesion layer, and cut it into patches of the required size after drying.

[0042] Example 4: Preparation of Ropinirole Transdermal Ointment formula: ropinirole: 15g Vaseline: 53g Lanolin: 12g Dimethyl sulfoxide: 10g Azone: 5g Oleic acid: 5g Preparation method: Mix petrolatum and lanolin and heat until melted; add a solution of ropinirone, dimethyl sulfoxide and azone dissolved in ethyl acetate and stir until homogeneous; cool to room temperature to obtain the transdermal ointment.

[0043] Experiment Example 5: Stability Test The transdermal non-aqueous solution prepared in Example 1 was subjected to accelerated testing at 40°C and 75%RH. After 6 months, the ropinirole content was tested, and the results showed that the content decreased by <5.0%, which met the requirements for veterinary drug stability.

[0044] Example 6: Clinical Treatment Trial Case 1: Dog accidentally eats corncob from kitchen trash can Treatment method: The ropinirole transdermal agent of Example 1 was administered to the dog that had swallowed the foreign object by administering 1 mL through the skin of the back of the neck.

[0045] Treatment result: Vomiting was successfully induced in the dog 15 minutes after administration, expelling the corn cob foreign object from its body.

[0046] Case 2: Dog accidentally eats owner's socks Treatment method: Squeeze out about 1 cm of the ropinirole transdermal gel from Example 2 and apply it evenly to the skin on the back of the dog's neck.

[0047] Treatment result: Vomiting was successfully induced in the dog 15 minutes after administration, expelling the swallowed sock from its body.

[0048] In summary, the ropinirole transdermal pharmaceutical composition of the present invention has significant technological advancements and clinical application value. Those skilled in the art can make changes to the above embodiments without departing from the spirit of the present invention, and all such changes fall within the protection scope of the present invention.

Claims

1. A ropinirole transdermal pharmaceutical composition, characterized in that, The composition comprises ropinirole or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient, and at least one transdermal promoting solvent; the active pharmaceutical ingredient comprises 1% to 30% by weight in the composition; and the composition is in the form of a transdermal non-aqueous solution, a transdermal ointment, a transdermal gel, or a transdermal patch.

2. The composition according to claim 1, characterized in that, When the composition is a transdermal non-aqueous solution, its solvent is selected from one or more of medium-chain glycerides, polyisobutylene, polybutene, propylene glycol diacetate, ethanol, and propylene carbonate.

3. The composition according to claim 1, characterized in that, When the composition is a transdermal non-aqueous solution, it further comprises a co-solvent selected from one or more of methanol, benzyl alcohol, dimethyl sulfoxide, and ethylene glycol.

4. The composition according to claim 1, characterized in that, The transdermal penetration enhancer solvent is selected from one or more of polyethylene glycol 400, ethanol, isopropyl myristate, oleic acid, and azone.

5. The composition according to claim 1, characterized in that, When the composition is a transdermal non-aqueous solution, it also contains an antioxidant, which is one or both of butylated hydroxyanisole and butylated hydroxytoluene.

6. The composition according to claim 1, characterized in that, When the composition is a transdermal gel formulation, it further comprises a gel matrix selected from one or more of carbomer, hydroxypropyl cellulose, sodium alginate, and xanthan gum.

7. The composition according to claim 1, characterized in that, When the composition is a transdermal patch, it further comprises a backing layer, a drug reservoir layer, and an adhesive layer; the drug reservoir layer comprises ropinirole or a pharmaceutically acceptable salt thereof and a transdermal-enhancing solvent.

8. A method for preparing the ropinirole transdermal pharmaceutical composition of claim 1, characterized in that, When the composition is a transdermal non-aqueous solution, it includes the following steps: dissolving ropinirole or its pharmaceutically acceptable salt in a co-solvent, adding it to a mixture containing an appropriate amount of solvent, antioxidant, and transdermal promoting solvent, stirring evenly, and finally adjusting the volume with solvent to obtain the final product.

9. A method for preparing the ropinirole transdermal pharmaceutical composition of claim 1, characterized in that, When the composition is a transdermal gel formulation, it includes the following steps: dispersing the gel matrix in water, swelling it, adding ropinirole or its pharmaceutically acceptable salt dissolved in a solvent and a transdermal promoting solvent, and stirring until homogeneous; adding a humectant, stirring until homogeneous, and finally adding water to the set total amount to obtain the final product.

10. The use of any one of the ropinirole transdermal pharmaceutical compositions according to claims 1-7 in the preparation of a medicament for inducing vomiting in animals, characterized in that, The animals are pets, including dogs and cats; the induced vomiting is used in cases where the animal has accidentally ingested toxic substances or foreign objects.