Formulation composition for the manufacture of a transdermal drug patch

Abstract

A transdermal patch composition for delivering medicines to the skin, consisting of: 3 to 7 percent by weight of a polymer mixture; 0.3 to 0.7% by weight of a non-opioid active ingredient; 0.1 to 0.2% by weight of a plasticizer; 0.5 to 0.9% by weight of a solubilizer; 90 to 94 percent by weight of a solvent mixture; and 0.03 to 0.07% by weight of at least one penetration enhancer; wherein the transdermal patch is adapted for anti-inflammatory drug delivery to reduce pain with reduced side effects.

Description

Technical field of the invention:

[0001] The present disclosure relates generally to the technical field of transdermal drug delivery systems and, more particularly, to a transdermal drug delivery system for improved delivery of effective therapeutic agents into the skin without adverse effects to the user. Background of the invention

[0002] Iontophoresis is a procedure that involves the enhanced transport of solute molecules into tissue or the skin. This technique can be used to deliver ionic drugs for local and systemic therapeutic effects in clinical settings. Transdermal drug delivery is playing an increasingly important role in modern drug therapy and is primarily used for non-ionized drugs that require relatively low dosages.

[0003] Transdermal drug delivery systems, commonly known as transdermal or skin patches, are adhesive drug-delivery patches applied to the skin to deliver topical medication through the skin through a process called percutaneous absorption. Skin patches are generally divided into two categories: reservoir-type and matrix-type. The reservoir patch contains either a pharmaceutical composition in the form of a gel, emulsion, or ointment, which cannot be applied to joints or curved areas of the body. A matrix patch, on the other hand, can be applied to any part of the body depending on the properties of the backing film and adhesive components.Although matrix patches can be applied to the skin for extended periods without causing irritation, a difficulty in the system architecture is that an absorption enhancer must be added to maintain continuous transdermal penetration.

[0004] Transdermal drug delivery systems are designed to deliver and deliver drugs, including therapeutic agents, at desired, consistent concentrations through absorption through the skin. Typically in the form of transdermal patches, transdermal drug delivery systems offer advantages such as minimally invasive and painless application, as well as bypassing first-pass metabolism and gastrointestinal degradation of drugs, which is not possible with other delivery methods. Transdermal patches are adhesive medicated patches that can be applied to the skin to deliver a consistent or time-released dose of drug through the skin into the bloodstream. Transdermal patches are used to deliver a wide variety of pharmaceutical agents.

[0005] In existing technology, naproxen sodium (NSAID) is the sodium salt of naproxen, a member of the arylacetic acid group of nonsteroidal anti-inflammatory drugs (NSAIDs) with anti-inflammatory, analgesic, and antipyretic properties. Naproxen sodium is used to treat musculoskeletal disorders. Currently, oral therapy with naproxen sodium (NSAID) is highly effective, but its clinical application is often limited by potential side effects such as heartburn, nausea, vomiting, diarrhea, irritation, and ulceration of the gastrointestinal (GI) mucosa. Gastric irritation and ulceration caused by nonsteroidal anti-inflammatory drugs (NSAIDs) are well known and can be influenced by oral administration.

[0006] Therefore, there is a need for a transdermal drug delivery system for the improved delivery of effective therapeutic agents into the skin without adverse effects for the user. There is a need for a drug delivery system for the treatment of musculoskeletal disorders that does not cause undesirable side effects. There is a need for a transdermal drug delivery system that improves drug permeability and exhibits a synergistic anti-inflammatory effect. There is a need for a suitable matrix-type transdermal drug delivery system that utilizes polymers for transdermal delivery to minimize side effects and control drug delivery. Objectives of the invention:

[0007] The main objective of the invention is to provide a transdermal drug delivery system for improved delivery of effective therapeutic agents into the skin without adverse effects for the user.

[0008] Another object of the invention is to provide cost-effective transdermal films that improve the safety and efficacy profile of oral administration.

[0009] Another object of the invention is to provide a transdermal drug delivery patch that bypasses first-pass metabolism in the liver and allows for a steady plasma level of the active ingredient over a longer period of time.

[0010] Another object of the invention is to provide transdermal patches that are easy to transport and easy to apply while improving patient adherence to therapy.

[0011] Another object of the invention is to provide transdermal administration of naproxen sodium with increased transdermal permeation rate by physical (iontophoresis) and chemical permeation enhancers.

[0012] Another object of the invention is to provide a transdermal drug delivery of naproxen sodium suitable for both local and systemic application while avoiding gastrointestinal disturbances.

[0013] Another object of the invention is to provide penetration enhancers to improve the permeability of the active ingredient and to achieve a synergistic anti-inflammatory effect of the transdermal patches.

[0014] Another object of the invention is to provide penetration enhancers such as emu oil, which reduces inflammation and relieves muscle and joint pain in arthritis.

[0015] Another aim of the invention is to reduce side effects such as epigastric pain, heartburn, nausea, diarrhea, vomiting, gastric ulcers and liver damage.

[0016] Another object of the invention is to provide transdermal patches that exhibit increased bioavailability through physical (iontophoresis) and chemical permeation enhancers.

[0017] Another object of the invention is to provide a transdermal drug delivery system for improved delivery of effective therapeutic agents into the skin for the treatment of headaches, muscle pain, tendonitis, toothache, musculoskeletal disorders and menstrual cramps.

[0018] The present disclosure proposes a transdermal patch formulation for delivering drugs to the skin. A simplified summary is presented below to provide a basic understanding of some aspects of the claimed subject matter. This summary does not constitute a comprehensive overview. It is not intended to identify critical elements or narrow the scope of the claimed subject matter. Its sole purpose is to present some concepts in a simplified form as an introduction to the detailed description provided later.

[0019] To overcome the above-mentioned deficiencies of the prior art, the technical object of the present disclosure is to provide a transdermal drug delivery system that enables improved delivery of therapeutic agents into the skin without adverse effects for the user.

[0020] According to one aspect, the invention provides a transdermal drug delivery patch for administering therapeutic agents to the skin. The therapeutic transdermal patches consist of 3 to 7 weight percent of a polymer mixture, 0.3 to 0.7 weight percent of a non-opioid drug, 0.1 to 0.2 weight percent of a plasticizer, 0.5 to 0.9 weight percent of a solubilizer, 90 to 94 weight percent of a solvent mixture, and 0.03 to 0.07 weight percent of at least one penetration enhancer. The anti-inflammatory drug delivery patch (transdermal drug delivery patch) is used to treat pain with reduced side effects.

[0021] Specifically, the polymer blend includes hydroxypropylmethylcellulose (HPMC) in grades such as HPMC E15 and HPMC E50, as well as other polymers that serve as release-control coating agents for drug delivery. The non-opioid active ingredient includes at least one nonsteroidal anti-inflammatory drug (NSAID) such as naproxen, naproxen sodium, ibuprofen, and diclofenac, COX-1 inhibitors, COX-2 inhibitors, and their derivatives.

[0022] The plasticizer consists of either polyethylene glycol 400 (PEG 400) or dibutyl phthalate and their derivatives to ensure the flexibility of the transdermal patch. The solubilizer comprises a non-ionic surfactant such as Tween 80 or other polysorbate molecules and their derivatives. The solvent mixture consists of a combination of dichloromethane and methanol in a ratio of approximately 1:1, or acetone, or water and their derivatives. The penetration enhancer includes menthol, eucalyptus oil, emu oil, and lemongrass oil, or any terpenoids such as D-limonene, vegetable oils, and their derivatives to achieve high permeability for drug delivery through transdermal patches.

[0023] A procedure for formulating transdermal drug delivery patches is also described. In the first step, a polymer mixture is dissolved in a solvent mixture to obtain a first mixture. This first mixture is allowed to swell for 6 hours to produce a polymeric mixture. Subsequently, a non-opioid drug is dissolved in 5 mL of the solvent mixture to obtain a second mixture. The second mixture and a plasticizer are then added to the polymeric solution to obtain a transdermal mixture.

[0024] The solubilizer and at least one penetration enhancer are then added to the transdermal mixture, and the mixture is set aside for 2 hours to remove any trapped air. Finally, the transdermal mixture is transferred to a Petri dish and dried at room temperature to obtain a transdermal patch.

[0025] Further objects and advantages of the present invention will become apparent from the following part of the description, the claims and the accompanying drawings. Short description of the drawings:

[0026] The accompanying drawings, which are incorporated in and constitute a part of the specification, illustrate an embodiment of the invention and, together with the description, explain the principles of the invention. Fig. 1 shows an exemplary procedure for producing a transdermal drug delivery patch of the invention. Fig. 2 shows an exemplary production of various transdermal patches with different mixing ratios according to an embodiment of the invention. Fig. Figure 3 shows exemplary in vivo bioavailability data of transdermal patches according to an embodiment of the invention. Detailed disclosure of the invention:

[0027] Various embodiments of the present invention will be described with reference to the accompanying drawings. Wherever possible, the same or similar reference numerals are used throughout the drawings and the description to refer to the same or similar parts or steps.

[0028] The present disclosure has been made with a view to solving the above-described problems of the prior art. It is an object of the present invention to provide a transdermal drug delivery system for improved delivery of effective therapeutic agents into the skin without adverse effects for the user.

[0029] According to an exemplary embodiment, the invention provides a transdermal drug delivery patch for administering therapeutic agents to the skin. The composition of the transdermal patch comprises 3 to 7 weight percent of a polymer blend, 0.3 to 0.7 weight percent of a non-opioid drug, 0.1 to 0.2 weight percent of a plasticizer, 0.5 to 0.9 weight percent of a solubilizer, 90 to 94 weight percent of a solvent mixture, and 0.03 to 0.07 weight percent of at least one penetration enhancer. The anti-inflammatory transdermal drug delivery patch is used to treat pain with reduced side effects.

[0030] Fig. 1 also shows an exemplary procedure 100 for formulating a transdermal drug delivery patch.

[0031] In step 102, a polymer mixture is dissolved in a solvent mixture to obtain a first mixture. This first mixture is then allowed to swell for 6 hours to produce a polymer mixture. The polymer mixture comprises hydroxypropylmethylcellulose (HPMC) in grades such as HPMC E15, HPMC E50, as well as other polymers used as release-control coating agents for drug delivery. The solvent mixture consists of a combination of dichloromethane and methanol in a ratio of approximately 1:1, or acetone, or water and their derivatives.

[0032] In step 104, a non-opioid drug is dissolved in 5 mL of the solvent mixture to obtain a second mixture. The non-opioid drug comprises at least one nonsteroidal anti-inflammatory drug (NSAID) such as naproxen, naproxen sodium, ibuprofen, and diclofenac, COX-1 inhibitors, COX-2 inhibitors, and their derivatives. In step 106, the second mixture and a plasticizer are added to the polymeric solution to obtain a transdermal mixture. The plasticizer consists of either polyethylene glycol 400 (PEG 400) or dibutyl phthalate and their derivatives to achieve the flexibility of the transdermal patch.

[0033] In step 108, the solubilizer and at least one penetration enhancer are added to the transdermal mixture, and the mixture is set aside for 2 hours to remove entrapped air from the transdermal mixture. The solubilizer comprises a nonionic surfactant such as Tween 80 or other polysorbate molecules and their derivatives. The penetration enhancer comprises menthol, eucalyptus oil, emu oil, and lemongrass oil, or various terpenoids such as D-limonene, vegetable oils, and their derivatives to achieve high permeability for drug delivery through the transdermal patches.

[0034] In step 110, the transdermal mixture is transferred to a Petri dish and dried at room temperature to obtain a transdermal patch. The developed patches are carefully removed, cut to a specific size (each with an area of ​​3.14 cm 2 ) and stored in a desiccator.

[0035] According to a further exemplary embodiment of the invention, Fig. Figure 2 shows an example of the production of various transdermal patches 200 with different mixing ratios. The matrix-type transdermal patches with naproxen sodium are manufactured using the solution-casting method. The patches are manufactured using naproxen sodium and HPMC E15 in ratios of 1:5, 1:7, 1:9, 1:10, and 1:15.

[0036] Naproxen is used to relieve pain from various conditions such as headaches, muscle pain, tendonitis, toothaches, and menstrual cramps. Naproxen also reduces pain, swelling, and joint stiffness caused by arthritis, bursitis, and gout attacks. The drug naproxen sodium is known as a nonsteroidal anti-inflammatory drug (NSAID). Naproxen sodium blocks the production of certain natural substances that cause inflammation.

[0037] For example, Table 1 shows nine transdermal patch formulations with different mixing ratios.

[0040] Table 1: Formulation ng / Ingredients fe F1 F2 F3 F4 F5 F6 F7 F8 F9 (1:5) (1:7) (1:9) (1:10) (1:15) (1:10) (1:10) (1:10) (1:10) Naproxen sodium (mg) 155 155 155 155 155 155 155 155 155 HPMC E15(mg) 775 1085 1395 1550 2325 1550 1550 1550 1550 Polyethylene glycol 600(µl) (20%v / wdry weight). 155 217 279 310 465 310 310 310 310 weight of the polymer) Menthol (µl) (1% v / v) - - - - - 15.5 - - - Eucalyptus oil (µl) (1% v / v) - - - - - - 15.5 - - Lemongrass oil (µI) (1%v / v) - - - - - - - 15.5 - Emu oil (µl) (1 %v / v) - - - - - - - - 15.5 Tween 80 (µl) - - - - - 200 200 200 200 Methanol (ml) 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 Dichloromethane (ml) 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5

[0038] All formulations contain 20% (v / w) PEG-600 as a plasticizer. The resulting patches are characterized with regard to various physicochemical parameters, moisture studies, and mechanical properties. The patches are evaluated using chemical (permeation enhancer) and physical (iontophoresis) methods, including ex vivo permeation studies and in vivo bioavailability studies.

[0039] For example, Table 2 shows the influence of iontophoresis on ex vivo drug permeation of transdermal patches through pig ear skin. Values ​​are given as mean ± SD; n = 3.

[0043] Table 2: Time (Hours) F4 F4 with iontophoresis F9 F9 with iontophores se 0 0 0 0 0 0.5 411.90±40 583.33±45 785.71±71 470.23±78 1 575.52±61 665.38±54 857.47±74 587.09±68 1.5 633.66±57 789.71±68 1047.619±92 734.61±94 2 727.95±64 980.47±74 1220.57±93 901.14±98 4 888.42±121 1220.33±98 1505.95±109 1211.81±112 6 943±139 1515.61±112 1709.81±91 1388±76 8 1111.04±78 1592.95±104 1877.52±105 1547.67±103 12 1500.61±93 2135.09±98 2298.9±95 2256.14±85 24 2000.38±104 2592.19±106 3050.52±106 4428.53±94 32 2521.9±95 2854.87±97 3637.42±89 4952.35±87 48 2899.85±107 3076.13±121 4301.04±118 5897.84±112

[0040] Of all formulations, F9 (ratio 1:10) proved to be the optimal formulation. Additional patches were prepared using a permeation enhancer (1% v / v emu oil F9). Table 2 shows that formulation F9 exhibits a maximum cumulative drug permeation of 4301.04 ± 118 µg and 5897.84 ± 112 µg through pig ear skin after 48 hours. The flux value for formulation F9 is calculated to be 25.11 µg / cm 2 / h using iontophoresis and 41.8 µg / cm 2 / h without the use of iontophoresis. This suggests that the flux value is increased by 1.66 times the normal value.

[0041] Fig.Figure 3 shows an example of in vivo bioavailability of transdermal patches 300. In vivo bioavailability studies were conducted on white rabbits, and blood samples from the white rabbits were analyzed using high-performance liquid chromatography with a UV spectrophotometer detector. The mean area under the curve (AUC) of the proposed naproxen sodium transdermal patches with emu oil and iontophoresis shows a statistically significant (p < 0.05) increase in bioavailability of 1.12 and 1.46 times, respectively, compared to oral administration and transdermal patches without iontophoresis, respectively. FTIR studies demonstrated drug-polymer compatibility. Drug permeation kinetics followed a zero-order profile with a diffusion mechanism. The transdermal naproxen sodium patches with the required flux are suitable for an anti-inflammatory effect.

[0042] Pharmacokinetic studies are conducted in rabbits, and the serum samples obtained are extracted accordingly and analyzed by HPLC. Comparative serum profile of naproxen sodium oral solution and transdermal patches containing 1% v / w emu oil as a chemical permeation enhancer. Physical methods such as iontophoresis utilize a 0.5 mA silver-silver chloride electrode. Transdermal iontophoretic drug delivery of naproxen sodium involves electrical contact of silver-silver chloride electrodes (0.5 mA applied) and a penetration enhancer derived from emu oil applied to the skin surface of the subjects for local drug delivery. A relative bioavailability study demonstrates that naproxen sodium is successfully released from the prepared transdermal films.Furthermore, the proposed naproxen sodium patch efficiently transports the active ingredient through different layers of the stratum corneum, resulting in improved skin permeation when chemical and physical enhancement methods are applied.

[0043] For example, Table 3 shows the pharmacokinetic parameters of transdermal patches. Table 3 Pharmacokinetics che parameters iontophoresis Oral intake Transdermal Pavement Cmax 483.45 336.26 480.11 Tmax 4.00 3.00 6.00 t ½ 8.59 10.34 8.58 Mrt 11.82 13.00 10.78 AUC(0-t) 4266.73 2837.13 3845.36 AUC(t-α) 204.80 212.98 167.15 AUC(0-α) 4471.54 3050.11 4012.52

[0044] The pharmacokinetic parameters of concentration (Cmax) (µg / ml), time (Tmax) (h), and area under the curve (AUC) of the therapeutic systems studied are presented. The Cmax (µg / ml) is 480.11 and 483.45, respectively, after administration of naproxen sodium as an oral solution, transdermal patches containing the chemical permeation enhancer emu oil, and transdermal patches using a chemical and physical enhancement method (iontophoresis). Absorption kinetics are higher with iontophoresis than with oral administration and transdermal patches containing emu oil.

[0045] Tmax(h) values ​​were prolonged in all animals with transdermal administration compared to oral administration; the difference was statistically significant (p < 0.05). The overall mean area under the curve (AUC) of the transdermal patch with the chemical and physical enhancement method was higher than with oral administration and with transdermal administration with a chemical permeation enhancer (emu oil), and the improvement was statistically significant (p < 0.05).

[0046] The improvement in bioavailability in rabbits was demonstrated using iontophoresis (0.5 mA for 2 h, pulsed current) as a physical enhancement method and emu oil (1% v / w) as a chemical permeation enhancer. Thus, transdermal naproxen sodium patches with emu oil and iontophoresis exhibit a statistically significant (p < 0.05) 1.12-fold and 1.46-fold increased bioavailability compared to oral administration and transdermal patches without iontophoresis, respectively, and are effectively used to treat pain and adverse effects associated with oral administration.

[0047] The proposed transdermal patches, for example, enhance the transdermal permeation of therapeutics. These therapeutics include, among others, hormone antagonists such as estrogens, progestins, and androgens for male and female health; adrenal cortex steroids and their synthetic analogues for inflammation and / or various manifestations of adrenal insufficiency or pituitary hormone excess; medications for nausea and vomiting; tricyclic antidepressants; migraine and other pain relievers, including NSAIDs and narcotics; hypnotics; some beta-blockers, alpha-blockers, neuromuscular blockers, diuretics, antimalarials, dermatologicals, antimetabolites, and peptides such as leuprolide, goserelin, or histrelin.In other embodiments, the therapeutic agent may be, but is not limited to, an Alzheimer's disease treatment agent, an anabolic agent, an analgesic, an anesthetic, an antacid, an antiasthmatic agent, an anticholesterolemic agent, an antilipid agent, an anticoagulant, an anticonvulsant, an antidiarrheal agent, an antiemetic, an anti-inflammatory agent, an antifungal agent, an antimanic agent, an antimigraine agent, or an antinausea agent.

[0048] Numerous advantages of the present disclosure emerge from the above discussion. According to the present disclosure, a transdermal drug patch enables the delivery of effective therapeutics into the skin without side effects for the user. The proposed transdermal patches are cost-effective and improve the safety and efficacy profile of oral administration. The proposed transdermal drug patch overcomes first-pass metabolism in the liver and ensures a constant plasma level of the drug over a longer period of time. The proposed transdermal patches are easy to wear and easy to apply and also improve patient compliance.

[0049] The proposed patches enable transdermal administration of naproxen sodium with increased transdermal permeation rate through physical (iontophoresis) and chemical permeation enhancers. Transdermal administration of naproxen sodium for potential local and systemic effects also avoids gastrointestinal disturbances. The penetration enhancers improve the drug's permeability and demonstrate the synergistic anti-inflammatory effect of the transdermal patches. Emu oil is rich in omega-3, omega-6, and omega-9 fatty acids. Penetration enhancers such as emu oil reduce inflammation and relieve muscle and arthritic joint pain.

[0050] The proposed patches reduce side effects such as upper abdominal pain, heartburn, nausea, diarrhea, vomiting, peptic ulcers, and liver dysfunction. The transdermal patches exhibit increased bioavailability through physical (iontophoresis) and chemical permeation enhancers. The proposed transdermal drug patches enable improved delivery of effective therapeutics into the skin for the treatment of headaches, muscle pain, tendonitis, toothache, musculoskeletal disorders, and menstrual discomfort.

[0051] Physical methods such as iontophoresis using silver-silver chloride electrodes at 0.5 mA can also be used. Transdermal iontophoretic administration of naproxen sodium occurs via electrical contact between a silver-silver chloride electrode (0.5 mA) and the permeation enhancer emu oil. This is applied to the skin surface of a subject to administer the drug locally and systemically. The emu oil can enhance the anti-inflammatory effects of naproxen sodium.

Claims

[1] A transdermal patch composition for delivering drugs to the skin, consisting of: 3 to 7 percent by weight of a polymer mixture; 0.3 to 0.7% by weight of a non-opioid active ingredient; 0.1 to 0.2% by weight of a plasticizer; 0.5 to 0.9% by weight of a solubilizer; 90 to 94 percent by weight of a solvent mixture; and 0.03 to 0.07% by weight of at least one penetration enhancer; wherein the transdermal patch is adapted for anti-inflammatory drug delivery to reduce pain with reduced side effects. [2] The transdermal patch composition for delivering drugs to the skin according to claim 1, wherein the polymer mixture contains various forms of hydroxypropylmethylcellulose (HPMC) such as HPMC E15, HPMC E50 and any other polymers and release-controlling coating agents for drug delivery. [3] The transdermal patch composition for delivering drugs to the skin according to claim 1, wherein the non-opioid active ingredient contains at least one nonsteroidal anti-inflammatory drug (NSAID) such as naproxen, naproxen sodium, ibuprofen, diclofenac, COX-1 inhibitors, COX-2 inhibitors and the like. [4] The transdermal patch composition for delivering drugs to the skin according to claim 1, wherein the solvent mixture contains a combination of dichloromethane and methanol in a ratio of about 1:1 or acetone or water and the like. [5] The transdermal patch composition for delivering drugs to the skin according to claim 1, wherein the plasticizer comprises either polyethylene glycol 400 (PEG 400) or dibutyl phthalate to impart flexibility to the transdermal patch. [6] The transdermal patch composition for delivering drugs to the skin according to claim 1, wherein the solubilizer contains a nonionic surfactant such as Tween 80 or other polysorbate molecules or the like. [7] The transdermal patch composition for delivering drugs to the skin according to claim 1, wherein the at least one penetration enhancer contains menthol, eucalyptus oil, emu oil and lemongrass oil or various terpenoids such as d-limonene, vegetable oils or the like to achieve high permeability in drug delivery of the transdermal patches.

Images