WO2024040897A1

WO2024040897A1 - Transdermal patch of thalidomide or analogue thereof and preparation method therefor

Info

Publication number: WO2024040897A1
Application number: PCT/CN2023/078000
Authority: WO
Inventors: 唐俭生
Original assignee: 新领医药技术(深圳)有限公司
Priority date: 2022-08-24
Filing date: 2023-02-23
Publication date: 2024-02-29

Abstract

The present invention relates to a transdermal formulation for single use of an immunomodulatory imide compound comprising thalidomide or an analogue thereof and combined use with dexamethasone, a preparation method therefor, and use thereof. Specifically, the present invention provides a transdermal patch comprising a backing layer, a drug reservoir layer, a semipermeable membrane layer, an adhesive layer and an optional release layer and used for single use of thalidomide or an analogue thereof and dexamethasone-based combined use, a preparation method therefor, and use thereof.

Description

Thalidomide or its analogue transdermal patch and preparation method thereof

Technical field

The present invention relates to a patch preparation for transdermal administration. More specifically, it relates to a patch comprising thalidomide or an analog thereof and a pharmaceutically acceptable salt thereof and a patch containing thalidomide or an analog thereof and dexamethasone and a pharmaceutically acceptable salt thereof Preparation of the agent and its preparation method.

Background technique

Among some drugs, transdermal drug delivery is a route of administration that is superior to oral drug administration. It maintains drug concentration in the blood at a constant level by continuously delivering drugs to the systemic blood system. The transdermal delivery route not only reduces the fluctuations in drug concentration in the blood between peaks and troughs, but also avoids the first-pass effect. In addition, since the transdermal route of administration avoids direct contact between drugs and excipients and the gastrointestinal system, side effects such as nausea and vomiting that are often associated with the oral route of administration are significantly reduced or eliminated. Another advantage of the transdermal route of administration is that it is not affected by diet. Administration can be easily terminated when necessary by removing the transdermal patch from the skin. Furthermore, transdermal patches improve patient compliance by reducing dosing frequency. This is particularly important for elderly patients and pediatric patients.

Common dosage forms for transdermal delivery include transdermal patch formulations. Currently common transdermal drug delivery patch preparations include, but are not limited to, drug reservoir type patches and matrix type patches. Drug reservoir-type patch formulations are those in which the drug is contained in a reservoir with a drug-permeable substrate surface, and matrix-type patch formulations are those in which the drug is dissolved or dispersed in a polymeric matrix layer.

Immunomodulatory imide compounds, including thalidomide and thalidomide analogs (collectively known as the thalidomide family of compounds), possess pleiotropic antimyeloma properties, including immunomodulatory, anti-angiogenic, anti-inflammatory, and anti-proliferative properties effect. Thalidomide analogues include lenalidomide, pomalidomide, ibedudomide, and apremilast.

Lenalidomide, a chemical analog of thalidomide, is approved for the treatment of multiple myeloma (MM) in combination with dexamethasone and as monotherapy for the treatment of bone marrow associated with 5q deletions and relapse or relapse. Transfusion-dependent anemia and refractory mantle cell lymphoma (MCL) caused by dysplastic syndrome (MDS).

The main adverse events (AEs) of lenalidomide are neutropenia and thrombocytopenia. Some adverse events of lenalidomide are often related to specific diseases. For example, venous thromboembolic events were more frequently observed in MM patients treated with lenalidomide/dexamethasone, whereas tumor lysis syndrome and tumor flare reactions were more frequently observed in patients receiving lenalidomide/dexamethasone therapy. Venous thromboembolism has become one of the major complications of lenalidomide. Furthermore, lenalidomide induced an increased burden of stroke and myocardial infarction. Combined treatment with lenalidomide and corticosteroids may increase the risk of stroke. 75% of patients receiving dexamethasone and lenalidomide experienced a thromboembolic event (along with 1 ischemic stroke) 50 days after stroke. High plasma exposure of lenalidomide is associated with an increased risk of neutropenia and thrombocytopenia. The high Cmax of the standard oral dosage form of lenalidomide is responsible for the high side effects.

Dexamethasone is available on a high-dose schedule (one 40 mg tablet taken every 28 days on days 1-4, 9-12, and 17-20) or a low-dose schedule (one 40 mg tablet taken every 28 days on days 1, 8, 15, and 22 Dexamethasone 40 mg tablet) is used in combination with lenalidomide. The incidence of toxicity was higher in the high-dose dexamethasone group than in the low-dose dexamethasone group. For example, cardiac ischemia (2.7% vs. 0.5%), hypercalcemia (5.8% vs. 1.8%), infection (18.8% vs. 9%), thromboembolism (18.4% vs. 5.4%), and nonhematologic grade 3 and above toxicities were higher in the high-dose dexamethasone group (22% vs. 12.6%) than in the low-dose dexamethasone group. Although side effects are lower with the low-dose dexamethasone regimen, they are still quite high. Toxicity and associated side effects need to be reduced.

Therefore, in order to solve the above-mentioned adverse reaction problems, there is an urgent need for a transdermal patch that can continuously deliver a therapeutically effective amount of lenalidomide over a long period of time, or a transdermal patch that contains both lenalidomide and dexamethasone. Transdermal patches.

Contents of the invention

An object of the present invention is to provide a thalidomide or its analogue depot transdermal patch, which can continuously deliver thalidomide or its analogue at a therapeutically effective amount of blood concentration over an extended period of time. or its pharmaceutically acceptable salt.

It is an object of the present invention to provide a depot transdermal patch containing thalidomide or an analog thereof and dexamethasone, which can continuously deliver thalidomide or an analogue thereof at a therapeutically effective blood concentration over an extended period of time. Lidomide or its analogues or its pharmaceutically acceptable salts and dexamethasone or its pharmaceutically acceptable salts.

Another object of the present invention is to provide a method for the treatment of multiple myeloma, transfusion-dependent anemia caused by low-risk or intermediate-risk myelodysplastic syndrome, mantle cell lymphoma, chronic lymphocytic leukemia, hematological cancers, solid tumors A method of cancer or inflammatory disease, comprising administering to a subject in need thereof a therapeutically effective amount of a thalidomide or analogue thereof transdermal patch.

Another object of the present invention is to provide a method for the treatment of multiple myeloma, transfusion-dependent anemia caused by low-risk or intermediate-risk myelodysplastic syndrome, mantle cell lymphoma, chronic lymphocytic leukemia, hematological cancers, solid tumors A method of cancer or inflammatory disease, comprising administering to a subject in need thereof a therapeutically effective amount of thalidomide or an analog thereof and dexamethasone or an acceptable transdermal patch thereof.

Another object of the present invention is to provide a therapeutically effective amount of thalidomide or its analog depot transdermal patch prepared for the treatment of multiple myeloma, low-risk or intermediate-risk myelodysplastic syndromes. Use in medicines caused by transfusion-dependent anemia, mantle cell lymphoma, chronic lymphocytic leukemia, hematological cancers, solid tumor cancers, or inflammatory diseases.

Another object of the present invention is to provide a depot-type transdermal patch in which a therapeutically effective amount of thalidomide or an analog thereof is combined with dexamethasone or an acceptable salt thereof for the treatment of multiple myeloid arthritis. transfusion-dependent anemia caused by low-risk or intermediate-risk myelodysplastic syndromes, mantle cell lymphoma, chronic lymphocytic leukemia, hematologic cancers, solid tumor cancers, or inflammatory diseases.

In some embodiments, thalidomide analogs include lenalidomide, pomalidomide, ibedudomide, and apremilast.

Lenalidomide, 3-(4'-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione, having formula I Structure, is an FDA-approved drug administered in the form of oral capsules.

Pomalidomide, 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione, has the structure shown in formula II and is FDA approved Medication, administered in the form of oral capsules.

Thalidomide, (2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione), is an FDA-approved drug that is administered as an oral capsule. Thalidomide is often used in combination with dexamethasone to treat patients with newly diagnosed multiple myeloma.

Apremilast, (S)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-methanesulfonylethyl]-4-acetylaminoisoindole Phospholine-1,3-dione, is an FDA-approved drug that is administered as an oral tablet. Apremilast is indicated for the treatment of patients with active psoriatic arthritis.

Iberdomide ((3S)-3-[7-[[4-(morpholin-4-ylmethyl)phenyl]methoxy]-3-oxo-1H-isoindole- 2-yl]piperidin-2,6-one), is being developed for the treatment of refractory multiple myeloma.

In one embodiment, the present invention provides a thalidomide or analogue depot transdermal patch, which includes:

1. Backing layer;

2. Drug storage layer;

3. Semi-permeable membrane layer;

4. Adhesive layer; and

5. Release layer.

In one embodiment, the present invention provides a thalidomide or analog thereof and dexamethasone depot transdermal patch, which includes:

1. Backing layer;

2. Drug storage layer;

3. Semi-permeable membrane layer;

4. Adhesive layer; and

5. Release layer.

In one embodiment, the drug reservoir layer further comprises a skin penetration enhancer.

In one embodiment, the skin penetration enhancer includes any one of a solvent, a polymer solubilizer, a surfactant, a medium molecular weight organic acid, and a low molecular weight organic acid, or any combination thereof.

In one embodiment, the skin penetration enhancer includes a polymeric solubilizer, a surfactant.

In one embodiment, the skin penetration enhancer further comprises a medium molecular weight organic acid, a low molecular weight organic acid, or a combination of a medium molecular weight organic acid and a low molecular weight organic acid on the basis of a polymer solubilizer and a surfactant.

In one embodiment, the skin penetration enhancer further includes a solvent based on the aforementioned combination. For example, the combination of polymer solubilizer, surfactant and solvent, the combination of polymer solubilizer, surfactant, medium molecular weight organic acid and solvent, the combination of polymer solubilizer, surfactant, low molecular weight organic acid and solvent, A combination of polymer solubilizer, surfactant, medium molecular weight organic acid, low molecular weight organic acid and solvent.

In one embodiment, the polymer solubilizer is selected from the group consisting of hydroxypropyl cellulose, povidone, copovidone, crospovidone, hydroxypropyl methylcellulose phthalate, hydroxypropyl acetate succinate Propylmethylcellulose, hydroxypropylmethylcellulose, hyaluronic acid, pectin, carboxymethylcellulose, alginic acid, carrageenan, or any combination; preferably hydroxypropylcellulose, povidone , crospovidone or combinations thereof. In one embodiment, the content of thalidomide or its analogues or pharmaceutically acceptable salts thereof is 0.5% to 50% by weight of the drug reservoir layer, preferably 2% to 50%, 2 to 30%, 5 to 25%, more preferably 2% to 10%.

In one embodiment, the content of thalidomide or an analog thereof or a pharmaceutically acceptable salt thereof is 0.5% to 50%, preferably 1% to 20%, more preferably 2% to 10% by weight of the drug reservoir layer. %. The content of dexamethasone or its acceptable salt used in combination with it is 0.1 to 50% of the drug reservoir layer, preferably 0.3% to 20%, more preferably 0.5% to 2%.

In one embodiment, the content of the polymer solubilizer is 2% to 50% of the drug reservoir layer, preferably 5% to 25%, more preferably 10% to 20%, and the thalidomide or its The weight ratio of the analog or pharmaceutically acceptable salt thereof to the polymer solubilizer is about 1:1 to 1:15.

In one embodiment, the content of surfactant is 1% to 50%, preferably 5 to 30% of the drug reservoir layer.

In one embodiment, the content of the medium molecular weight organic acid is 0.2-60% of the drug reservoir layer, preferably 0.2-30%, 0.5-30%, and more preferably 1-15%.

In one embodiment, the content of the low molecular weight organic acid is 0.1 to 10% by weight of the drug reservoir layer, preferably 0.1 to 5%, 0.5 to 5%, more preferably 0.5 to 3%.

In one embodiment, the medium molecular weight organic acid includes a C ₅ to C ₈ organic acid, preferably including levulinic acid, sorbic acid, itaconic acid, mesaconic acid, ketoglutaric acid, glutaric acid, methyl Succinic acid, valeric acid, isovaleric acid, pivalic acid, cis-aconitic acid, trans-aconitic acid, ascorbic acid, citric acid, isocitric acid, adipic acid, hexanoic acid, benzoic acid, salicylic acid, lonzoic acid Cholic acid, protocatechuic acid, gallic acid, cyclohexanecarboxylic acid, pimelic acid, phthalic acid, isophthalic acid, isophthalic acid, terephthalic acid, terephthalic acid, phenylacetic acid, toluene Formic acid, o-toluic acid, m-toluic acid, p-toluic acid, mandelic acid, homogentistic acid, suberic acid, caprylic acid, or combinations thereof, more preferably including levulinic acid, glutaric acid, adipic acid and combinations thereof.

In one embodiment, the low molecular weight organic acid includes C ₁ to C ₄ organic acid, preferably including formic acid, glyoxylic acid, oxalic acid, acetic acid, glycolic acid, acrylic acid, pyruvic acid, malonic acid, propionic acid, 3 -Hydroxypropionic acid, lactic acid, glyceric acid, fumaric acid, maleic acid, oxaloacetic acid, crotonic acid, acetoacetic acid, 2-oxobutyric acid, methylmalonic acid, succinic acid, malic acid, L-tartaric acid , DL-tartaric acid, meso-tartaric acid, dihydroxytartaric acid, butyric acid, isobutyric acid, hydroxybutyric acid, or combinations thereof, more preferably, including lactic acid.

In one embodiment, the adhesive layer includes a skin contact adhesive and optionally antioxidants, anti-skin irritants, cohesion promoters, plasticizers, and tackifiers.

In one embodiment, the skin contact adhesive includes acrylic glue, methacrylic glue, polyisobutylene glue, styrene-isoprene-styrene block copolymer, silicone adhesive, acrylic- Copolysiloxane copolymer adhesive, or a combination of two or more of the above.

In one embodiment, the skin contact adhesive is a cross-linked adhesive or a non-cross-linked adhesive.

In one embodiment, the cohesion promoter includes colloidal silica, zinc oxide, polyvinylpyrrolidine, acrylate copolymer, crospovidone, croscarmellose, ethylcellulose, acrylic acid Copolymers, bentonites, clays or a combination of two or more of the above.

In one embodiment, the present invention provides a method for preparing the above-mentioned thalidomide or its analogue transdermal patch, which includes:

1) Mix thalidomide or its analogues or its pharmaceutically acceptable salts with a skin penetration enhancer to form a uniform liquid, semi-solid or solid mixture;

2) Evenly distribute or coat the resulting liquid, semi-solid or solid mixture on the backing film; and bond the side of the backing film distributed or coated with the mixture to the far side of the semi-permeable membrane layer Laminate one side of the agent layer/release layer; or

The uniform liquid, semi-solid or solid is distributed or coated on the side of the semi-permeable membrane layer away from the adhesive layer/release layer, and then the side of the semi-permeable membrane layer that is distributed or coated with the mixture is Laminated with backing layer.

In one embodiment, it also includes sealing the peripheral edges of the backing layer membrane and the semipermeable membrane by heat, pressure, or a combination of heat and pressure, such that the liquid, semi-solid or solid mixture is confined to the periphery Steps within the edge range.

1) Mix thalidomide or its analogues or its pharmaceutically acceptable salts and dexamethasone or its pharmaceutically acceptable salts with a skin penetration enhancer to form a uniform liquid, semi-solid or solid mixture;

2) Laminate the backing layer and the side of the semi-permeable membrane layer away from the adhesive layer/release layer, and seal the backing layer and semi-permeable membrane by heat, pressure or a combination of heat and pressure a portion of the peripheral edge of the layer and filling the resulting liquid, semi-solid or solid mixture from the unsealed peripheral edge portion to an area between the backing layer and the semipermeable membrane layer;

3) Then, the unsealed peripheral edge portions of the backing layer and the semipermeable membrane layer are sealed by heat, pressure, or a combination of heat and pressure, thereby forming a sealed drug reservoir layer.

In one embodiment, the present invention provides a method for preparing a transdermal patch of the above-mentioned thalidomide or its analogue combined with dexamethasone, which includes:

1) Mix thalidomide or its analogues or its pharmaceutically acceptable salts and dexamethasone or its pharmaceutically acceptable salts with the skin penetration enhancer to form a uniform liquid, semi-solid or solid mixture;

In one embodiment, the present invention provides a therapeutically effective amount of the above-mentioned thalidomide or analogues thereof transdermal patch prepared for use in multiple myeloma, blood transfusions caused by low-risk or intermediate-risk myelodysplastic syndromes. Use in medicines for the treatment of dependent anemia, mantle cell lymphoma, chronic lymphocytic leukemia, hematological cancers, solid tumor cancers, or inflammatory diseases.

In one embodiment, the invention provides a method for the treatment of multiple myeloma, transfusion-dependent anemia caused by low-risk or intermediate-risk myelodysplastic syndromes, mantle cell lymphoma, chronic lymphocytic leukemia, hematologic cancers, Methods for solid tumor cancer or inflammatory diseases, which comprise administering a therapeutically effective amount of the above-mentioned thalidomide or analogue thereof transdermal patch to a subject in need.

In one embodiment, the present invention provides a therapeutically effective amount of the above-mentioned thalidomide or analog thereof in combination with dexamethasone in a transdermal patch prepared for multiple myeloma, low-risk or intermediate-risk bone marrow hyperplasia. Use in drugs for the treatment of transfusion-dependent anemia caused by abnormal syndromes, mantle cell lymphoma, chronic lymphocytic leukemia, hematological cancers, solid tumor cancers or inflammatory diseases.

In one embodiment, the invention provides a method for the treatment of multiple myeloma, transfusion-dependent anemia caused by low-risk or intermediate-risk myelodysplastic syndromes, mantle cell lymphoma, chronic lymphocytic leukemia, hematologic cancers, A method for solid tumor cancer or inflammatory diseases, which includes administering a therapeutically effective amount of the above-mentioned thalidomide or analog thereof and a dexamethasone transdermal patch to a subject in need.

In one aspect, a method of providing transdermal delivery of a therapeutically effective amount of a pharmaceutical composition or formulation comprising lenalidomide is provided. In some embodiments, the method delivers lenalidomide at a predetermined hourly rate. In some embodiments, the predetermined hourly rate may be in the range of 16 to 1400 μg/hour, such as 30 μg to 750 μg/hour, 30 μg to 145 μg/hour, 70 μg to 285 μg/hour, or 185 μg to 725 μg/hour, such as 35 μg/hour. hour, 75μg/hour, 90μg/hour, 140μg/hour, 180μg/hour, 190μg/hour, 275μg/hour, 450μg/hour or 700μg/hour, or between any two of these enumerated rates (inclusive) The hourly rate is, for example, between 35-140 μg/hour or 75-280 μg/hour or 190 to 700 μg/hour.

In some embodiments, the method continuously delivers lenalidomide to achieve steady-state plasma levels of thalidomide or analog thereof in the range of 3-140 μg/L, e.g., 3.5-140 μg/L, 3-75 μg/L , 3.5-75μg/L, 3.5-14μg/L, 7.5-28μg/L, 19-70μg/L, 9μg/L, 18μg/L or 45μg/L.

In some embodiments, the method delivers lenalidomide transdermally to achieve steady-state plasma levels of thalidomide or analog thereof in the range of 3-140 μg/L, e.g., 3.5-140 μg/L, 3-75 μg/L L, 3.5-75μg/L, 3.5-14μg/L, 7.5-28μg/L, 19-70μg/L, 9μg/L, 18μg/L or 45μg/L.

In some embodiments, the method delivers thalidomide or an analog thereof continuously for a predetermined number of days. In some embodiments, the predetermined number of days is half a day, 23 hours, one day, two days, three days, four days, five days, six days, seven days, eight days, nine days, ten days, eleven days, twelve days, ten Three days or fourteen days. In other embodiments, the predetermined number of days is 12 hours, 23 hours, 1-14 days, 1-12 days, 1-10 days, 1-7 days, 1-5 days, 1-3 days, 2-14 days 2 -12 days 2-10 days 2-7 days 2-5 days 2-3 days 3-14 days 3-12 days 3-10 days 3-7 days 3-5 days, 4-14 days, 4-10 days, 7-14 days or 7-10 days.

In some embodiments, lenalidomide transdermal patch administration achieves transdermal delivery of a therapeutic agent that is bioequivalent to an orally administered therapeutic agent, wherein bioequivalence is determined by (a) the therapeutic agent administered from The 90% confidence interval for the relative mean Cmax and AUC determined to be between 0.70 and 1.43 or between 0.80 and 1.25 for transdermal delivery systems and oral administration, or (b) for treatments from transdermal delivery systems and oral administration The 90% confidence interval for the geometric mean ratio of AUC and Cmax for an agent is between 0.70 and 1.43 or between 0.80 and 1.25.

In some embodiments, the hourly rate is selected to achieve a plasma concentration of thalidomide or an analog thereof that is consistent with that provided by the oral dose within 0 to 24 hours, such as about 1 to 24 hours, further, such as about 5 to 24 hours. Comparable plasma concentrations are achieved even further, such as between about 5 hours and 23 hours or between about 10 hours and 16 hours after ingestion. Oral dosage may be 2.5 to 50 mg once daily, for example 2.5 mg, 4.0 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg or 50 mg of the immunomodulatory imide compound once daily or once every two days.

In some embodiments, the method continuously delivers thalidomide or an analog thereof in a manner wherein its AUC is between 10-60% of the exposure obtained from standard of care treatment. Standard of care treatment may be intraperitoneal injection, such as 500mcg once daily, or may be 2.5-50mg orally once daily, such as 2.5mg, 4.0mg, 5mg, 10mg, 15mg, 20mgmg, 25mg, 30mg or 50mg thalidomide or Its analogues are administered orally once daily or once every two days. In another embodiment, the methods herein provide for continuous administration of lenalidomide to provide an AUC between about 10% and 60% of the AUC provided by standard of care treatment. In some embodiments, the standard of care treatment is an oral dose of lenalidomide 2.5 mg to 50 mg once daily, such as 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg, or 25 mg or 50 mg once daily or every two days.

In some embodiments, the method continuously delivers thalidomide or an analog thereof (e.g., lenalidomide) once daily at a dose rate that provides blood levels comparable to those obtained from daily oral administration at time points 10 to 16 hours Doses of 2.5-50 mg (eg, 2.5 mg, 5 mg, 10 mg, or 25 mg of lenalidomide once daily). In the most preferred embodiment, the method continuously delivers thalidomide or the like at a dose rate that provides a 12-hour blood level comparable to that obtained from a daily oral dose of 2.5 to 50 mg (e.g., 5 mg, 10 mg) once daily. things. or lenalidomide 25 mg once daily.

In some embodiments, the method continuously delivers thalidomide or an analog thereof (e.g., lenalidomide) at a dose ratio such that the daily dose of the method is 10-75% of the daily dose of standard of care therapy, e.g., 15 -70%, 15-25%, 40-50%, 10-45%, 45%-70%, 60-70%, 15%, 16%, 17%, 18%, 19%, 20%, 21% ,22%,23%,24%,25%,26%,27%,28%,29%,30%,40%,41%,42%,43%,44%,45%,46%,47 %, 48%, 49%, 50%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69% or 70%. In some embodiments, the standard of care treatment is an intraperitoneal injection of, for example, 500 mcg once daily. In some embodiments, the standard of care treatment is an FDA-approved once-daily oral dose of thalidomide or an analog thereof, such as 5 mg, 10 mg, or 25 mg of lenalidomide orally once daily.

In some lenalidomide in combination with dexamethasone transdermal patch embodiments, the method provides daily high-dose regimens with dexamethasone obtained orally (days 1-4, 9-12, and 17-20 The mean blood levels per 28 oral 40 mg tablets were comparable to those delivered continuously at a dose rate but its Cmax was less than that of the oral high-dose regimen of dexamethasone.

In some lenalidomide in combination with dexamethasone transdermal patch embodiments, the method is provided daily with a low dose regimen of dexamethasone obtained orally (orally on days 1, 8, 15, and 22 every 28 days). The mean blood levels of one dexamethasone 40 mg tablet) were comparable to those delivered continuously at a dose rate but its Cmax was less than that of the oral low-dose regimen of dexamethasone.

Description of drawings

Figure 1 shows a schematic diagram of a drug reservoir type patch according to the present invention.

Figure 2 shows a schematic diagram of a pharmaceutical solid matrix type patch.

Figure 3 shows measurement curves of lenalidomide skin flux for the transdermal patches of compositions 11-18.

Figure 4 shows a measurement curve of dexamethasone skin flux for the transdermal patches of compositions 11-18.

Figure 5 shows measurement curves of lenalidomide skin flux for the transdermal patches of compositions 19-26.

Figure 6 shows measurement curves of dexamethasone skin flux for the transdermal patches of compositions 19-26.

Figure 7 shows measurement curves of lenalidomide skin flux for the transdermal patches of compositions 27-33.

Figure 8 shows a measurement curve of dexamethasone skin flux for the transdermal patches of compositions 27-33.

Figure 9 shows a measurement curve of lenalidomide skin flux for the transdermal patch of compositions 34-45.

Figure 10 shows a measurement curve of dexamethasone skin flux for the transdermal patches of compositions 34-45.

Figure 11 shows measurement curves of lenalidomide skin flux for transdermal patches of compositions 46-52.

Figure 12 shows measurement curves of dexamethasone skin flux for transdermal patches of compositions 46-52.

Figure 13 shows measurement curves of lenalidomide skin flux for the transdermal patches of compositions 53-58.

Figure 14 shows measurement curves of dexamethasone skin flux for transdermal patches of compositions 53-58.

Figure 15 shows measurement curves of lenalidomide skin flux for transdermal patches of compositions 59-61.

Figure 16 shows measurement curves of dexamethasone skin flux for transdermal patches of compositions 59-61.

Figure 17 shows measurement curves of lenalidomide skin flux for transdermal patches of compositions 62-66.

Figure 18 shows a measurement curve of dexamethasone skin flux for the transdermal patches of compositions 62-66.

Detailed ways

definition

As used herein, the term "pharmaceutically acceptable salt" means a salt suitable for use in contact with a subject (e.g., a human subject) without undue toxicity, irritation, allergic reaction, etc., within the scope of reasonable medical judgment, with reasonable benefit/risk ratio and are effective for their intended use. "Pharmaceutically acceptable salts" as described in the present invention include inorganic acid addition salts and organic acid addition salts, which can be prepared in situ during the final isolation and purification of the compound, or by converting the purified compound in the free base form (eg lenalidomide) is prepared by reacting alone with a suitable organic or inorganic acid and isolating the salt thus formed. Examples of inorganic acid addition salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates , pyrophosphate, hydrochloride, hydrobromide, hydroiodide, phosphite, borate, etc. Examples of organic acid addition salts include, but are not limited to, acetate, propionate, Butyrate, isobutyrate, valerate, caproate, caprylate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate Lenate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate , phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate oleate, palmitate, stearate, luosilicate, benzoate, lactate acid salt, tosylate, succinate, tartrate, methanesulfonate naphthoate, glucoheptonate, lactosuronate, lauryl sulfonate and isethionate, etc.

As used herein, the term "medium molecular weight organic acid" includes, but is not limited to, C ₅ to C ₈ organic acids. Non-limiting examples thereof include levulinic acid, sorbic acid, itaconic acid, mesaconic acid, ketoglutaric acid, glutaric acid, methylsuccinic acid, valeric acid, isovaleric acid, pivalic acid, cis-aconitum Acid, trans-aconitic acid, ascorbic acid, citric acid, isocitric acid, adipic acid, caproic acid, benzoic acid, salicylic acid, gentisic acid, protocatechuic acid, gallic acid, cyclohexanecarboxylic acid, heptane Diacid, phthalic acid, isophthalic acid, isophthalic acid, terephthalic acid, terephthalic acid, phenylacetic acid, toluic acid, o-toluic acid, m-toluic acid, p-toluic acid, mandelic acid, homogentistic acid, suberic acid, caprylic acid, or combinations thereof. Preferably, the medium molecular weight organic acids include levulinic acid, glutaric acid, adipic acid and combinations thereof, which are less skin irritating and non-sensitizing.

As used herein, the term "low molecular weight organic acid" includes, but is not limited to, C ₁ to C ₄ organic acids. Non-limiting examples include formic acid, glyoxylic acid, oxalic acid, acetic acid, glycolic acid, acrylic acid, pyruvic acid, malonic acid, propionic acid, 3-hydroxypropionic acid, lactic acid, glyceric acid, fumaric acid, maleic acid, oxalic acid Acetoacetic acid, crotonic acid, acetoacetic acid, 2-oxobutyric acid, methylmalonic acid, succinic acid, malic acid, L-tartaric acid, DL-tartaric acid, meso-tartaric acid, dihydroxytartaric acid, butyric acid, isobutyric acid acid, hydroxybutyric acid, or combinations thereof. Preferably, the low molecular organic acid is lactic acid.

As used herein, the term "therapeutically effective amount" means an amount of a compound or molecule of the invention that, when administered to a subject, (i) treats or prevents a particular disease, condition or disorder, (ii) attenuates, ameliorate or eliminate one or more symptoms of a particular disease, disorder, or disorder, or (iii) prevent or delay the onset of one or more symptoms of a particular disease, disorder, or disorder described herein.

As used herein, the term "about" means plus or minus 10% of the indicated number. For example, "about 10%" may represent a range of 9% to 11%, and "about 1" may represent 0.9-1.1.

As used herein, the term "treatment" refers to clinical intervention that attempts to alter the natural course of the individual being treated, and may be for prevention or in the course of clinical pathology. Desired effects of treatment include, but are not limited to, preventing the occurrence or recurrence of disease, alleviating symptoms, attenuating any direct or indirect pathological consequences of the disease, preventing metastasis, reducing the rate of disease progression, ameliorating or alleviating the disease state, and alleviating or improving prognosis.

The invention provides a thalidomide or its analogue transdermal patch, which includes:

1.Backing layer

The backing layer serves as the upper surface of the patch formulation and serves as the primary structural element that provides flexibility to the patch formulation. Preferably, the backing layer is substantially impermeable to transdermally administered pharmaceutical compositions.

The backing layer is preferably made from a sheet or film of flexible elastic material. The backing layer is preferably air-impermeable. The backing layer used in the patch of the present invention is preferably made of a flexible, biocompatible material that mimics the elastic properties of the skin and conforms to the skin during movement. Non-occlusive backing layers allow the area to breathe (i.e. promote water vapor transmission across the skin surface), while occlusive backing layers reduce air/vapor penetration. Preferably, the backing layer of reservoir type transdermal patches (Fig. 1) and matrix type transdermal patches (Fig. 2) is occlusive.

Preferably, the backing layer contains synthetic polymers such as polyolefins, polyesters, polyethylene, polyvinylidene chloride and polyurethanes. Preferably, the thickness of the backing layer is from about 0.5 mil to about 5 mils; more preferably, the thickness of the backing layer is from about 1 mil to about 3 mils. Preferably, the oxygen transmission rate is from about 2 cc/m/24hr to about 100 cc/m/24hr, and more preferably, the oxygen transmission rate is from about 70 g/m/24hr to about 90 g/m/24hr. Preferably, the MVTR is from about 0.3 g/m/24hr to about 50g/m/24hr, more preferably, the MVTR is from about 5g/m/24hr to about 30g/m/24hr.

In a preferred embodiment, the backing layer is an approximately 2.0 mil thick layer of occlusive polyester film (commercially available, e.g., Scotchpak 9733, 3M Drug Delivery Systems, St. Paul Minn.). Scotchpak 9733 consists of polyester and medium density polyethylene/ethylene vinyl acetate heat sealable laminates that are translucent, conformable, occlusive and heat sealable. It can be used in the depot type patch formulation shown in Figure 1.

2.Drug reservoir layer

The drug reservoir layer contains thalidomide or its analogues or its pharmaceutically acceptable salts, skin penetration enhancers, etc., wherein the penetration enhancers include solvents, polymer solubilizers, surfactants, medium molecular weight organic acids and low Molecular weight of any one of the organic acids or any combination thereof.

Solvents, also known as Type A skin penetration enhancers, can partially or completely dissolve not only one or more other skin penetration enhancers but also thalidomide or its analogues or Its pharmaceutically acceptable salt. In addition, the solvent itself is also beneficial to enhance the skin permeability of thalidomide or its analogs or its pharmaceutically acceptable salts. Non-limiting examples of solvents include C ₁ to C ₆ alkyl alcohols, propylene glycol, butylene glycol, dipropylene glycol, hexylene glycol, diethylene glycol monoethyl ether (transcutol), dimethyl sulfoxide, N,N-dimethyl Acetamide, N,N-dimethylformamide, N-methylpyrrolidone, glycerol, water or a combination of two or more of the above. Preferably, the solvent is selected from ethanol, dimethyl sulfoxide or a combination of both.

Other skin penetration enhancers include polymer solubilizers (type B skin penetration enhancers), surfactants (type C skin penetration enhancers), medium molecular weight organic acids (type D skin penetration enhancers) and low molecular weight organic acids (type D skin penetration enhancers). E-type skin penetration accelerator), etc.

Polymeric solubilizers include, but are not limited to, hydroxypropylcellulose, povidone, copovidone, crospovidone, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate , hydroxypropyl methylcellulose, hyaluronic acid, pectin, carboxymethylcellulose, alginic acid, Eudrgit S, Eudragit L, Eudrgit L-55, carrageenan, or two or more of the above The combination. Preferred are hydroxypropylcellulose, povidone, and crospovidone.

The weight percentage of the polymer solubilizer is 0.1% to 50% of the drug reservoir layer, such as 2% to 50%, 2 to 30%, preferably 5 to 25%, 10 to 20%. If the content of the polymer solubilizer is less than 2% of the drug reservoir, it will cause the maximum blood drug concentration (Cmax) of thalidomide or its analogues to be too high; if the content of the polymer solubilizer exceeds the drug reservoir At 30% of the reservoir layer, the rate of outward diffusion of thalidomide or its analogues from the reservoir layer would be excessively inhibited, resulting in a significant reduction in skin permeability. Moreover, the weight ratio of thalidomide or its analogue or its pharmaceutically acceptable salt to the polymer solubilizer is about 1:0.1 to 1:20, preferably 1:1 to 1:5, more preferably is 1:1 to 1:2.

Surfactants include, but are not limited to, lauryl lactate, myristyl lactate, cetyl lactate, palmityl lactate, Ceraphyl 31, ethyl laurate, methyl laurate, isopropyl myristate, isopropyl palmitate , fatty alcohols, menthol, saturated or unsaturated C ₉ to C ₃₀ fatty acids, fatty acid esters, diisoadipate, medium chain fatty acid triglycerides, diethyl sebacate, sesquisorban, Span 20, Span 40, Span 80, Tween 20, Tween 40, Tween 80, pentalactone, glyceryl monolactylate, glyceryl monostearate, glyceryl monoolein or combinations thereof. Preferably, the active agent includes lauryl lactate, isopropyl myristate, isopropyl palmitate and/or oleic acid, etc.

The term fatty alcohol refers to compounds having the formula ROH, where R is C ₇ -C ₃₀ alkyl or C ₃ -C ₃₀ alkenyl containing one, two, three or four double bonds. Fatty alcohols may include, but are not limited to, one or more saturated, monounsaturated, or polyunsaturated fatty alcohols; they may include, but are not limited to, one or more of the following: octanol, nonanol, decanol, undecanol Alcohol, lauryl alcohol, isomylauryl alcohol, trans-isolauryl alcohol, tridecanol, myristyl alcohol, isomyristyl alcohol, trans-isomyristyl alcohol, pentadecyl alcohol, cetyl alcohol, palmityl alcohol, isopalmityl alcohol, trans- Isopalmityl alcohol, heptadecanol, stearyl alcohol, isostearyl alcohol, trans-isostearyl alcohol, oleyl alcohol, linoleyl alcohol, nonadecanol, arachidonic alcohol, octyldodecanol, behenyl alcohol Alcohol, mustard alcohol, wood wax alcohol and wood wax alcohol, etc. In some embodiments, the saturated fatty alcohol may include, but is not limited to, one or more of the following: lauryl alcohol, isolauryl alcohol, trans-isolauryl alcohol, myristyl alcohol, isomyristyl alcohol, trans-isomyristyl alcohol, cetyl alcohol Wax alcohol, isopalmityl alcohol, trans-isopalmityl alcohol, stearyl alcohol, isostearyl alcohol and trans-isostearyl alcohol. In some embodiments, the fatty alcohol is myristyl alcohol.

The term fatty acid ester refers to an ester resulting from the combination of a fatty acid and an alcohol, where the fatty acid and the alcohol are compounds having the formulas RCOOH and R'OH, respectively, where R and R' are each a C ₁ -C ₃₀ alkyl group.

Exemplary C ₉ to C ₃₀ fatty acids include saturated, unsaturated, monounsaturated and polyunsaturated fatty acids, branched or unbranched fatty acids, such as omega 3, omega 6, omega 7, omega 9 fatty acids, capric acid, lauric acid Acid, palmitic acid, stearic acid, isostearic acid, 5-dodecenoic acid (C12:1), 7-tetradecenoic acid (14:1), palmitoleic acid (16:1), oleic acid (C18:1), vaccenic acid (C18:1), elaidic acid (C18:1), pterostilbene acid (C20:1), gondolanic acid (C20:1), erucic acid (C22:1), mustard Acid, nervonic acid, and simonic acid, 15-docosenoic acid (C22:1), 17-tetracosenoic acid (24:1), nervonic acid (C24:1), and simonic acid (C26: 1), Cetosatrienoic acid (16:3), linoleic acid (C18:2), ruminal acid (C18:2), α-linolenic acid (C18:3), γ-linolenic acid (C18:3 ), calendula acid (C18:3), stearic acid (C18:4) honey acid (C20:3), eicosadienoic acid (C20:3)), eicosatrienoic acid (C20: 3), dihomo-γ-linolenic acid (C20:3), arachidonic acid (C20:4), docosadienoic acid (C22:2), epinephrine (C22:4), Osborne Eicosapentaenoic acid (C22:5), eicosapentaenoic acid (C24:4), eicosapentaenoic acid (C24:5).

Surfactants also include, but are not limited to, glycerides (monoglycerides, diglycerides, and triglycerides), polyoxyethylene stearate, octasteidate-4 phosphate, and ethylene glycol palm stearin. A mixture of acid esters and diethylene glycol palm stearate, one or more PEG-6 stearates in a mixture of polyglyceryl-3 diisostearate and ethylene glycol palm stearate And PEG-32 stearate, oleoyl polyoxy-6 glyceride, lauroyl polyoxy-6 glyceride, capryloyl polyoxy-8 glyceride, propylene glycol monocaprylate type I, propylene glycol monolaurin Acid ester type II, propylene glycol monolaurate type I, propylene glycol monooctanoate type II, polyglyceryl-3 dioleate, mixture of PEG-6 stearate and PEG-32 stearate, lecithin , cetyl alcohol, cholesterol, sodium dioctyl sulfosuccinate, sodium lauryl sulfate, triethanolamine stearate, potassium laurate, polyoxyethylene fatty alcohol ether, glyceryl monostearate, dehydrated sorbate Sugar alcohol monolaurate, lanolin alcohol and ethoxylated lanolin alcohol, sorbitan fatty acid ester, sucrose distearate.

The weight percentage of surfactant is 1% to 70% of the drug reservoir layer, preferably 5 to 35%.

Medium molecular weight organic acids include, but are not limited to, C ₅ to C ₈ organic acids. Non-limiting examples include levulinic acid, sorbic acid, itaconic acid, mesaconic acid, ketoglutaric acid, glutaric acid, Methyl succinic acid, valeric acid, isovaleric acid, pivalic acid, cis-aconitic acid, trans-aconitic acid, ascorbic acid, citric acid, isocitric acid, adipic acid, caproic acid, benzoic acid, salicylic acid , gentisic acid, protocatechuic acid, gallic acid, cyclohexanecarboxylic acid, pimelic acid, phthalic acid, isophthalic acid, isophthalic acid, terephthalic acid, terephthalic acid, phenylacetic acid , toluic acid, o-toluic acid, m-toluic acid, p-toluic acid, mandelic acid, homogentistic acid, suberic acid, suberic acid, caprylic acid, or combinations thereof. Preferably, the medium molecular weight organic acids include levulinic acid, glutaric acid, adipic acid and combinations thereof, which are less skin irritating and non-sensitizing.

The content of medium molecular weight organic acid is 0.2-60% of the drug reservoir layer, preferably 0.2-30%, 0.5-30%, and more preferably 1-15%. If the content of medium molecular weight organic acids is less than 0.2% of the drug reservoir layer, the skin penetration enhancement effect will become meaningless. If the content of medium molecular weight organic acid exceeds 60%, it may not be completely dissolved by the solvent.

Low molecular weight organic acids include, but are not limited to, C ₁ to C ₄ monocarboxylic acids or dicarboxylic acids. Non-limiting examples include formic acid, glyoxylic acid, oxalic acid, acetic acid, glycolic acid, acrylic acid, pyruvic acid, malonic acid, propionic acid, 3-hydroxypropionic acid, lactic acid, glyceric acid, fumaric acid, maleic acid, oxalic acid Acetoacetic acid, crotonic acid, acetoacetic acid, 2-oxobutyric acid, methylmalonic acid, succinic acid, malic acid, L-tartaric acid, DL-tartaric acid, meso-tartaric acid, dihydroxytartaric acid, butyric acid, isobutyric acid acid, hydroxybutyric acid, or combinations thereof. Preferably, the low molecular organic acid is lactic acid.

The content of low molecular weight organic acid is 0.1 to 10% by weight of the reservoir layer, preferably 0.1 to 5%, 0.5 to 5%, more preferably 0.5 to 3%. If the content of low molecular weight organic acids is less than 0.1% by weight of the reservoir layer, the skin penetration enhancing effect will become meaningless. If the content of low molecular weight organic acids exceeds 10% by weight of the reservoir layer, it can cause unacceptable levels of skin irritation.

In one embodiment, the drug reservoir layer comprises thalidomide or an analog thereof or a pharmaceutically acceptable salt thereof and a skin penetration enhancer including a polymeric solubilizer (Type B skin penetration enhancer agent), surfactant (type C skin penetration enhancer) and medium molecular weight organic acid (type D skin penetration enhancer); among them, both polymer solubilizers and medium molecular weight organic acids can dissolve thalidomide or its analogs . Only dissolved molecules of thalidomide or its analogs can penetrate the skin, while undissolved crystals of thalidomide or its analogs will not penetrate the skin. Medium molecular weight organic acids and dissolved molecules of thalidomide or its analogues can penetrate the skin. As more and more medium molecular weight organic acids penetrate the skin, less and less organic acids remain in the drug reservoir. However, polymer solubilizers do not penetrate the skin but remain in the drug reservoir layer, and therefore polymer solubilizers provide a longer-lasting penetration enhancement effect than medium molecular weight organic acids, lasting about less than 24 hours, e.g., 6 to 23 hours, 24 hours, 48 hours, 72 hours, 84 hours, 96 hours, 120 hours, 144 hours or more than 168 hours. The polymer solubilizer also increases the viscosity of the drug reservoir layer, thereby reducing the rate at which dissolved thalidomide or its analogues diffuses outward from the drug reservoir layer to reduce Cmax. The reduction in Cmax helps provide a more constant amount of skin penetration over 24 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours and 168 hours.

In another embodiment, the drug reservoir layer comprises thalidomide or an analog thereof or a pharmaceutically acceptable salt thereof and a skin penetration enhancer including a solvent (Type A skin penetration enhancer) , polymer solubilizer (type B skin penetration accelerator), surfactant (type C skin penetration accelerator), medium molecular weight organic acid (type D skin penetration accelerator). Medium molecular weight organic acids have low skin irritation. In a preferred embodiment, the drug reservoir layer contains thalidomide or an analog thereof or a pharmaceutically acceptable salt thereof and a skin penetration enhancer, wherein the skin penetration enhancer includes a solvent (type A skin penetration enhancer) , polymer solubilizer (type B skin penetration accelerator), surfactant (type C skin penetration accelerator), medium molecular weight organic acid (type D skin penetration accelerator) and low molecular weight organic acid (type E skin penetration accelerator) ). Medium molecular weight organic acids have low skin irritation. Low molecular weight organic acids are less irritating to skin at low concentrations. Low molecular weight organic acids dissolve drugs and penetrate the skin faster than medium molecular weight organic acids, but they also disappear faster. Therefore, the skin penetration effect of low molecular weight organic acids is short-lived. The low molecular weight organic acid enhances the skin penetration of thalidomide or its analogues through at least two functions. It dissolves alidomide or its analogs into solution and also improves the physiological properties of thalidomide or its analogs by forming acid-base addition salts to increase skin permeability. Medium molecular weight organic acids dissolve thalidomide or its analogs at lower concentrations and can form acid-base addition salts. Medium molecular weight organic acids have a delayed skin penetration enhancement effect, but also have a more sustained penetration enhancement effect, that is, the enhancement time is longer than that of low molecular weight organic acids.

If the drug reservoir layer contains only low molecular weight organic acids, the duration of enhanced skin penetration ranges from a few hours to 24 hours. If the drug reservoir layer contains only medium molecular weight organic acids, there will be no appreciable penetration of thalidomide or its analogues during the first 24 hours. There is no meaningful skin penetration of thalidomide or its analogues if the drug reservoir layer contains only solvents and polymer solubilizers. If the drug reservoir layer only contains surfactant, there is no meaningful skin penetration of thalidomide or its analogues because the drug is not in a dissolved state for penetration.

The weight of the drug reservoir layer coating is from about 55 grams to about 1000 grams per square meter. The thickness of the drug reservoir layer coating ranges from about 40 microns to about 1000 microns.

3. Semi-permeable membrane layer

The semipermeable membrane layer is used to contain liquid or semi-solid matrix material within the drug reservoir layer, and its function is to control the diffusion of thalidomide or its analogues from the liquid or semi-solid drug reservoir layer to the adhesive layer. . The semipermeable membrane layer and backing layer may be sealed together around the peripheral edge.

Semipermeable membrane layers include, but are not limited to, ethylene-co-vinyl acetate copolymer membranes, polyethylene polymer membranes, and polypropylene polymer membranes. Non-limiting examples of ethylene-co-vinyl acetate include 3M Cotran 9709, Cotran 9712, Contan 9716 and Contran 9728. Non-limiting examples of polyethylene films include Solupore. Non-limiting examples of polypropylene films include Celgard 2400.

Suitable semipermeable membrane layers include continuous membranes and microporous membranes, which may be woven or non-woven materials. The semipermeable membrane is preferably made of a flexible polymeric material commonly used by those skilled in the art. Polymer films that may be used to make the semipermeable membrane layer include, but are not limited to, those containing low density polyethylene, high density polyethylene, ethyl vinyl acetate copolymer, polypropylene, and other suitable polymers. In one embodiment, the semipermeable membrane layer is a microporous membrane prepared from an ethylene-vinyl acetate copolymer containing from about 0.5 to about 28 wt. % vinyl acetate. Suitable braided materials include Saatifil PES, such as PES 105/52 available from Saatitech, Inc. A suitable nonwoven fabric is Sontara from DuPont Nonwovens Sontara Technologies. In preferred embodiments, the semipermeable membrane layer is an ethylene-vinyl acetate copolymer membrane available from 3M™, such as Cotran 9702, Cotran 9705, Cotran 9706, Cotran 9707, Cotran 9712, Cotran 9715, Cotran 9716, and Cotran 9728 ( Available from 3MTM).

The thickness of the semipermeable membrane layer may generally be from about 10 um to about 100 um, preferably from about 15 μm to about 50 μm.

4. Adhesive layer

The adhesive layer serves to adhere the thalidomide or its analog transdermal patch to the skin surface. It can also be used to control the rate of delivery of thalidomide or its analogues to the skin after the release layer is removed. The adhesives include, but are not limited to, acrylic adhesives, methacrylic adhesives, polyisobutylene adhesives, styrene-isoprene-styrene block copolymer adhesives, silicone adhesives agent, acrylic-copolysiloxane copolymer adhesive, or a combination of two or more of the above. Non-limiting examples of acrylic adhesives include Henkel's Duro-Tak Adhesives 387-2051, 387-2054, 387-2353, 87-235, 387-2516, 387-2287, 387-2510, 87-287- 2054, 87-210294 (Sanyo Chemical Industry Co., Ltd.). Non-limiting examples of polyisobutylene binders include Oppanol N150, Oppanol B150, Oppanol N100, Oppnaol B100, Oppanol N80, Oppanol B80, Oppanol B10, B11, B12 and low molecular weight polybutene H1900 from Ineos with mineral oil tackification agent. Non-limiting examples of silicone adhesives include DuPont Bio-PSA 7-4100, 7-4200, 7-4300, 7-4400, 7-4500 and 7-4302. Non-limiting examples of acrylic-co-polysiloxane copolymer adhesives include DuPont Bio-PSA 7-6100, 7-6200 and 7-6300 and 7-6302. Combinations of acrylic adhesives with silicone adhesives and polyisobutylene adhesives with styrene-isoprene-styrene block copolymer adhesives are also acceptable adhesive choices. Preferably, the adhesive is a polyisobutylene adhesive, a styrene-isoprene-styrene block copolymer adhesive, a silicone adhesive and an acrylic-co-polysiloxane copolymer adhesive. agent.

The inventors have found that cross-linked adhesives such as Duro-Tak 387-2054 adhere to the skin better than non-cross-linked adhesive 387-2051, and cross-linked 387-2516 adheres better to skin than non-cross-linked 387-2287 adhere to the skin.

The inventors also found that by adding the additives Eudragit E100, Plastoid B, crospovidone CML, colloidal silica under the trade name Cabo-Sil-5 or aluminum magnesium metasilicate (e.g. Neusilin from Fuji Chemical Industries) and kaolin The adhesion of the skin to the adhesive layer can be further improved. Magnesium aluminum metasilicate is preferably an amorphous composite oxide formed by three-dimensional polymerization of aluminum, magnesium and silicon atoms through oxygen atoms. This composite oxide is more specifically represented by the following formula: Al ₂ O ₃ /aMgO/bSiO ₂ -nH ₂ O, where a=0.3-3 and b=0.3-5. Due to its porous structure, this magnesium metaaluminosilicate is believed to have further improved adhesion in the presence of water.

The skin contact adhesive layer may also contain one or more pharmaceutically acceptable additives, non-limiting examples of which include antioxidants, anti-skin irritants, cohesion promoters, plasticizers, tackifiers wait.

The additive is included in the skin contact adhesive layer in an amount of about 0.05% to about 40% by weight of the adhesive, preferably about 1% to about 30%, more preferably about 3% to about 30%, most preferably adhesive Approximately 20% of the weight of the agent material.

Non-limiting examples of antioxidants include tocopherol, tocopheryl acetate, butylated hydroxytoluene, butylated hydroxyanisole, potassium metabisulfite, sodium metabisulfite, sodium bisulfite, sodium sulfite, propyl gallate, Thioglycerol, sodium thiosulfate, sodium dioxide, sodium formaldehyde sulfoxylate, and chelating agents as synergistic antioxidants include citric acid, tartaric acid, calcium disodium edetate, disodium edetate, and EDTA.

Non-limiting examples of cohesion promoters include colloidal silica, zinc oxide, polyvinylpyrrolidine, acrylate copolymers, crospovidone, croscarmellose (cross-linked hydroxymethylcellulose), Ethyl cellulose, acrylic copolymers, bentonites, clays and mixtures thereof. In a preferred embodiment, the cohesion promoter is colloidal silica. The cohesion promoter is present in the adhesive layer in an amount from about 3% to about 40% by weight of the adhesive material, preferably from about 5% to about 30% by weight of the adhesive material. The inventors have found that when the skin contact layer adhesive is a polyisobutylene adhesive, a silicone adhesive, or a styrene-isoprene-styrene-based adhesive, the addition of a cohesive enhancer effectively The integrity of the adhesive is maintained.

Non-limiting examples of plasticizers include mineral oil, silicone oil, triethyl citrate, and combinations thereof. The plasticizer is present in the adhesive layer in an amount from about 0% to about 40% by weight of the adhesive material, preferably from about 0% to about 30% by weight of the adhesive material, more preferably for adhesion. From about 0% to about 30% by weight of the agent material, most preferably about 20% by weight of the adhesive material.

Non-limiting examples of tackifiers include silicone oil, mineral oil, polybutene, terpenes, and mixtures thereof. The tackifier is present in the adhesive layer in an amount from about 0% to about 40% by weight of the adhesive material, preferably from about 0% to about 30% by weight of the adhesive material.

Preparation

In one factual solution, the present invention provides a method for preparing a thalidomide or analogue transdermal patch, which transdermal patch includes a backing layer, a drug reservoir layer, a semipermeable membrane layer, a skin layer, and a backing layer. A contact layer, and optionally a protective release liner layer, comprising:

In one embodiment, first, a liquid, semi-solid or solid drug reservoir layer is prepared. Completely dissolve the polymer solubilizer (Type B skin penetration enhancer) in the solvent (Type A skin penetration enhancer) at room temperature or elevated temperature (e.g. 85°C), then add thalidomide or its analogues Or its pharmaceutically acceptable salt, mix at room temperature or high temperature (such as 85°C) to completely or partially dissolve, and then add surfactant (type C skin penetration enhancer), medium molecular weight organic acid (type D skin penetration enhancer) agent) and optional low molecular weight organic acid (E-type skin penetration enhancer), mixed at room temperature or high temperature (such as 85°C) to form a uniform liquid, semi-solid or solid. Then cool to room temperature. A uniform liquid, semi-solid or solid is dispensed or coated onto the backing film and laminated to the side of the semi-permeable film layer away from the adhesive layer/release layer.

In another embodiment, the uniform liquid, semi-solid or solid prepared as described above can be dispensed or coated on the side of the semi-permeable membrane layer away from the adhesive layer/release layer, and then combined with the backing layer laminated.

In another embodiment, the method of preparing a thalidomide or analogue transdermal patch may further include sealing the backing layer film and the semipermeable membrane by heat, pressure, or a combination of heat and pressure. The step of peripheral edge, the step of causing the liquid, semi-solid or solid mixture to be confined within the peripheral edge.

In another embodiment, the three edges of the side of the backing layer film close to the skin and the three edges of the side of the semipermeable membrane layer away from the skin contacting the adhesive layer/protective release liner layer can be first For edge sealing, liquid or semi-solid drug reservoir material is filled from the unsealed fourth edge into the three-sided sealed reservoir, and then the fourth edge is sealed to form a four-sided sealed drug reservoir layer.

In one embodiment, the invention provides a method for the treatment of multiple myeloma, transfusion-dependent anemia caused by low-risk or intermediate-risk myelodysplastic syndromes, mantle cell lymphoma, chronic lymphocytic leukemia, hematologic cancers, A method of solid tumor cancer or inflammatory disease, comprising administering to a patient in need thereof a therapeutically effective amount of a thalidomide or analogue thereof transdermal patch, comprising:

1) Backing layer;

2) Drug reservoir layer, which contains thalidomide or its analogs or its pharmaceutically acceptable salts;

3) Semi-permeable membrane layer;

4) adhesive layer; and optionally

5) Release layer.

In one embodiment, the thalidomide or analog thereof transdermal patch can provide high skin flux.

In one embodiment, the present invention provides a method for preparing a transdermal patch for use of thalidomide or its analogues in combination with dexamethasone. The transdermal patch includes a backing layer and a drug reservoir layer. , a semipermeable membrane layer, a skin contact layer, and optionally a protective release liner layer, which includes:

3) Mix thalidomide or its analogues or its pharmaceutically acceptable salts and dexamethasone or its pharmaceutically acceptable salts with the skin penetration enhancer to form a uniform liquid, semi-solid or solid mixture;

4) Evenly distribute or coat the resulting liquid, semi-solid or solid mixture on the backing film; and bond the side of the backing film distributed or coated with the mixture to the far side of the semi-permeable membrane layer Laminate one side of the agent layer/release layer; or

In one embodiment, first, a liquid, semi-solid or solid drug reservoir layer is prepared. Completely dissolve the polymer solubilizer (Type B skin penetration enhancer) in the solvent (Type A skin penetration enhancer) at room temperature or elevated temperature (e.g. 85°C), then add thalidomide or its analogues Or its pharmaceutically acceptable salt and dexamethasone or its pharmaceutically acceptable salt, mix at room temperature or high temperature (such as 85°C) to completely or partially dissolve, and then add surfactant (type C skin penetration enhancer) , medium molecular weight organic acid (type D skin penetration enhancer) and optional low molecular weight organic acid (type E skin penetration enhancer), mixed at room temperature or high temperature (such as 85°C) to form a uniform liquid, semi-solid or solid. Then cool to room temperature. A uniform liquid, semi-solid or solid is dispensed or coated onto the backing film and laminated to the side of the semi-permeable film layer away from the adhesive layer/release layer.

In another embodiment, the method of preparing a transdermal patch of thalidomide or an analog thereof in combination with dexamethasone may further comprise sealing the backing by heat, pressure, or a combination of heat and pressure The step of layering the peripheral edge of the membrane and the semi-permeable membrane makes the liquid, A step in which a semi-solid or solid mixture is confined within said peripheral edge.

In one embodiment, the invention provides a method for the treatment of multiple myeloma, transfusion-dependent anemia caused by low-risk or intermediate-risk myelodysplastic syndromes, mantle cell lymphoma, chronic lymphocytic leukemia, hematologic cancers, A method of solid tumor cancer or inflammatory disease, comprising administering to a patient in need thereof a therapeutically effective amount of thalidomide or an analog thereof together with a dexamethasone transdermal patch, comprising:

1) Backing layer;

3) Semi-permeable membrane layer;

4) adhesive layer; and optionally

5) Release layer.

In one embodiment, the thalidomide or analog thereof and dexamethasone transdermal patch can increase skin flux.

Example

The invention is described in detail below through examples. This example is only used to further illustrate the invention and cannot be understood as limiting the scope of the invention. Those skilled in the art will make some non-essential conclusions based on the content of the above invention. Improvements and adjustments all fall within the protection scope of the present invention.

The experimental methods used in the following examples are conventional methods unless otherwise specified. The materials and reagents used can be obtained from commercial sources unless otherwise specified.

abbreviation

Lena = lenalidomide

K90＝Povidone K90

HPC=Hydroxypropylcellulose

HPMCP = Hydroxypropyl Methylcellulose Phthalate

DMAC=N,N-dimethylacetamide

DMSO = dimethyl sulfoxide

CL-M=crospovidone

6302 or 7-6302 = Adhesive Bio-PSA7-6302

2516 or 387-2516 = Adhesive Duro-Tak 387-2516

4302 or 7-4302 = Adhesive Bio-PSA 7-4302

Examples 1 to 10

Solubility studies of thalidomide or its analogues. Before a drug can permeate the skin, the drug crystals must first be dissolved in the drug reservoir layer, and the dissolved drug molecules can penetrate the skin. The present invention measured the solubility of lenalidomide and dexamethasone in various polymer solubilizers, and the results are listed in Table 1. Surprisingly, the inventors found that lenalidomide in hydroxypropylcellulose has a better crystallization inhibitory effect than traditional crystallization inhibitors such as povidone (PVP). However, dexamethasone in povidone It has better solubility and crystallization inhibition.

Table 1. Solubility of lenalidomide and dexamethasone in polymers

Lena=Lenalidomide, K90=Povidone K90, HPC=Hydroxypropylcellulose, HPMCP=Hydroxypropylmethylcellulose phthalate, DMAC=N,N-dimethylacetamide

In addition, the present invention also measured the solubility of lenalidomide and dexamethasone in small molecule solvents, and the results are listed in Table 2 and Table 3. In addition, other types of skin penetration enhancers such as solvents (type A skin penetration enhancer), surfactants (type C skin penetration enhancer), medium molecular weight organic acids (type D skin penetration enhancer) and Low molecular weight organic acid (E-type skin penetration enhancer) is used to prepare transdermal patches.

Table 2. Solubility of lenalidomide in small molecule solvents

Table 3. Solubility of dexamethasone in small molecule solvents

In vitro skin flux assay of lenalidomide and dexamethasone

In vitro penetration testing using a vertical statically modified Franz unit. The receiving unit has a volume of 28 ml and is filled with a buffer solution of pH 7.4 containing monopotassium phosphate, sodium chloride and sodium azide. The effective skin penetration size is 0.61cm2. Install 700 to 800um thick human cadaver skin on the receiving unit with the dermal layer side facing up. Place the O-ring on top of the skin. Fill the O-ring with pre-weighed reservoir liquid or semi-solid formulation. Secure the donor cells to the top of the recipient unit with clamps. Place the Franz unit in a 32 °C incubator on a magnetic stir plate. Take 2 ml of solution at each prearranged time point, pour off the remaining solution, and refill with new receiving solution. The received solution was immediately analyzed by HPLC for the amount of lenalidomide and dexamethasone.

Examples 11 to 18

Weigh each component according to the prescription of preparation composition 11-18 in Table 4-5, mix lenalidomide and dexamethasone and other excipients in a glass bottle and completely dissolve in HPC, lenalidomide and dexamethasone Liquid or semi-solid formulations are prepared by heating in an oven if completely or partially dissolved. Preparation compositions 11-18 correspond to Examples 11-18 respectively. Skin flux testing was performed according to the previously described procedures. The results of the in vitro skin flux assay for lenalidomide are summarized in Table 4 and the results of the in vitro skin flux assay for dexamethasone are summarized in Table 5. It can be seen that formulation combinations 15 and 16 containing only polymer solvent B (HPC) have very low skin fluxes of lenalidomide and dexamethasone. In other formulation combinations containing polymer solubilizer B, a small amount of solvent A (dimethyl sulfoxide) and the adhesive Duro-Tak 387-2516 or Bio-PSA7-6302, the skin flux of lenalidomide and dexamethasone is also very low.

Examples 19 to 26

Weigh each component according to the prescription of preparation compositions 19-26 in Table 6-7, and prepare the preparation compositions of Examples 19-26 according to a method similar to Examples 11-18. Skin flux testing was performed according to the previously described procedures. The in vitro skin flux measurement results of lenalidomide are summarized in Table 6, and the skin flux release curve is shown in Figure 5. The in vitro skin flux measurement results of dexamethasone are summarized in Table 7, and the skin flux release curve is shown in Figure 6. .

The measurement results in Tables 6 and 7 show that the skin flux of formulation compositions 19 to 24 using skin penetration enhancer combinations of B+C, B+D and A+B+C or A+B+D is very low. Surprisingly, the skin flux of lenalidomide of compositions 25 and 26 was found when the skin penetration enhancer combination was B+C+D (polymer solvent B, surfactant C and medium molecular weight organic acid D). is higher, and the skin flux of dexamethasone is also higher.

Examples 27 to 33

Weigh each component according to the prescription of preparation compositions 27-33 in Table 8-9, and prepare the preparation compositions of Examples 27-33 according to a method similar to Examples 11-18. Skin flux testing was performed according to the previously described procedures. The in vitro skin flux measurement results of lenalidomide are summarized in Table 8, and the skin flux release curve is shown in Figure 7. The in vitro skin flux measurement results of dexamethasone are summarized in Table 9, and the skin flux release curve is shown in Figure 8. .

The measurement results in Tables 8 and 9 show that when the skin penetration enhancer combination adopts A+B+C, the preparation composition 28 has a certain skin flux. The skin flux of formulations 27 and 29-33 increased when the skin penetration enhancer combination A+B+C+D was used.

When hydroxypropylcellulose was selected as polymer solubilizer B, skin flux of formulations 27-29 was sustained for up to 96 hours. When polymer solubilizer B is cross-linked povidone Cl-M (B), the skin flux of formulation compositions 30-33 also lasts up to 168 hours. When hydroxypropyl cellulose is selected as polymer solubilizer B, the overall skin flux of the preparation composition is higher than that of cross-linked povidone Cl-M (B).

Examples 34 to 45

Weigh each component according to the prescription of preparation compositions 34-45 in Table 10-11, and prepare the preparation compositions of Examples 34-45 according to a method similar to Examples 11-18. Skin flux testing was performed according to the previously described procedures. The in vitro skin flux measurement results of lenalidomide are summarized in Table 10, and the skin flux release curve is shown in Figure 9. The in vitro skin flux measurement results of dexamethasone are summarized in Table 11, and the skin flux release curve is shown in Figure. 10.

The measurement results in Tables 10 and 11 show that polymer solvent B will affect the skin flux of the formulation composition after 72 hours. Formulations 35, 39, 40, 44 and 45, which used medium molecular weight organic acid D but not polymer solvent B, had reduced skin flux after 72 hours. Formulations 34, 36, 37, 38, 41, 42 and 43 used medium molecular weight organic acid D and used polymer solvent B hydroxypropyl cellulose or crospovidone, and the skin flux after 72 hours was Skin fluxes were maintained at relatively high levels.

Examples 46 to 52

Weigh each component according to the prescription of preparation compositions 46-52 in Tables 12-13, and prepare the preparation compositions of Examples 46-52 according to a method similar to Examples 11-18. Skin flux testing was performed according to the previously described procedures. The in vitro skin flux measurement results of lenalidomide are summarized in Table 12, and the skin flux release curve is shown in Figure 11. The in vitro skin flux measurement results of dexamethasone are summarized in Table 13, and the skin flux release curve is shown in Figure 12. .

The measurement results in Tables 12 and 13 further prove that the skin flux of formulation compositions 46, 48, 49, 51 and 52 with polymer solvent B and containing medium molecular weight organic acid D is continuously high, and that of the formulation without polymer solvent B Skin flux decreased from 72 hours for compositions 47 and 50.

Examples 53 to 58 Weigh each component according to the prescription of the preparation compositions 53 to 58 in Table 14-15, and prepare the preparation compositions of Examples 53 to 58 in a similar manner to Examples 11 to 18. Skin flux testing was performed according to the previously described procedures. The in vitro skin flux measurement results of lenalidomide are summarized in Table 14, and the skin flux release curve is shown in Figure 13. The in vitro skin flux measurement results of dexamethasone are summarized in Table 15, and the skin flux release curve is shown in Figure 14. .

The data in Tables 14 and 15 further demonstrate that formulations 53 to 58 using polymer solubilizer B and medium molecular weight organic acid D in the formulation composition have consistently high skin flux.

Examples 59 to 61

Weigh each component according to the prescription of preparation compositions 59-61 in Tables 16-17, and prepare the preparation compositions of Examples 59-61 according to a method similar to Examples 11-18. Skin flux testing was performed according to the previously described procedures. The in vitro skin flux measurement results of lenalidomide are summarized in Table 16, and the skin flux release curve is shown in Figure 15. The in vitro skin flux measurement results of dexamethasone are summarized in Table 17, and the skin flux release curve is shown in Figure 16. .

From Table 16 and Table 17, formulations 59 and 60 containing polymer solvents B and C and a small amount of medium molecular weight organic acid D and formulation 61 containing polymer solvents B and C and no medium molecular weight organic acid have a certain amount of skin flux. This shows that the skin permeability of the B+C combination is within the acceptable range.

Examples 62 to 66

Weigh each component according to the prescription of preparation compositions 62-66 in Tables 18-19, and prepare the preparation compositions of Examples 62-66 according to a method similar to Examples 11-18. Skin flux testing was performed according to the previously described procedures. The in vitro skin flux measurement results of lenalidomide are summarized in Table 18, and the skin flux release curve is shown in Figure 17. The in vitro skin flux measurement results of dexamethasone are summarized in Table 19, and the skin flux release curve is shown in Figure 18. .

From Table 18 and Table 19, formulation 62 containing polymer solvent B and a small amount of low molecular weight organic acid E, or formulation 64 containing polymer solvent B and medium low molecular weight organic acid D, or containing polymer solvent B without low molecular weight or medium Organic acid formula with molecular weight 63 has considerable skin flux. The skin flux was very low for formulation 65 containing polymer solvent B and medium low molecular weight organic acid with binder 387-2516 and formulation 66 containing polymer solvent B and no low molecular weight organic acid with binder.

Claims

A transdermal patch comprising:

1) Backing layer;

2) Drug reservoir layer, which contains thalidomide or an analog thereof or a pharmaceutically acceptable salt thereof; the thalidomide analog is preferably lenalidomide, pomalidomide, ibedudomide or alpra ster;

3) Semi-permeable membrane layer;

4) adhesive layer; and optionally

5) Release layer.
The transdermal patch according to claim 1, characterized by comprising:

1) Backing layer;

2) a drug reservoir layer, which contains thalidomide or its analogs and dexamethasone or its pharmaceutically acceptable salt;

3) Semi-permeable membrane layer;

4) Adhesive layer; and optionally a release layer.
The transdermal patch according to claims 1 and 2, wherein the drug reservoir layer further comprises a skin penetration enhancer.
The transdermal patch according to claim 3, wherein the skin penetration enhancer is selected from any one of solvents, polymer solubilizers, surfactants, medium molecular weight organic acids and low molecular weight organic acids or any combination thereof .
The transdermal patch of claim 4, wherein the skin penetration enhancer includes a polymer solubilizer and a surfactant.
The transdermal patch according to claim 5, wherein the skin penetration enhancer further comprises a medium molecular weight organic acid, a low molecular weight organic acid, or a medium molecular weight organic acid and a low molecular weight organic acid on the basis of a polymer solubilizer and a surfactant. A combination of acids.
The transdermal patch according to claim 5 or 6, wherein the skin penetration enhancer further comprises a solvent.
The transdermal patch according to any one of claims 4-7, wherein the polymer solubilizer is hydroxypropyl cellulose, povidone, copovidone, cross-linked povidone, phthalic acid Hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose, hyaluronic acid, pectin, carboxymethylcellulose, alginic acid, carrageenan, or any Combination; preferably hydroxypropylcellulose, povidone, crospovidone or combinations thereof.
The transdermal patch according to any one of claims 1 to 8, wherein the weight percentage of thalidomide or its analog or its pharmaceutically acceptable salt is 0.5% to 50% of the drug reservoir layer %, preferably 1% to 20%, more preferably 2% to 10%.
The transdermal patch according to any one of claims 4-8, wherein the weight percentage of the polymer solubilizer is 0.1% to 50% of the drug reservoir layer, preferably 2% to 50%, 2 to 30%, 5 to 25%, more preferably 10% to 20%, and the weight ratio of thalidomide or its analog or pharmaceutically acceptable salt thereof to the polymer solubilizer is about 1:0.1 to 1:20, preferably about 1:0.5 to 1:15, more preferably about 1:1 to 1:10.
The transdermal patch according to any one of claims 4 to 7, wherein the weight percentage of the surfactant is 1% to 50% of the drug reservoir layer, preferably 5 to 30%.
The transdermal patch according to any one of claims 4 or 6-7, wherein the weight percentage of the medium molecular weight organic acid is 0.2-60% of the drug reservoir layer, preferably 0.2-30%, 0.5 -30%, more preferably 1-15%.
The transdermal patch according to any one of claims 4 or 6-7, wherein the weight percentage of the low molecular weight organic acid is 0.1 to 10% of the drug reservoir layer, preferably 0.1 to 5%, 0.5 to 5%, more preferably 0.5 to 3%.
The transdermal patch according to any one of claims 4 or 6-7 or 12, wherein the medium molecular weight organic acid includes C 5 to C 8 organic acid, preferably including levulinic acid, sorbic acid, itaconic acid Acid, mesaconic acid, ketoglutaric acid, glutaric acid, methylsuccinic acid, valeric acid, isovaleric acid, pivalic acid, cis-aconitic acid, trans-aconitic acid, ascorbic acid, citric acid, isocitonic acid Acid, adipic acid, caproic acid, benzoic acid, salicylic acid, Gentisic acid, protocatechuic acid, gallic acid, cyclohexanecarboxylic acid, pimelic acid, phthalic acid, isophthalic acid, isophthalic acid, terephthalic acid, terephthalic acid, phenylacetic acid, Toluic acid, o-toluic acid, m-toluic acid, p-toluic acid, mandelic acid, homogentistic acid, suberic acid, caprylic acid, or combinations thereof, more preferably including levulinic acid, glutaric acid, adipic acid and combinations thereof .
The transdermal patch according to any one of claims 4-7 or 13, wherein the low molecular weight organic acid includes C 1 to C 4 organic acid, preferably including formic acid, glyoxylic acid, oxalic acid, acetic acid, ethanol Acid, acrylic acid, pyruvic acid, malonic acid, propionic acid, 3-hydroxypropionic acid, lactic acid, glyceric acid, fumaric acid, maleic acid, oxaloacetic acid, crotonic acid, acetoacetic acid, 2-oxobutyric acid, Methylmalonic acid, succinic acid, malic acid, L-tartaric acid, DL-tartaric acid, meso-tartaric acid, dihydroxytartaric acid, butyric acid, isobutyric acid, hydroxybutyric acid, or combinations thereof, more preferably, including lactic acid .
The transdermal patch according to any one of claims 4 or 7, wherein the solvent is selected from C 1 to C 6 alkyl alcohol, propylene glycol, butylene glycol, dipropylene glycol, hexylene glycol, diethylene glycol Monoethyl ether, dimethyl sulfoxide, N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, glycerin, water or a combination of two or more of the above; ethanol is preferred , dimethyl sulfoxide or a combination of both.
The transdermal patch according to any one of claims 1-16, wherein the adhesive layer comprises a skin contact adhesive and optional antioxidants, anti-skin irritants, cohesion promoters, plasticizers Agents, tackifiers.
The transdermal patch of claim 17, wherein the skin contact adhesive comprises an acrylic adhesive, a methacrylic adhesive, a polyisobutylene adhesive, a styrene-isoprene-styrene inlaid adhesive. segment copolymer adhesive, silicone adhesive, acrylic-copolysiloxane copolymer adhesive, or a combination of two or more of the above.
The transdermal patch according to claim 17 or 18, wherein the skin contact adhesive is a cross-linked adhesive or a non-cross-linked adhesive.
The transdermal patch according to claim 17, wherein the cohesion promoter includes colloidal silicon dioxide, zinc oxide, polyvinylpyrrolidine, acrylate copolymer, crospovidone, croscarmellose , ethylcellulose, acrylic copolymer, bentonite, clay, or a combination of two or more of the above.
The transdermal patch according to claim 20, wherein the weight percentage of the cohesion promoter is about 3% to about 50% of the adhesive layer, preferably about 5% to about 30%.
A therapeutically effective amount of the transdermal patch according to any one of claims 1-21 is prepared for the treatment of multiple myeloma, transfusion-dependent anemia caused by low-risk or moderate-risk myelodysplastic syndrome, mantle cell lymphoma tumors, chronic lymphocytic leukemia, hematological cancers, solid tumor cancers or inflammatory diseases.
A method of treating multiple myeloma, transfusion-dependent anemia caused by low-risk or intermediate-risk myelodysplastic syndrome, mantle cell lymphoma, chronic lymphocytic leukemia, hematologic cancer, solid tumor cancer, or inflammatory disease, It involves administering to a subject in need thereof a therapeutically effective amount of the transdermal patch of any one of claims 1-21.
The method according to claim 23, wherein the transdermal patch is applied every 12 hours, every 23 hours, 24 hours, every 32 hours, every 48 hours, every 72 hours, every 84 hours, every 96 hours, every 120 hours. hour, every 144 hours, or every 168 hours.
The method of claim 24, wherein the thalidomide or analog thereof transdermal patch and the thalidomide or analog thereof and dexamethasone transdermal patch deliver from about 1 mg to about 40 mg every 24 hours of thalidomide or an analog thereof, preferably about 2.5 mg to about 10 mg of thalidomide or an analog thereof, to the blood system of the subject.