WO2020092990A1 - Compositions pharmaceutiques et procédés de fabrication d'une formulation de timbre pour administration transdermique - Google Patents

Compositions pharmaceutiques et procédés de fabrication d'une formulation de timbre pour administration transdermique Download PDF

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Publication number
WO2020092990A1
WO2020092990A1 PCT/US2019/059515 US2019059515W WO2020092990A1 WO 2020092990 A1 WO2020092990 A1 WO 2020092990A1 US 2019059515 W US2019059515 W US 2019059515W WO 2020092990 A1 WO2020092990 A1 WO 2020092990A1
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Prior art keywords
transdermal patch
pharmaceutical composition
patch
amount
sensitive adhesive
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Application number
PCT/US2019/059515
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English (en)
Inventor
Onkar N. Singh
Wei Zhang
Meredith Roberts CLARK
Gustavo F. Doncel
Ashana PURI
Ajay K. Banga
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Eastern Virginia Medical School
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Publication of WO2020092990A1 publication Critical patent/WO2020092990A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate

Definitions

  • the present invention relates to skin patches for the transdermal administration of drugs, and processes of manufacture, uses thereof, and corresponding methods of treatment therewith.
  • Transdermal matrix patches may exhibit physical stability issues due to crystallization, a common stability problem associated with dissolved drugs in a transdermal patch formulation under long-term storage, hence achieving higher permeation flux becomes challenging.
  • problems with the dissolved drug in a transdermal patch including: (a) drug content issues, (b) inhomogeneity and (c) inadequate drug release. These issues all adversely influence the therapeutic drug level.
  • a transdermal patch formulation capable of overcoming issues with respect to crystallization, release of a therapeutically effective amount of drug over time and minimal changes to release of the drug after storage to provide a formulation exhibiting improved stability and release profile.
  • the present application relates to compositions and methods of making adhesive suspension type patch formulations for transdermal delivery of a drug, such as an antiviral, more particularly an antiretroviral, for HIV treatment or prevention that resolve some of the issues associated with solubilized drugs in transdermal patches.
  • a drug such as an antiviral, more particularly an antiretroviral
  • this application relates to pharmaceutical compositions and methods of making transdermal patches containing suspended particles of drug that are capable of delivering an anti-retroviral drug (ARV), such as tenofovir alafenamide (TAP), for about seven to ten days across human epidermis in a sufficient flux to be therapeutically or prophylactically effective.
  • AMV anti-retroviral drug
  • TEP tenofovir alafenamide
  • the patches disclosed herein may be used to provide protection from HIV-1, HSV and HBV and may also be used for treatment of these and other viral infections.
  • a transdermal patch includes a backing layer and a pharmaceutical composition layer on the backing layer, wherein the pharmaceutical composition layer includes a pressure-sensitive adhesive (PSA), an antiviral drug, wherein the antiviral drug is suspended in the pressure sensitive adhesive as particles; and optionally a penetration enhancer, wherein the pharmaceutical composition layer comprises a therapeutically effective amount of the antiviral drug.
  • PSA pressure-sensitive adhesive
  • the pharmaceutical composition layer comprises a therapeutically effective amount of the antiviral drug.
  • the antiviral drug is an antiretroviral drag selected from the group consisting of dolutegravir, bictegravir, tenofovir, tenofovir disoproxil fumarate (TDF), delavirdine, nevirapine (NVP), tenofovir alafenamide, pharmaceutically acceptable salts thereof, prodrugs thereof and mixtures thereof.
  • the antiretroviral drug is tenofovir or a tenofovir prodrug.
  • the pressure-sensitive adhesive is a silicone or polyisobutylene (PIB) pressure sensitive adhesive.
  • the pressure sensitive adhesive is a silicone pressure sensitive adhesive.
  • the pharmaceutical composition layer includes a penetration enhancer in an amount of about 5 to 15% by weight based on the pharmaceutical composition.
  • the penetration enhancer is selected from the group consisting of oleic acid, oleyl alcohol and mixtures thereof.
  • the penetration enhancer comprises oleic acid and oleyl alcohol.
  • the antiviral drug is present in an amount of about 5 to 25% by weight based on the pharmaceutical composition.
  • the pressure sensitive adhesive is present in an amount of about 45 to 75% by weight based on the pharmaceutical composition.
  • the pharmaceutical composition comprises tenofovir alafenamide free base in an amount of about 5 to 25% by weight, a silicone or polyisobutylene pressure sensitive adhesive in an amount of about 45 to 75% by weight and a penetration enhancer in an amount of about 5- 15% by weight based on the
  • the pharmaceutical composition comprises tenofovir alafenamide free base in an amount of about 10 to 20% by weight, a silicone pressure sensitive adhesive in an amount of about 50 to 65% by weight and a penetration enhancer in an amount of about 5-15% by weight based on the pharmaceutical composition, wherein the penetration enhancer comprises oleic acid and oleyl alcohol.
  • the pharmaceutical composition further includes a plasticizer in an amount of about 5 to 20% by weight based on the pharmaceutical composition.
  • the plasticizer comprises mineral oil.
  • the transdermal patch provides a therapeutically effective amount of the drug over about 168 hours of administration.
  • the transdermal patch provides a permeation rate ranging from 0.1 to 7 pg/cm 2 /hr across human epidermis.
  • the particles of the antiviral drug have an average particle size of about 0.5 to about 50 pm, more particularly from about 1 to about 25 pm and still more particularly from about 2 to 15 pm.
  • the backing layer is a silicone-coated PET film.
  • the transdermal patch further includes a release liner laminated to the pharmaceutical composition layer opposite the backing layer.
  • the pharmaceutical composition layer further comprises an antiviral drug.
  • a method for treating or preventing a viral infection in a subject comprising administering the transdermal patch disclosed herein to the subject is described.
  • the viral infection is selected from the group consisting of HTV, HSV and HBV.
  • the transdermal patch is applied on the patient’s skin for more than 96 hours. According to some aspects, the transdermal patch is applied on the patient’s skin for about 168 hours.
  • a method of preparing a transdermal patch may include mixing antiviral drug particles with excipients to form a slimy, introducing a silicone or polyisobutylene pressure sensitive adhesive to the slurry to form a blend, homogenizing the blend while keeping the antiviral drug particles suspended in the pressure sensitive adhesive to form a pharmaceutical composition, casting said pharmaceutical composition to obtain a pharmaceutical composition layer having said drug particles suspended therein and having a skin contacting surface and a non-skin contacting surface thereof and laminating a backing membrane to said non-skin contacting surface.
  • FIG. 1 is a bar chart showing transdermal flux of TAF following the application of 2% w'/w and 10% wAv TAF loaded clear (soluble) patches with acrylate adhesive and 15% w/w TAF loaded silicone suspension patches for 7 days.
  • FIG. 2 provides a pharmacokinetics profile of plasma tenofovir (TFV) following the application of 2% w/w, 10% w/w TAF soluble (clear) acrylate adhesive patches vs 15% w/w TAF loaded silicone suspension patch for 7 days.
  • TFV plasma tenofovir
  • FIG. 3 is a bar chart showing TFV concentration in the plasma and vaginal tissue following the application of silicone suspension patches for 7 days.
  • FIG. 4 provides pharmacokinetic profiles of plasma TFV following intravenous and transdermal administration of TAF for 6 days.
  • FIG. 5 is a graph showing plasma concentration curves comparing different routes of administration (transdermal vs oral vs intravenous).
  • FIG. 6 is a graph showing permeation profiles of acrylate-based transparent TAF
  • FIG. 7 is a graph showing permeation profde of PIB-based TAF suspension (15%, w/w) transdermal patch formulation through human epidermis for 7 days.
  • FIG. 8 is a graph showing permeation profiles of silicone-based TAF suspension transdermal patch formulations at three different dosing levels through human epidermis for 7 days.
  • FIG. 9 is a graph showing permeation profiles of silicone-based TAF suspension (15%, w/w) transdermal patch formulations prepared with different parameters for homogenization speed and duration through human epidermis for 7 days.
  • FIG. 11 provides a graph showing in vitro drug release profiles for 15% TAF silicone suspension patch under storage conditions at room temperature and at 40° C.
  • FIG. 12A and FIG. 12B show crystal formation in soluble clear patch (17% TAF) after one week at room temperature.
  • FIG. 13 shows slide crystallization studies for different TAF concentrations in soluble clear patches based on acrylate adhesive.
  • FIG. 14 is a graph showing average drag amount per square cm of the patch through human epidermis comparing 10% TAF formulations in a soluble patch and a suspension patch.
  • FIG. 15 is a graph showing average drag amount per square cm of the patch through human epidermis comparing 15% TAF suspension patch with a 17% TAF soluble patch.
  • FIG. 16 provides permeation profiles of silicone-based TAF suspension (15%, w/Sv) transdermal patch formulations prepared with different homogenization speed and duration through human epidermis for 7 days.
  • FIG. 17 is a bar chart showing skin irritation potential of a 15% TAF silicone suspension patch produced in accordance with one embodiment of the present invention.
  • treatment refers generally to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and/or adverse effect attributable to the disease.
  • Treatment covers any treatment of a disease in a subject, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom, may or may not be diagnosed as having it; (b) inhibiting the disease symptom, i.e., arresting its development; or (c) relieving the disease symptom, i.e., causing regression of the disease or symptom.
  • the expression“therapeutically effective amount” refers to an amount of an agent disclosed herein, that is effective for preventing, ameliorating, treating or delaying the onset of a disease or condition.
  • compositions of the inventions can be administered to any animal that can experience the beneficial effects of the agents of the invention.
  • animals include humans and non-humans such as primates, pets and farm animals.
  • Examples of drugs for use herein include, but are not limited to, antivirals, mote specifically antivirals and/or combinations thereof.
  • the drug is a hydrophilic anti-viral drug, such as tenofovir alafenamide (TAP).
  • TAP refers to Tenofovir Alafenamide as a free base and Tenofovir Alafenamide Fumarate as a salt form.
  • the pharmaceutical composition contains an antiviral, more particularly an antiretroviral.
  • antiretrovirals include, but are not limited to, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate (TDF), tenofovir disoproxil hemifumarate, dolutegrevir (DTG), bictegravir, delavirdine, nevirapine (NVP) salts thereof and prodrugs therefor.
  • the pressure-sensitive adhesives suitable for use in the disclosed transdermal patches include, but are not limited to, polymer-based pressure-sensitive adhesives.
  • Particularly useful polymer-based pressure-sensitive adhesives include those based on polysiloxanes or polyisobutylenes. These pressure-sensitive adhesives may provide for suitable tack for quick bonding to various skin types, including wet skin,
  • the pressure-sensitive adhesives may be supplied and used in solvents such as heptane, ethyl acetate, volatile silicone fluids, or the like.
  • solvents such as heptane, ethyl acetate, volatile silicone fluids, or the like.
  • the solids content of the adhesives can vary but typically is between 30 and 80%.
  • Pressure-sensitive adhesives based on polysiloxanes or polyisobutylenes for use in the present invention may be obtained commercially.
  • polysiloxanes such as BIO- Dow Coming® PSA Standard Silicone Adhesives may be obtained from DuPont.
  • BIO- PSA 74301 and BIO-PSA 74201 Silicone Adhesives may be particularly useful.
  • Polyisobutylenes such as DURO-TAK® 87-6908, can also be used and are available from Henkel Corporation.
  • the pharmaceutical composition layer of the transdermal patch may further include other various excipients or additives, including but not limited to, plasticizers, solubilizers, fillers, tackifiers, penetration enhancers, pH regulators, and preservatives. These excipients may be present in the pharmaceutical composition layer in an amount of about 2 to 25%, or 5 to 20%, more particularly from about 8 to 15%, and in some cases from about 10 to 12% by weight based on the pharmaceutical composition.
  • Incorporation of penetration enhancers into the pharmaceutical composition layer of the transdermal patch formulations can be particularly beneficial to improve the dmg penetration kinetic profile by reversible modification of the barrier resistance.
  • chemical penetration enhancers can be used.
  • a number of compounds have been extensively investigated for skin penetration enhancement capability and may be included in the transdermal patch disclosed herein.
  • Such compounds include, but are not limited to, alcohols and alkanols (e.g., ethanol), saturated and unsaturated fatty acids and their esters, glycerides, glycols (e.g., dipropylene glycol, propylene glycol, polyethylene glycol), sulphoxides (dimethylsulphoxide), pyrrolidones (e.g., 2-pyrrolidone), azones (e.g., laurocapram), terpenes, and surfactants (e.g., transcutol).
  • Other agents include oleic and linoleic acids, ascorbic acid, panthenol, butyiated
  • penetration enhancers such as oleic acid, oleyl alcohol, propylene glycol, triacetin, and/or octisalate can be used.
  • the pharmaceutical composition may include a penetration enhancer at a concentration of about 3-20%, more particularly from about 5-15% and in some cases from about 7-12% by weight.
  • the penetration enhancer may include oleic acid alone or oleic acid in combination with one or more of the following: oleyl alcohol, propylene glycol, triacetin and/or octisalate.
  • the penetration enhancer may comprise about 3-7% oleic acid and about 7-12% oleyl alcohol by weight.
  • the pharmaceutical composition layer may include a plasticizer.
  • suitable plasticizers include, but are not limited to, mineral oil, linseed oil, octyl palmitate, squalene, squalane, silicone oil, isobutyl myristate, isostearyl alcohol, and oleyl alcohol, and the like.
  • a plasticizer, such as mineral oil may be present in an amount of between about 10 and 30 weight percent, more particularly about 10 to 20 weight percent and still more particularly about 12 to 16 weight percent based on the pharmaceutical composition.
  • the backing layer serves to retain and maintain the pharmaceutical composition disposed thereon in a defined size and shape, prevent loss of the drug and/or enhancers to the environment, render the individual unit or delivery system (in conjunction with the release liner) transportable, and generally provide protection both prior to and after application of the unit or system to a subject.
  • Suitable materials that can be used, singularly, in combination, as laminates or as coextrusions, to form the backing layer are well known in the art and include films or sheets of polyethylene, polyester, polypropylene, polyurethane, polyolefin, polyvinyl alcohol, polyvinyl chloride, polyvinylidene, polyamide, vinyl acetate resins, BAREX®, ethylene/vinyl acetate copolymers, ethylene/ethylacrylate copolymers, metal-vapor deposited films or sheets thereof, rubber sheets or films, expanded synthetic resin sheets or films, non-woven fabrics, fabrics, knitted fabrics, clothes, foils and papers.
  • the backing layer generally has a thickness in the range of 2 to 1000 micrometers.
  • the backing layer may be pigmented, for example colored to either match with or conversely easily distinguish from the site of application, and/or contain printing, labeling and other means of identification and/or traceability of the unit or system itself.
  • the backing layer may further be made opaque or substantially opaque (i.e., preventing light or certain energy wavelengths from penetrating or passing through), such as by metallization, fillers, inks, dyes and the like, for purposes of protecting photosensitive active agents from degradation and/or preventing photoallergic reactions or irritations on the subject.
  • the release liner or peel strip is also intended to prevent loss of the drug and/or enhancers to the environment, and render the individual unit or delivery system (in conjunction with the backing layer) transportable, as well as generally protect the dermal composition from contamination and the like until its application to a subject.
  • the release liner is typically also impermeable and occlusive, and it must be compatible with the particular polymers or drugs so as not to interfere with the ultimate application and therapeutic effect of the transdermal patch.
  • Suitable materials that can be used, singularly, in combination, as laminates or as coextrusions, to form the release liner are also well known in the art and include any material suitable for the backing layer.
  • a coating material such as a silicone may be applied to the release liner by any conventional means.
  • Particularly useful release liners are films commercially available from DuPont, Wilmington, Del., under the trademark Mylar® 1 , and fluoropolymer (silicone) coated films commercially available from Rexam Release, Oak Brook, Ill. under the trademark FL2000® and MRL2000®, and from 3M Corporation, St. Paul, Minn under the trademark ScotehPak® 1022.
  • the configuration of an individual unit or delivery system of the present invention can be in any shape, preferably a defined geometric shape, and size (i.e., surface area of application) as is necessary or desirable.
  • the shape is achieved by conventional techniques, for example, cutting or punching, and such techniques are described, for example, in U.S.
  • the pharmaceutical composition layer may be coated at any dry weight, but is typically coated ranging from about 6 mg/cm 2 to about 60 mg/cm 2 , or from about 10 mg/cm 2 to about 50 mg/cm 2 , more particularly from about 20 mg/cm 2 to about 40 mg/cm 2 , or from about 25 mg/cm 2 to about 35 mg/cm 2 .
  • the drug, salt thereof or prodrug thereof may be present in the pharmaceutical composition layer at a concentration of about 2% to about 25%, or from about 5% to about 20%, or from about 8% to about 20%, or from about 10% to about 20%, or from about 4% to about 15%, or from about 7% to about 15%, or from about 8 to about 15%, or from about 9 to about 15% based on the total dry weight of the dry pharmaceutical composition layer.
  • the patch sizes may vary depending on the desired delivery' rates of drug (e.g., TAF free base) and the duration for the patch application on the human skin. Typically, increasing in the surface area of the patch can lead to the increase in the amount of the drug substance permeated into the skin.
  • drug e.g., TAF free base
  • the area of the patch may range from about 1 cm 2 to about 60 cm 2 , or ranges from about 2 to about 50 cm 2 , or from about 5 to about 40 cm 2 , or from about 8 to about 35 cm 2 .
  • the size of the transdermal patch is from about 5 to about 50 cm 2 .
  • the transdermal patch disclosed herein provides a skin permeate rate are from about 0.1 to about 7 pg/cm 2 /hr, more particularly from about 0.5 to about 5 pg/cm 2 /hr and in some cases from about 1 to about 4 pg/cm 2 /hr.
  • In vitro skin flux testing was conducted using human epidermis in vertical Franz diffusion cell system for up to 7 days to evaluate the permeation profiles of TAF transdermal patch formulations.
  • human epidermis was freshly isolated from dermatomed human skin by heat-separation method. Resistance of human epidermis was measured using silver-silver chloride electrode method to select the pieces with acceptable epidermal integrity for in vitro skin flux studies. Epidermis pieces with suitable electrical resistance (>10 kil/sq.cm) were selected for the in vitro skin flux study. The thickness of epidermis pieces was also measured using a thickness gauge prior to the permeation testing.
  • phosphate buffer from the donor was pipetted out, and the epidermis was removed, placed flat on a glass plate and dried with the help of Kim wipes.
  • the release liner of the TAF transdermal patch with suitable size to cover the diffusion area was removed and applied carefully on the dried epidermis, and then the adhesive layer of the patch was adhered to the stratum comeum side of the skin. Glass rod was rolled on the patches to ensure the proper adherence to the skin.
  • the epidermis pieces with the applied patch formulation were then mounted between the donor and receptor compartment and the entire set up was secured in place using a clamp.
  • Receptor (0.3 mL) was sampled at 0, 2, 4, 6, 8 h, and the entire receptor (5 mL) was removed and replaced with fresh buffer at 24, 48, 72, 96,120, 144, 168 h, respectively. All the flux samples were analyzed using HPLC. Using the in vitro technique described herein, the TAF human skin permeation rate can be calculated and used to screen the transdermal prototypes effectively.
  • the transdermal patch disclosed herein provides for HTV prevention for periods ranging from about 24 to 168 hours with a permeation rate ranging from about 0.1 to about 7pg/cm 2 /hr across human epidermis while the patch is being used. More particularly, embodiments of the invention include patch formulations for HIV prevention for 72 hours and 168 hours.
  • the pharmaceutical composition of TAF free base suspension transdermal patch comprises (a) a free base form of tenofovir alafenamide in amount of 5 to 20%, more particularly 7 to 18, and still more particularly 10 to 15% (w/w), (b) a silicone or PIB pressure sensitive adhesive in amount of 45 to 75% (50 to 70%; 55 to 65%)(w/w), (c) penetration enhancers: oleic acid and oleyl alcohol in amount of 5-15% (7- 12%)(W/H'), respectively, and (d) mineral oil as a plasticizer in amount of 5-20% ( 7 - 18%; 10-15%)(w/w).
  • a method of preparing a TAF free base suspension, silicone or PIB-based matrix transdermal patch formulation comprises the steps of: (a) mixing a desired amount of tenofovir alafenamide free base with mineral oil oleic acid and oleyl alcohol to form a slurry; (b) adding heptane as necessary into the slurry' and homogenizing the blend; (c) evaporating heptane under heating and then adding the desired amount of pressure sensitive adhesive ; (d) mixing the blend as necessary, and then homogenizing the mixture prior to the film casting; (e) film casting the mixture to obtain a polymeric film matrix having the drug substance folly dispersed/suspended therein and having a skin contacting surface and a non-skin contacting surface thereof, and (f) laminating a release liner to the skin contacting surface of the film matrix, and a backing membrane to the non-skin contacting surface.
  • the transdermal patch as disclosed herein is for use in a method of treating and/or preventing viral infections, more particularly HIV and/or HBV.
  • the transdermal patch in accordance with certain aspects provides for therapeutically effective amounts of drag for a period of time from one to seven days (i.e., 24 to 168 hours) on the skin of a patient.
  • the transdermal patch can also be applied for other time periods as required for the treatment method in question. Typical time periods include about four days (i.e., 96 hours) or about five days (i.e., 120 hours) or about six days (i.e., 144 hours).
  • the application of the transdermal patch for about 168 horns is particularly useful.
  • the invention relates to a method of manufacture of a transdermal patch for the transdermal administration of an antiretroviral drug, such as TAF.
  • the method of manufacturing the transdermal patch is not particularly limited.
  • One exemplary method comprises: (a) mixing desired amount of drag (e.g., tenofovir alafenamide free base) with excipients (e.g., mineral oil, oleic acid and oleyl alcohol) to form a slurry; (b) adding heptane as necessary into the above mentioned slurry and homogenizing the blend; (c) allowing heptane to evaporate under heating; (d) adding the desired amount of pressure sensitive adhesive; (e) mixing the blend as necessary, and homogenizing the mixture prior to film casting; (f) film casting said mixture to obtain a polymeric film matrix having said drug substance fully dispersed/suspended therein and having a skin contacting surface and a non-skin contacting surface thereof, and (g) la
  • the focus is on the suspended or dispersed particles of the antiviral drug.
  • this does not exclude that a small portion of drug is dissolved rather than present as suspended or dispersed particles in the adhesive matrix.
  • some smaller particles after homogenization (or any other particle size-reduction process) in the blend but prior to addition of the adhesive may not be visible under the microscopy and therefore cannot be reliably measured using available equipment and relevant software.
  • the antiviral drag e.g., TAF
  • TAF is in particulate form with an average particle size of less than 50 pm or from about 1 to 50 pm, more particularly from about 2 to 25 pm and in certain cases from about 5 to 15 pm.
  • the particle size of the drag and the suspension of the drag in the pressure sensitive adhesive unexpectedly provides for a physically stable transdermal patch capable of delivering drag at sufficient levels for up to seven days for HTV and/or HBV prevention and/or treatment.
  • FIG. 1 shows transdermal flux of TAF following the application of 2% w/w and 10% w/w TAF loaded clear (soluble) 25-sq.cm patches with acrylate adhesive and 15% w/w TAF loaded silicone suspension patches for 7 days.
  • the flux was calculated based on the assumption that TAF from the 25-sq.cm patches was delivered to rat at a constant rate over the 168-hour period in which the patch was on the rat.
  • FIG. 2 is a graph of the pharmacokinetics profile of plasma tenofovir (TFV) following tiie application of 2% w/w, 10% w/w TAF soluble (clear) acrylate adhesive patches vs 15% w/w TAF loaded silicone suspension patch for 7 days.
  • the compositions of the 2% w/w and 10% w/w, clear patches with soluble TAF in acrylate adhesive are provided below in Table 1 :
  • composition of the silicone suspension patch with 15% w/w of TAF is provided below in Table 2:
  • FIG. 3 is a bar chart showing the TFV concentration in the plasma and vaginal tissue following the application of silicone suspension patches for 7 days TFV and total TFV (free TFV, TFV monophosphate, and TFV diphosphate) levels in rat vaginal tissue were quantified at the end of the 7th day for the 15% w/w TAF silicone suspension patch group.
  • FIG. 4 provides pharmacokinetic profiles of plasma TFV following intravenous and transdermal administration of TAF for 6 days.
  • 14 rectangular strips instead of two bigger patches with a total area of 25 sq.cm were used to alleviate the skin reactions.
  • the intravenous group here was preliminary data based on two male rats (plasma level lasted longer as they have aged and possibly shown slower metabolism).
  • the intravenous groups were formally tested on new female rats and resulted in the profiles shown in FIG. 5, which also provides the results for oral administration of TFV at a dosage of 10 mg/kg.
  • the suspension type transdermal patch formulation disclosed in the present application demonstrates an unexpected improvement in stability in overcoming issues such as crystallization, inconsistent drug release and instability of the drug under typical storage conditions.
  • the claimed patch formulation shows significantly higher flux of approximately 12 times (FIG. 1) compared to TAF loaded soluble patches.
  • the higher flux provided by the transdermal patches disclosed herein is enough to provide the drug level in the therapeutic range for sustained period of up to seven days in rats (FIG. 2) and with no issue of crystallization.
  • Table 3 presents details of various adhesives evaluated for the development of TAF transdermal patch formulations
  • compositions of acrylate-based TAP transdermal patches (2%, w/w) are shown in Table 4.
  • TAF patch formulations were prepared using acrylate (DURO-TAK 87-2516) adhesive.
  • Pre -determined amounts of TAF, acrylate adhesive (DURO-TAK 87-2516), and additives (oleic acid, oleyl alcohol, propylene glycol, octisalate and triacetin) were weighed into glass jars with airtight lids to minimize loss of organic solvents. The blends were kept overnight on the rotary mixer (Preiser Scientific Inc., St. Albans, WV, USA).
  • the solids content of DURO-TAK 87-2516 (41.5% solids) was used for the calculation of the wet weight of DURO-TAK 87-2516 required for the formulation development.
  • the homogenous mixtures were then casted on the release liner (fluoropolymer coated side of ScotchpakTM 1022) using a Gardner film casting knife (BYK-AG-4300 series, Columbia, MD, USA).
  • the casted sheets were dried in a flameproof oven at 95 ° C for 40 min, and then laminated using ScotchpakTM 9733 (backing membrane).
  • FIG. 6 provides permeation profiles of acrylate-based transparent TAF (2%, w/w) transdermal patch formulations through human epidermis for 7 days from the formulations in Table 4.
  • composition of a pharmaceutical composition layer for a polyisobutylene (PIB)- based TAF suspension transdermal patch (15%, w/w) is shown in Table 5.
  • TAF suspension patch formulation was prepared using PIB (DURO-TAK 87- 6908) adhesive. TAF was levigated with mineral oil and oleic acid was then added to it. The mixture was mixed using BenchmixerTM (Benchmark Scientific Inc., Edison, NJ, US). Heptane was added to the above-mentioned blend and the drug suspension was
  • FIG. 7 provides a permeation profile of PIB-based TAF suspension (15%, wAv) transdermal patch formulation from Table 5 through human epidermis for 7 days.
  • compositions of silicone-based TAF suspension transdermal patch formulations are shown in Table 6.
  • TAF suspension patch formulations in Table 6 were prepared using silicone (BIO-PSA 7-4301) adhesive. TAF was firstly levigated with mineral oil, and other additives (oleic acid and oleyl alcohol) were then added and mixed using BenchmixerTM (Benchmark Scientific Inc., Edison, NJ, US). Heptane was added to the above-mentioned blend and the drag suspension was homogenized using a high-speed homogenizer at 32000rpm for 5 min (OmniTHQ, Omni International, GA, US). Heptane was allowed to evaporate at 90° C for 5 min and then the adhesive was added to the dried drug particles.
  • silicone BIO-PSA 7-43011 adhesive
  • the blend was allowed to mix overnight, homogenized at 32000rpm for 1 min, and then casted on the release liner (uncoated side of ScotchpakTM 1022). It was allowed to air dry for 15 min, and then the casted film was laminated with the appropriate backing membrane.
  • FIG. 8 provides the permeation profiles of silicone-based TAF suspension transdermal patch formulations from Table 6 with three different dosing levels through human epidermis for 7 days.
  • formulations #c-l and #c-2 were manufactured as described in EXAMPLE 8, except homogenization speed and time pre- and post- addition of adhesive were at 30000rpm for 20min, and 30000rpm for 1 min, respectively.
  • the drying condition was air drying for 5 min, followed by drying at 78°C for 15 min.
  • formulation #c-3 was manufactured as described in EXAMPLE 4, except homogenization speed and time pre- and post- addition of adhesive were at 32000rpm for 30 min, and 32000rpm for 1 min, respectively.
  • the drying condition was air drying for 5 min, followed by drying at 78°C for 15 min.
  • FIG. 9 provides permeation profiles of silicone-based TAF suspension (15%, w/ ⁇ v) transdermal patch formulations from Table 7 prepared with different homogenization speed and duration through human epidermis for 7 days.
  • Silicone suspension patch formulations were prepared with 20% w/w and 25% w/w TAF to determine the effect of concentration on flux. However, there were not significant improvements in the flux over 15% w/w suspension patch formulation observed.
  • Table 9 summarizes the compositions of various silicone suspension based transdermal patch formulations ranging in TAF concentrations from 5% w/w to 25% w/w studied for permeation studies across human epidermis.
  • TAP suspension patches in accordance with certain aspects may contain TAP at concentrations ranging from 5% to 25% w/w in the
  • silicone-based suspension patch formulations containing TAP was projected to provide a stable patch formulation through the expected shelf life.
  • the physical stability of the suspension patch is also proven due to uniformity in drug release profiles after storage of patches at different conditions (room temperature (RT) at seven days, 1.5 months and 3 months and at 40 °C at 1.5 months and 3 months). No significant difference in the total percentage of TAP released from the patches exposed to different test conditions was observed (p>0.05). This depicted uniformity in the release profile and percentage of drug released after exposure to higher temperature for 3 months, further indicating stability of TAP in the suspension-based patches.
  • FIG. 11 provides a graph showing in vitro drug release profiles for 15% TAP silicone suspension patch under storage conditions at room temperature and at 40° C showing the stability of the formulation.
  • FIG. 12A and FIG. 12B show crystal formation in soluble clear patch (17% TAF) after one week at room temperature.
  • FIG. 13 shows slide crystallization studies for different TAF concentrations in soluble clear patches based on acrylate adhesive. The nature of the crystal was identical to the TAF API crystal. Crystal formation was also observed with 3%, 5% and 12% soluble clear formulations. For the suspension patch microscopy was not possible as the drug amount was suspended and high and the patch was opaque white. Crystal formation is not an issue with the transdermal patches disclosed herein since the tenofovir alafenamide is suspended or dispersed in the pressure sensitive adhesive rather than dissolved.
  • Table 11 provides data summarizing average flux for suspension patches compared to soluble patches showing the significant improvement obtained with suspension patches.
  • FIG. 14 is a graph showing average drag amount per square cm of the patch through human epidermis comparing 10% TAF formulations in a soluble patch and a suspension patch. The results clearly show the improved drug release obtained with the suspension patch.
  • FIG. 15 is agraph showing average drag amount per square cm ofthe patch through human epidermis comparing 15% TAF suspension patch with a 17% TAF soluble patch. Again, the results clearly show the improved drag release obtained with the suspension patch.
  • FIG. 16 provides permeation profiles of silicone-based TAF suspension (15%, wM) transdermal patch formulations from Table 12 prepared with different homogenization speed and duration through human epidermis for 7 days.
  • the amount of TAF permeation after 7 days was found to be similar among suspension patches (SP5, SP6, and SP7) with different size of TAF particles ranging from approximately 5 to 12 um in size prepared at different homogenization speeds and times.
  • FIG. 17 is a bar chart showing skin irritation potential of a 15% TAF silicone suspension patch produced in accordance with one embodiment of the present invention.
  • the principle of irritation assay using the in vitro skin model is based on the premise that irritant chemicals can penetrate the stratum comeum by diffusion and are cytotoxic to the cells in the underlying layers.
  • the drug by itself or in combination with other additives can be irritant to skin.
  • the entire patch was tested for its irritation potential, and not just the drug by itself.
  • the tested transdermal patch (SP7- 15% TAP Silicone Suspension Patch) resulted in a mean relative cell viability of 104.64 ⁇ 7.42 % which was comparable to the negative control (100.00 ⁇ 6.09) and significantly higher than the positive control (14.27 ⁇ 8.09).
  • SP7 silicone suspension patch

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Abstract

L'invention concerne un timbre transdermique pour l'administration transdermique de médicaments, et ses procédés de fabrication, des utilisations, et des procédés de traitement correspondants l'utilisant.
PCT/US2019/059515 2018-11-02 2019-11-01 Compositions pharmaceutiques et procédés de fabrication d'une formulation de timbre pour administration transdermique WO2020092990A1 (fr)

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WO2021236944A1 (fr) 2020-05-21 2021-11-25 Gilead Sciences, Inc. Compositions pharmaceutiques contenant du bictégravir
WO2022087149A2 (fr) 2020-10-22 2022-04-28 Gilead Sciences, Inc. Protéines de fusion d'interleukine-2-fc et méthodes d'utilisation
ES2936735A1 (es) * 2021-09-20 2023-03-21 Paterna Jesus Paterna Dispositivo para preparar manualmente sistemas terapéuticos transdérmicos y procedimiento

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Publication number Priority date Publication date Assignee Title
WO2021236944A1 (fr) 2020-05-21 2021-11-25 Gilead Sciences, Inc. Compositions pharmaceutiques contenant du bictégravir
WO2022087149A2 (fr) 2020-10-22 2022-04-28 Gilead Sciences, Inc. Protéines de fusion d'interleukine-2-fc et méthodes d'utilisation
ES2936735A1 (es) * 2021-09-20 2023-03-21 Paterna Jesus Paterna Dispositivo para preparar manualmente sistemas terapéuticos transdérmicos y procedimiento

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