CA2664548C - Packaging for 1-(2-methylpropyl)-1h-imidazo[4,5-c]quinolin-4-amine-containing formulation - Google Patents
Packaging for 1-(2-methylpropyl)-1h-imidazo[4,5-c]quinolin-4-amine-containing formulation Download PDFInfo
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- CA2664548C CA2664548C CA2664548A CA2664548A CA2664548C CA 2664548 C CA2664548 C CA 2664548C CA 2664548 A CA2664548 A CA 2664548A CA 2664548 A CA2664548 A CA 2664548A CA 2664548 C CA2664548 C CA 2664548C
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
Abstract
A packaged composition 1-(2-methylpropyl)-1-H-imidazo[4,5-c]quinolin-4-amine dissolved in a fatty acid formulation and contained in a laminated packaging material having a contact layer that includes an acrylonitrile-methyl acrylate copolymer; an outer layer; and a moisture barrier layer disposed between the contact layer and outer layer.
Description
.. =
PACKAGING FOR. 1-(2-IVIRTHYLPROPYL)-1H4tvIDAZO(4,5-4QUINOLIN-4-AlvfiNE-CONTAINING FORMULATION
There has been a major effort in recent years, with significant successes, to discover new drug compounds that act by stimulating certain key aspects of the immune system, as well as by suppressing certain other aspects (see, e.g., US. Pat Nos. 6,039,969 and 6,200,592). These compounds, sometimes referred to as immune response modifiers IS (IRMO, appear to act through basic immune system mechanisms known as toil-like receptors. to induce selected cytokine biosynthesis and may be used to treat a wide variety of diseases and conditions. For example, certain !Ms may be useful for treating viral diseases (e.g., human papilloma virus, hepatitis, herpes), ncopleslas (e4, beset cell carcinoma, squamous cell carcinoma, actinic keratosis), and TH2-mediated diseases (e.g., 20 asthma, allergic rhinitis, atopic dermatitis), and are also useful as vaccine adjuvants.
Unlike many conventional anti-viral or anti-tumor compounds, the primary mechanism of action for IRMs is indirect, by stimulating the immune system to recognize and take appropriate action against a pathogen:
Many of the IRM compounds are small organic molecule imidaaoquinoline amine 25 derivatives (see, e.g., U.S. Pat No. 4,689,338), but a number nf other compound classes are now known as well (see, e.g, U.S. Pat. Isfos. 5,446,153; 6,194,425; and 6,110,929) and more arc Still being discovered. 1-(2-methyIpropy1)-11/-imidazo(4,5-e)quinolin-4-arnine, an rRm that has very low aqueous solubility and can be particularly challenging to formulate and package.
It ifat been fdlind that 1-(2-dijdpriVy1)-Iff-iihidizo(4,5-elquinolin-4-Smine formulated in compositions that include fatty acids (e.g., isosteario acid) are often incompatible with packaging materials, particularly conventional laminates which often use an adhesive to bond two layers together. Such formulations can cause delamination of such laminates. Also, preservatives are often important ingredients, but when used in formulations of 1-(2-methylpropy1)-1H-imidazo[4,5-:clquinolin-4-amine with substantial.
fatty acid content the preservatives can suffer problems from absorption into the layer of =
the laminate that contacts the formulation (i.e., the contact layer).
The present invention provides a packaging laminate that can withstand formulations of 1-(2-methylpropy1)-1H-imidazo[4,5-chuinolin-4-amine with fatty acids by using an acrylonitrile-methyl acrylate copolymer contact layer; an outer layer; and a moisture barrier layer disposed between the contact layer and outer layer. Thus, there is provided a packaged composition that includes:- a durable laminated packaging material and a 1-(2-methylpropy1)-1H-imidazo[4,5-clquinolin-4-amine-containing formulation enclosed within the laminated packaging material. The durable laminated packaging material includes-a contact layer that includes an acrylonitrile-methyl acrylate copolymer; an outer layer; and a moisture barrier layer disposed between the contact layer and outer layer. In certain embodiments, an adhesive is disposed between the contact layer and the moisture barrier layer. In certain embodiments, the outer layer and the moisture barrier layer are bonded together with a polyethylene tie layer.
In certain embodiments, the contact layer is 25 microns to 8() microns thick.
In certain embodiments, the moisture barrier layer is 5 microns to 15 microns thick. In certain embodiments, the outer layer is 5 millimeters to 20 millimeters thick.
The moisture barrier layer generally includes a metal foil, which may be aluminum. The outer layer generally comprises an organic polymer, which may be polyethylene terephthalate.
The formulation preferably includes 1-(2-rnethylpropy1)-1H-imidazo[4,5-ciquinolin-4-amine and a fatty acid;
In certain embodiments, the fatty acid is isostearic acid, oleic acid, myristic acid, palmitic acid, palmitoleic acid, margaric acid, stearic acid, linoleic acid, linolenic acid, or mixtures thereof. Preferably, the fatty acid includes isostearic acid, oleic acid, or mixtures thereof. More preferably, the fatty acid is isostearic acid.
In certain'biribodiMentS, the 1-(2-Metliylpropy1)4H-iniidazo[4,5-clquinolin-4--amine-containing formulation further includes a preservative. Preferably, the preservative includes mothylparaben, propylparaben, benzyl alcohol, or mixtures thereof.
In certain embodiments, the '1-(2,methylpropy1)-11-T-imidaz6{4,5-c]quinofin-4-. amirie-containing fOrmUlation further includes an emollient, an emulsifier, a thickener, a .
solubilizing agent, Or mixtures thereof, =
The term "comprises" and variations thereof do not have a limiting meaning where these terms appear in the description and claims.
As used herein, "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a complex that comprises "a" preservative can be interpreted to mean that the complex inclUdes "one or more" preservatives.
Similarly; a composition comprising "a" complex can be interpreted to mean that the composition 10. includes "one or more" complexes.
. = .Also herein, the recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).
The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The description.
that follows more particularly exemplifies illustrative embodiments. In several places throughout the application, guidance is provided through lists of examples, which examples can be used individually and in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
OF THE INVENTION
The present invention is directed to packaged preparations (i.e., compositions or formulations) of 1-(2-methylpropy1)-1H-imidazo[4,5-c]quinolin-4-amine (as described in Exarriple 99, U.S. Patent no. 4,689,338) that can be stored for an extended period of time.
The packaging includes materials that are compatible with the 1-(2-methylpropy1)-1H-imidazo[4,5-clquinolin-4-amipe-containing formulation contained therein such that the formulation is preferably stable for at least 6 weeks at 60*C and ambient relative humidity (RHO, more 'preferably, for at least 6 nitnithS at 40T and 75% RH; even more preferably, for at least 1 year .at 30*C and 65% RH, and even more preferably, for at least 2 years at 2.5*C and 60% RH. Preferably, the laminated packaging material is also durable.
There has been a major effort in recent years, with significant successes, to discover new drug compounds that act by stimulating certain key aspects of the immune system, as well as by suppressing certain other aspects (see, e.g., US. Pat Nos. 6,039,969 and 6,200,592). These compounds, sometimes referred to as immune response modifiers IS (IRMO, appear to act through basic immune system mechanisms known as toil-like receptors. to induce selected cytokine biosynthesis and may be used to treat a wide variety of diseases and conditions. For example, certain !Ms may be useful for treating viral diseases (e.g., human papilloma virus, hepatitis, herpes), ncopleslas (e4, beset cell carcinoma, squamous cell carcinoma, actinic keratosis), and TH2-mediated diseases (e.g., 20 asthma, allergic rhinitis, atopic dermatitis), and are also useful as vaccine adjuvants.
Unlike many conventional anti-viral or anti-tumor compounds, the primary mechanism of action for IRMs is indirect, by stimulating the immune system to recognize and take appropriate action against a pathogen:
Many of the IRM compounds are small organic molecule imidaaoquinoline amine 25 derivatives (see, e.g., U.S. Pat No. 4,689,338), but a number nf other compound classes are now known as well (see, e.g, U.S. Pat. Isfos. 5,446,153; 6,194,425; and 6,110,929) and more arc Still being discovered. 1-(2-methyIpropy1)-11/-imidazo(4,5-e)quinolin-4-arnine, an rRm that has very low aqueous solubility and can be particularly challenging to formulate and package.
It ifat been fdlind that 1-(2-dijdpriVy1)-Iff-iihidizo(4,5-elquinolin-4-Smine formulated in compositions that include fatty acids (e.g., isosteario acid) are often incompatible with packaging materials, particularly conventional laminates which often use an adhesive to bond two layers together. Such formulations can cause delamination of such laminates. Also, preservatives are often important ingredients, but when used in formulations of 1-(2-methylpropy1)-1H-imidazo[4,5-:clquinolin-4-amine with substantial.
fatty acid content the preservatives can suffer problems from absorption into the layer of =
the laminate that contacts the formulation (i.e., the contact layer).
The present invention provides a packaging laminate that can withstand formulations of 1-(2-methylpropy1)-1H-imidazo[4,5-chuinolin-4-amine with fatty acids by using an acrylonitrile-methyl acrylate copolymer contact layer; an outer layer; and a moisture barrier layer disposed between the contact layer and outer layer. Thus, there is provided a packaged composition that includes:- a durable laminated packaging material and a 1-(2-methylpropy1)-1H-imidazo[4,5-clquinolin-4-amine-containing formulation enclosed within the laminated packaging material. The durable laminated packaging material includes-a contact layer that includes an acrylonitrile-methyl acrylate copolymer; an outer layer; and a moisture barrier layer disposed between the contact layer and outer layer. In certain embodiments, an adhesive is disposed between the contact layer and the moisture barrier layer. In certain embodiments, the outer layer and the moisture barrier layer are bonded together with a polyethylene tie layer.
In certain embodiments, the contact layer is 25 microns to 8() microns thick.
In certain embodiments, the moisture barrier layer is 5 microns to 15 microns thick. In certain embodiments, the outer layer is 5 millimeters to 20 millimeters thick.
The moisture barrier layer generally includes a metal foil, which may be aluminum. The outer layer generally comprises an organic polymer, which may be polyethylene terephthalate.
The formulation preferably includes 1-(2-rnethylpropy1)-1H-imidazo[4,5-ciquinolin-4-amine and a fatty acid;
In certain embodiments, the fatty acid is isostearic acid, oleic acid, myristic acid, palmitic acid, palmitoleic acid, margaric acid, stearic acid, linoleic acid, linolenic acid, or mixtures thereof. Preferably, the fatty acid includes isostearic acid, oleic acid, or mixtures thereof. More preferably, the fatty acid is isostearic acid.
In certain'biribodiMentS, the 1-(2-Metliylpropy1)4H-iniidazo[4,5-clquinolin-4--amine-containing formulation further includes a preservative. Preferably, the preservative includes mothylparaben, propylparaben, benzyl alcohol, or mixtures thereof.
In certain embodiments, the '1-(2,methylpropy1)-11-T-imidaz6{4,5-c]quinofin-4-. amirie-containing fOrmUlation further includes an emollient, an emulsifier, a thickener, a .
solubilizing agent, Or mixtures thereof, =
The term "comprises" and variations thereof do not have a limiting meaning where these terms appear in the description and claims.
As used herein, "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a complex that comprises "a" preservative can be interpreted to mean that the complex inclUdes "one or more" preservatives.
Similarly; a composition comprising "a" complex can be interpreted to mean that the composition 10. includes "one or more" complexes.
. = .Also herein, the recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).
The above summary of the present invention is not intended to describe each disclosed embodiment or every implementation of the present invention. The description.
that follows more particularly exemplifies illustrative embodiments. In several places throughout the application, guidance is provided through lists of examples, which examples can be used individually and in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
OF THE INVENTION
The present invention is directed to packaged preparations (i.e., compositions or formulations) of 1-(2-methylpropy1)-1H-imidazo[4,5-c]quinolin-4-amine (as described in Exarriple 99, U.S. Patent no. 4,689,338) that can be stored for an extended period of time.
The packaging includes materials that are compatible with the 1-(2-methylpropy1)-1H-imidazo[4,5-clquinolin-4-amipe-containing formulation contained therein such that the formulation is preferably stable for at least 6 weeks at 60*C and ambient relative humidity (RHO, more 'preferably, for at least 6 nitnithS at 40T and 75% RH; even more preferably, for at least 1 year .at 30*C and 65% RH, and even more preferably, for at least 2 years at 2.5*C and 60% RH. Preferably, the laminated packaging material is also durable.
In tbis.cordzst, etas*" formttlation is one that does not significantly chahge in content This i.an be measured by evaluating the changes in content over time of various.
components of the formulation. For example, for formulations that include methylparaben and/orpropylparabenõ the content of each of these components does not change by more S than 10% for a formulation to be stable. More specifically, for example, as.descdbed in the Test Procedure herein, preferably, a cream that contains methylparaben and propyiparaben in a laminatelachet passes testing if the metthylparaben and propylparaben content are within the rents, inclusive, of0.18% to 0.22% and 0.018% to 0.022%
by weight; respectively, after stability testing. Alternatively, stability can be measured by evaluating the appearance of impurides, particularly drug-related impurities, over time. In this context, a stable formulation does not produce more than 03% by Weight impurities.
In this context, a "durable" laminated packaging material is one that does not significantly change in structure when in contact with a formulation over time. The formulation for such evaluation is a 1-(2-methylpropy1)-1K-huidazo[4,5-elquinolin-4-amine-containing cream available from 3M Company under the trade designation AMARA, which also includes components such as fhtty acids and preservatives.
The method of evaluation is more specifically described in the Test Procedure herein. For example, a laminate can he evaluated for separation of one or more laminate layers by observing a laminate's appearance for &lamination, perforations, wrinkles, discoloration, and other laminate delimits overtime when brought in contact with such formulation. .
Preferably, a 'durable' laminated packaging material is one that does not show Separation of one or more layers of a laminate when in contact with the formulation described in the Test Procedure over a pbrIod of at least six months.
Preferably, the fonnulation.is an emulsion (More preferably, an oil-in-water =
ernulsion).that is typically in the form of a cream, although other formulations, such as ointments or lotions, can be advantageously packaged with the materials described herein.
Typical components of the formulation can include one or more fatty acids, such as isostearic and/Or oleic acid, and one or more preservatives, such as bawl alcohol, .
methylparaben, and/or propylparaben; Such component; are advantageously conigatibIe with the packaging materials described herein.
components of the formulation. For example, for formulations that include methylparaben and/orpropylparabenõ the content of each of these components does not change by more S than 10% for a formulation to be stable. More specifically, for example, as.descdbed in the Test Procedure herein, preferably, a cream that contains methylparaben and propyiparaben in a laminatelachet passes testing if the metthylparaben and propylparaben content are within the rents, inclusive, of0.18% to 0.22% and 0.018% to 0.022%
by weight; respectively, after stability testing. Alternatively, stability can be measured by evaluating the appearance of impurides, particularly drug-related impurities, over time. In this context, a stable formulation does not produce more than 03% by Weight impurities.
In this context, a "durable" laminated packaging material is one that does not significantly change in structure when in contact with a formulation over time. The formulation for such evaluation is a 1-(2-methylpropy1)-1K-huidazo[4,5-elquinolin-4-amine-containing cream available from 3M Company under the trade designation AMARA, which also includes components such as fhtty acids and preservatives.
The method of evaluation is more specifically described in the Test Procedure herein. For example, a laminate can he evaluated for separation of one or more laminate layers by observing a laminate's appearance for &lamination, perforations, wrinkles, discoloration, and other laminate delimits overtime when brought in contact with such formulation. .
Preferably, a 'durable' laminated packaging material is one that does not show Separation of one or more layers of a laminate when in contact with the formulation described in the Test Procedure over a pbrIod of at least six months.
Preferably, the fonnulation.is an emulsion (More preferably, an oil-in-water =
ernulsion).that is typically in the form of a cream, although other formulations, such as ointments or lotions, can be advantageously packaged with the materials described herein.
Typical components of the formulation can include one or more fatty acids, such as isostearic and/Or oleic acid, and one or more preservatives, such as bawl alcohol, .
methylparaben, and/or propylparaben; Such component; are advantageously conigatibIe with the packaging materials described herein.
*Trademark The packaging includes a laminate that includes a contact layer, an outer layer, and a moisture barrier layer disposed between the contact layer and outer layer.
One or more.
tie layers can be disposed between the layers for bonding the layers together.
The tie layers can be adhesives.or extruded polymeric materials. For example, the outer layer and' the moisture barrier layer can be bonded together with an extruded polymer (e.g.', polyethylene), = The thickness of each layer, and that of the overall laminate constructipn are sufficiently thick to provide the desired moisture barrier properties and mechanical strength. Each layer, and the overall laminate are also sufficiently thin to be readily torn by hand.
The moisture barrier layer is sufficiently thick to provide moisture barrier properties. The moisture barrier is preferably at least 5 microns thick. The moisture barrier is preferably no greater than 15 microns thick.
Preferably the moisture barrier includes a metal foil, such as aluminum Or copper, for example. The metal foil moisture barrier is preferably a layer that includes aluminum foil, which is preferably 9 microns thick.
The outer layer is sufficiently thick to provide mechanical strength. The outer layer is preferably at least 5 millimeters (mm) thick. The outer layer is preferably no greater than 20 mm thick.
Preferably, the outer layer includes an organic polymer, such as polyethylene terephthlate (PET), paper, cellophane, or other clear protective packaging layer, for example. The outer layer is preferably a layer that includes PET, which is preferably 0.48 mil (12 microns) thick.
The contact layer is preferably at least 25 microns thick. The contact layer is preferably no greater than 89 microns thick.
Preferably, the contact layer includes acrylenitrile-methyl acrylate (AMA) copolymer. The polymeric contact layer is preferably 51 microns (2 mils) thick.
Examples of materials that can be incorporated into adhesives suitable for use in the present invention, particularly for bonding the contactlayer to the moisture barrier layer and/or the outer layer to the moisture barrier layer, include (ethylene acrylic acid) ethylene ethylacrylate (PEA), ethylene methylacrylate (EMA), ethylene vinyl acetate (EVA), ethylene methyl acrylic acid (EMAA), and urethane.
One or more.
tie layers can be disposed between the layers for bonding the layers together.
The tie layers can be adhesives.or extruded polymeric materials. For example, the outer layer and' the moisture barrier layer can be bonded together with an extruded polymer (e.g.', polyethylene), = The thickness of each layer, and that of the overall laminate constructipn are sufficiently thick to provide the desired moisture barrier properties and mechanical strength. Each layer, and the overall laminate are also sufficiently thin to be readily torn by hand.
The moisture barrier layer is sufficiently thick to provide moisture barrier properties. The moisture barrier is preferably at least 5 microns thick. The moisture barrier is preferably no greater than 15 microns thick.
Preferably the moisture barrier includes a metal foil, such as aluminum Or copper, for example. The metal foil moisture barrier is preferably a layer that includes aluminum foil, which is preferably 9 microns thick.
The outer layer is sufficiently thick to provide mechanical strength. The outer layer is preferably at least 5 millimeters (mm) thick. The outer layer is preferably no greater than 20 mm thick.
Preferably, the outer layer includes an organic polymer, such as polyethylene terephthlate (PET), paper, cellophane, or other clear protective packaging layer, for example. The outer layer is preferably a layer that includes PET, which is preferably 0.48 mil (12 microns) thick.
The contact layer is preferably at least 25 microns thick. The contact layer is preferably no greater than 89 microns thick.
Preferably, the contact layer includes acrylenitrile-methyl acrylate (AMA) copolymer. The polymeric contact layer is preferably 51 microns (2 mils) thick.
Examples of materials that can be incorporated into adhesives suitable for use in the present invention, particularly for bonding the contactlayer to the moisture barrier layer and/or the outer layer to the moisture barrier layer, include (ethylene acrylic acid) ethylene ethylacrylate (PEA), ethylene methylacrylate (EMA), ethylene vinyl acetate (EVA), ethylene methyl acrylic acid (EMAA), and urethane.
An eiamplenfa material for atie layer that is suitable, particularly for bonding the outer layer tothe moisture barrier layer, is an extruded low-density polyethylene coati*
A preferred laminate is Product.No. 60012-36 available from Ludlow Coated Products (Constantine. MO that includes a 124n3cketthick Par outer layer, a layer of $ whitelow-clen:sity polyethylene (number 10) tie layer, a 9-micron thick aluminum layer, an adhesive, and a BARIDC acrylonitrile-methyl eorylate copolymer layer.
The laminate can be sealed to form a package under appropriate sealing conditions sufficient to provide a good seal and not damage the paCkage contents. Such conditions can be determined readily by one of skill in the art. A typical sealing temperature for laminates is at least 150 C, and preihmbly at least 200 C. Preferably the sealing temperature-is kW greater than 350 C:
Porendarion A pharmaceutical formulation of the invention can be in a form Of a cream, an ointment, or a lotion, for example, each particular form containing 1-(2-methylpropy1)-1H-imidazo[4,5-elquinolin-4-amine. Other additives can include one or more fatty acids, one 4r more preservatives, and other optional additives.
1-(2-methylpropy1)-1/1:fraidazo(4,56c]quinolin-4-amine, is in a class of compounds known as immune response modifiers (IBM) that are known antiviral agents that can also induce Interferon biosynthesis. Such compounds can be used to treat viral infections, such as Type I or Type ff Herpes simplex infections and genital warts, as well as numerous other diseases, such as rheumatoid arthritis, warts, eczema, hepatitis B, psoriasis, multiple sclerosis, essential thrombocythaemist, and cancer, such as basal cell carcinoma and other neoplastic diseases. The amount of 1-(2-inethylpropy1)-111-imidazo[4,5-c]quinolin-4-amine present hi a formulation of the invention will be an amount effeCtive to treat' the targeted disease state to prevent the recurrence of such a disease or to promote immunity against such a disease.
In addititim to 1-(2-1nethylpropy1)4H-irnidazo[4,5-clquiriolin-4-amine, the larninated=parikaging material of the invention is useful with other IRIvls inn Amy acid containing formulation. Other IBMs are small organic molecules (e.g., molecular weight under about 1000 Dalkon.% 'KeferablY under about SOO Daltons, as opposed to large biological molecules such as proteins, peptides, and the like) such as those disclosed in, *Trademark for example; U.S. Patent Nos. 4,689,338; 4,929,624; 5,266,575; 5,268,376;
5,346,905;
- 5,352,784; 5;389,640;5;446,153; 5,482,936; 5,756,747; 6,110,929; 6,194,425;
6,331,539;
. 6,376,669; .6,451,810; 0,525,064; 6,541,485; 6,545,016; 6,545,017;
6,573,273; 6,656,938;
6,660,735; 6,660,747; 6,664,260;6,664,264; 6,664,265; 6,667,312; 6,670,372;
6,677,347;
6,677,348; 6,677,349; 6,683,088; 6,756,382; 6,797,718; and 6,818,650; and U.S.
Patent Publication Nos. 2004/0091491; 2004/0147543; and 2004/0176367.
The total amount of 1-(27methylpropy1)-1H-imidazo[4,5-elquinolin-4-amine is preferably at least 0.5 percent by weight, based on the total weight of a formulation.
Preferably, the total amount of 1-(2-methyIpropy1)-1H-imidaze[4,5-c]quinolin-4-amine is no more than 9 percent by weight, based on the total weight of a formulation.
A cream preferably includes 1-(2-ntethylpropy1)-1H-imidazo[4,5-c]quinolin-4-amine in an amount of at least 0.5 percent, and more preferably at least 1 percent, based on the total weight of the cream. A cream preferably includes 1-(2-methylpropy1)-1H-imidazo[4,5-clquinolin-4-amine in an amount of no greater than 9 percent, and more preferably no greater than 5 percent, based on the total weight of the cream. The total amount of 1-(2-methylpropy1)-1H-inairla7o[4,5-c]quinolin-4-arnine in an ointment is preferably at least 0.5 percent, based on the total weight of the ointment. The total amount of 1-(2-methylpropy1)-1H-imidazo[4,5-e]quinolin-4-amine in an ointment is preferably no greater than 9 percent, and more preferably no greater than 5 percent, based on the total weight of the ointment.
The total amount of one or more fatty acids present in the formulation will generally be in an amount sufficient to solubilize the 1-(2-methylpropyI)-1H-imidazo[4,5-c]quinolin-4-amine compound. The total amount of one or more fatty acids present in a formulation may, for example, be at least 5 percent by weight, at least 15 percent by weight, or at least 20 percent by weight, based on the total weight of a formulation. For formulations having 5% 1-(2-methylpropy1)-1H4midazo[4,5-c]quinolin-4-arnine the total amount of fatty acid, preferably oleic acid and/or isostearic acid, lathe formulation will generally be at least 15% by weight, and more preferably at least 20% by weight, for example about 25% by weight.. The total amount of one or more fatty acids present in a formulation is no more that 45 gercent by weight or no mole that 30 'percentby Weight, based on the total weight of a formulation. Preferably, the total amount of one or more fatty acids present in a fOrmulation is about 25 percent by weight based on the formulation.
A preferred laminate is Product.No. 60012-36 available from Ludlow Coated Products (Constantine. MO that includes a 124n3cketthick Par outer layer, a layer of $ whitelow-clen:sity polyethylene (number 10) tie layer, a 9-micron thick aluminum layer, an adhesive, and a BARIDC acrylonitrile-methyl eorylate copolymer layer.
The laminate can be sealed to form a package under appropriate sealing conditions sufficient to provide a good seal and not damage the paCkage contents. Such conditions can be determined readily by one of skill in the art. A typical sealing temperature for laminates is at least 150 C, and preihmbly at least 200 C. Preferably the sealing temperature-is kW greater than 350 C:
Porendarion A pharmaceutical formulation of the invention can be in a form Of a cream, an ointment, or a lotion, for example, each particular form containing 1-(2-methylpropy1)-1H-imidazo[4,5-elquinolin-4-amine. Other additives can include one or more fatty acids, one 4r more preservatives, and other optional additives.
1-(2-methylpropy1)-1/1:fraidazo(4,56c]quinolin-4-amine, is in a class of compounds known as immune response modifiers (IBM) that are known antiviral agents that can also induce Interferon biosynthesis. Such compounds can be used to treat viral infections, such as Type I or Type ff Herpes simplex infections and genital warts, as well as numerous other diseases, such as rheumatoid arthritis, warts, eczema, hepatitis B, psoriasis, multiple sclerosis, essential thrombocythaemist, and cancer, such as basal cell carcinoma and other neoplastic diseases. The amount of 1-(2-inethylpropy1)-111-imidazo[4,5-c]quinolin-4-amine present hi a formulation of the invention will be an amount effeCtive to treat' the targeted disease state to prevent the recurrence of such a disease or to promote immunity against such a disease.
In addititim to 1-(2-1nethylpropy1)4H-irnidazo[4,5-clquiriolin-4-amine, the larninated=parikaging material of the invention is useful with other IRIvls inn Amy acid containing formulation. Other IBMs are small organic molecules (e.g., molecular weight under about 1000 Dalkon.% 'KeferablY under about SOO Daltons, as opposed to large biological molecules such as proteins, peptides, and the like) such as those disclosed in, *Trademark for example; U.S. Patent Nos. 4,689,338; 4,929,624; 5,266,575; 5,268,376;
5,346,905;
- 5,352,784; 5;389,640;5;446,153; 5,482,936; 5,756,747; 6,110,929; 6,194,425;
6,331,539;
. 6,376,669; .6,451,810; 0,525,064; 6,541,485; 6,545,016; 6,545,017;
6,573,273; 6,656,938;
6,660,735; 6,660,747; 6,664,260;6,664,264; 6,664,265; 6,667,312; 6,670,372;
6,677,347;
6,677,348; 6,677,349; 6,683,088; 6,756,382; 6,797,718; and 6,818,650; and U.S.
Patent Publication Nos. 2004/0091491; 2004/0147543; and 2004/0176367.
The total amount of 1-(27methylpropy1)-1H-imidazo[4,5-elquinolin-4-amine is preferably at least 0.5 percent by weight, based on the total weight of a formulation.
Preferably, the total amount of 1-(2-methyIpropy1)-1H-imidaze[4,5-c]quinolin-4-amine is no more than 9 percent by weight, based on the total weight of a formulation.
A cream preferably includes 1-(2-ntethylpropy1)-1H-imidazo[4,5-c]quinolin-4-amine in an amount of at least 0.5 percent, and more preferably at least 1 percent, based on the total weight of the cream. A cream preferably includes 1-(2-methylpropy1)-1H-imidazo[4,5-clquinolin-4-amine in an amount of no greater than 9 percent, and more preferably no greater than 5 percent, based on the total weight of the cream. The total amount of 1-(2-methylpropy1)-1H-inairla7o[4,5-c]quinolin-4-arnine in an ointment is preferably at least 0.5 percent, based on the total weight of the ointment. The total amount of 1-(2-methylpropy1)-1H-imidazo[4,5-e]quinolin-4-amine in an ointment is preferably no greater than 9 percent, and more preferably no greater than 5 percent, based on the total weight of the ointment.
The total amount of one or more fatty acids present in the formulation will generally be in an amount sufficient to solubilize the 1-(2-methylpropyI)-1H-imidazo[4,5-c]quinolin-4-amine compound. The total amount of one or more fatty acids present in a formulation may, for example, be at least 5 percent by weight, at least 15 percent by weight, or at least 20 percent by weight, based on the total weight of a formulation. For formulations having 5% 1-(2-methylpropy1)-1H4midazo[4,5-c]quinolin-4-arnine the total amount of fatty acid, preferably oleic acid and/or isostearic acid, lathe formulation will generally be at least 15% by weight, and more preferably at least 20% by weight, for example about 25% by weight.. The total amount of one or more fatty acids present in a formulation is no more that 45 gercent by weight or no mole that 30 'percentby Weight, based on the total weight of a formulation. Preferably, the total amount of one or more fatty acids present in a fOrmulation is about 25 percent by weight based on the formulation.
Typical fatty acids for use in formulations desbribed herein include isostearlc acid, agile aold, myristiC acid, pahiritic mid, palnritolek acid, margaric acid, steak acid, linoteic acid, lharienic acid, or mixtures thereof. hefailed fatty acids include isostearic acid, oleic acid, or mixtures thereof Optionally, and preferably, one or niore preservatives such as methylparaben, propylparaben, benzyl alcohol, or mixtures thereof can be present in the formulations described herein. The appropriate amount of such preserVative(s) can be readily determined-Irk those skilled in the att.
Optionally, a cream can contain emollients, emulsifiers, and/or thickeners.
Emollients, such as long chain alcohols, e.g, cetyl alcohol, stearyl alcohol, and cetearyl alcohol; hydrocarbons such as petrolatum and light mineral oil; or acetylated lanolin can.
be included in creams described herein. A cream can contain one or more of these emollients. A cream preferably includes a total amount of emollient of at least 5 percent, based on the total weight of the cream. A cream preferably Includes a total amount of IS emollient of no greater than 30 percent, and more pretbrably no greater than 10 percent based on the total weight of the cream. =
Eniulsifiers such as nonionic surface active agents, e.g., polysorbate 60 (available from ICI Americas), sorbitan monostearate, polyglycery1-4 crimes, and polyoxyetirylene4)lauryl ether, can be included in creams described herein. A
cream can contain one or more emulsifiers. A cream preferably includes a total amount of emulsifier of at least 2 percent, based on the total weight of the cream. 'A cream preferably includes a total amount of emulsifier of no greater than 14 percent, and more preferably no greater than 6 percent, based on the total weight of the cream.
Pharniaceutically acceptable thickeners, such as VEEGUM K (available from R.T.
Vanderbilt Company, Inc.), and king chain alcohols (e.g., cetyl alcohol, stearyl alcohol or ceteraY1 alcohol) can be used. A cream can contain one or more thickeners. A
cream prelbrablyincludes a total amount of thickener Of at least 3 percent, based on the total weight of the meant. A cream prefirrably includes a total amount of thickener of no glider' than 12Pe' d& 'ileac!' On 'the teal weight of the &Wm.
Optiorrally, one or more additional solubllizing agents such as bonny!
alcohol, = lactic acid, acetic acid, ktearic acid, or hydrochloric acid can be included in the creams described herein. If one or morn additional solubilieing agents=are used, the total amount *Trademark present is preferably at least 'l percent, based on the total weight of the cream. If one or more additional solubilizing agents are used, the total amount present is preferably no greater than 12 percent, based on the total weight of the cream.
Optionally, the creams described herein can contain a humectant, such as glycerin, skin penetration enhancers, such as butyl stearate, and additional solubilizing agents.
It is known td those skilled in the art that a single ingredient can perform more than one function in a cream, i.e., cetyl alcohol can serve both as an emollient and as a thickener.
Generally, a cream consists of an oil phase and a water phase mixed together to form an emulsion. Preferably, the amount of water present in a cream of the invention is at least 45 percent, based on the total weight of the cream. Preferably, the amount of water present in a cream of the invention is no greater than 85 percent, based on the total weight of the cream.
The oil phase of a cream of the invention can be prepared, for example, by first combining 1-(2-methylpropy1)-1H-imidazo[4,5-clquinolin-4-amine and one or more fatty acids (if the cream contains benzyl alcohol it can also be added at this point) and heating with occasional stirring to a temperature of 50 C to 85 C. When the 1.-(2-methylpropyl)-1H-imidazo[4,5-ciquinolin-4-amine appears to be completely dissolved, the remaining oil phase ingredients are added and heating is continued until dissolution appears to be complete. The water phase can be prepared by combining all other ingredients and heating with stirring until dissolution appears to be complete. The creams of the invention are generally prepared by adding the water phase to the oil phase with both phases at a temperature of 65 C to 75 C. The resulting emulsion is mixed with a suitable mixer apparatus to give the desired cream.
An ointment preferably contains an ointment base in addition to 142-methylpropy1)-1H4midazo[4,5-chuinolin-4-amine and one or more fatty acids. A
pharmaceutically acceptable ointment base such as petrolattun or polyethylene glycol 400 (available from Union Carbide) in combination with polyethylene glycol 3350 (available from Union Carbide). can be-u-Sed. The .amount or ointMent base present in an Ointinent of the invention is preferably at least 60 percent, based on the total weight: of ointment. The amount of ointment base present in an ointment of the invention is preferably no greater than 95 percent, based on the total weight of ointment.
Optionally, a cream can contain emollients, emulsifiers, and/or thickeners.
Emollients, such as long chain alcohols, e.g, cetyl alcohol, stearyl alcohol, and cetearyl alcohol; hydrocarbons such as petrolatum and light mineral oil; or acetylated lanolin can.
be included in creams described herein. A cream can contain one or more of these emollients. A cream preferably includes a total amount of emollient of at least 5 percent, based on the total weight of the cream. A cream preferably Includes a total amount of IS emollient of no greater than 30 percent, and more pretbrably no greater than 10 percent based on the total weight of the cream. =
Eniulsifiers such as nonionic surface active agents, e.g., polysorbate 60 (available from ICI Americas), sorbitan monostearate, polyglycery1-4 crimes, and polyoxyetirylene4)lauryl ether, can be included in creams described herein. A
cream can contain one or more emulsifiers. A cream preferably includes a total amount of emulsifier of at least 2 percent, based on the total weight of the cream. 'A cream preferably includes a total amount of emulsifier of no greater than 14 percent, and more preferably no greater than 6 percent, based on the total weight of the cream.
Pharniaceutically acceptable thickeners, such as VEEGUM K (available from R.T.
Vanderbilt Company, Inc.), and king chain alcohols (e.g., cetyl alcohol, stearyl alcohol or ceteraY1 alcohol) can be used. A cream can contain one or more thickeners. A
cream prelbrablyincludes a total amount of thickener Of at least 3 percent, based on the total weight of the meant. A cream prefirrably includes a total amount of thickener of no glider' than 12Pe' d& 'ileac!' On 'the teal weight of the &Wm.
Optiorrally, one or more additional solubllizing agents such as bonny!
alcohol, = lactic acid, acetic acid, ktearic acid, or hydrochloric acid can be included in the creams described herein. If one or morn additional solubilieing agents=are used, the total amount *Trademark present is preferably at least 'l percent, based on the total weight of the cream. If one or more additional solubilizing agents are used, the total amount present is preferably no greater than 12 percent, based on the total weight of the cream.
Optionally, the creams described herein can contain a humectant, such as glycerin, skin penetration enhancers, such as butyl stearate, and additional solubilizing agents.
It is known td those skilled in the art that a single ingredient can perform more than one function in a cream, i.e., cetyl alcohol can serve both as an emollient and as a thickener.
Generally, a cream consists of an oil phase and a water phase mixed together to form an emulsion. Preferably, the amount of water present in a cream of the invention is at least 45 percent, based on the total weight of the cream. Preferably, the amount of water present in a cream of the invention is no greater than 85 percent, based on the total weight of the cream.
The oil phase of a cream of the invention can be prepared, for example, by first combining 1-(2-methylpropy1)-1H-imidazo[4,5-clquinolin-4-amine and one or more fatty acids (if the cream contains benzyl alcohol it can also be added at this point) and heating with occasional stirring to a temperature of 50 C to 85 C. When the 1.-(2-methylpropyl)-1H-imidazo[4,5-ciquinolin-4-amine appears to be completely dissolved, the remaining oil phase ingredients are added and heating is continued until dissolution appears to be complete. The water phase can be prepared by combining all other ingredients and heating with stirring until dissolution appears to be complete. The creams of the invention are generally prepared by adding the water phase to the oil phase with both phases at a temperature of 65 C to 75 C. The resulting emulsion is mixed with a suitable mixer apparatus to give the desired cream.
An ointment preferably contains an ointment base in addition to 142-methylpropy1)-1H4midazo[4,5-chuinolin-4-amine and one or more fatty acids. A
pharmaceutically acceptable ointment base such as petrolattun or polyethylene glycol 400 (available from Union Carbide) in combination with polyethylene glycol 3350 (available from Union Carbide). can be-u-Sed. The .amount or ointMent base present in an Ointinent of the invention is preferably at least 60 percent, based on the total weight: of ointment. The amount of ointment base present in an ointment of the invention is preferably no greater than 95 percent, based on the total weight of ointment.
Optionally, an ointment can also contain emoMents, emulsifiers, and/or thickeners.
The-emoillents, emulsifiers, and/or thicken= and the preferred amounts therebf described;
above in connection with creams are also generally suitable *ruse in an ointment of the.
invention.
An-ointment can be prepared, for example, by combining 1-(2-methylprqpy1)-12T-imidazo[4,5-ejqtanolin-4-tanine with one or more Any acids and heating with occasional stirring to a tenirmture of 65 C. When the 1-(2-methylpropy1)-1H-imidazo[4,5-clquinolin-4-sanine appears to be completely dissolved, the remaining ingredients are added and heated to 65 C. The resulting mixture is mixed with a suitable mixer while being allowed to cool to room temperature.
TEST PROCDDRR
The structure of a laminated packaging material (e.g., laminate) is tested in a two-step process. First, a 5.08 centimeter by 5.08 centimeter sachet of each laminate is formed by folding a 5.08 centimeter by 10.16 centimeter strip of laminate in half and sealing 6.35 .
millimeter wide semis on the two open sides perpendicular to the bottom fold.
Laminates * =
are sealed using a Sencorp (HYamds, MA) heat sealer with either a double heated jaw configuration (260-300 C, 206.8-241.3 iPa, dwell time of 0.4-0.7 seconds) or a single heated jaw configuration (375-400 C, 206.8-240 kPa, dwelltirne of 1.0-2.0 seconds).
The Ouches are filled with approximately two milliliters of 1-(2-methylprepy1)-114Litnidazo(4,5-elquinolin-4-amine-ebntaining cream available front 3M
Company under the trade designation ALDARA (imiquimod 5% cream) and sealed at the top with a 6.35 millhneter seam creating a sachet. The sachets are transferred into a 60 C/ambient relative humidity (RH) storage oven and stored up to six weeks. One sachet of each laminate is removed from the storage oven each week, out open with a scissors and visually inspected for deIarnbuition, perforations, wrinkles, discoloration.
and Other laminate defects. Preferably, a laminate failt testing if it shows at least one defbet after at lemt 4 weeks Ofteiting,, And a laminate passes testing if it does not show any laminate defects. ' . =
' If a laminate passes the above method, the laminate is then further tested in the following Method. The laminate is Used to create sachets with an outer dimensions of 4.7.6 =
centimeters by &35 centimeters with a bottled shape area containing 250 rag of 1-(2- =
- to..
*Trademark meAMPEoPY.07ifFilaidt0i4;k9tOOM'aminct-gontpining mew.. The sachet is fninialaci).4114,81/4444190 01% anEe04413exteiells, EPSia) Packaging =Gigue using verg.gatlitwtoMP817140 qf Ma. C..enti an upper jaw temperature of 160 C.
Sachets,are placed in 40 C175% RH or 25 C(60% .R11 chambers. After initial placement in the S 490,1eTs .are rlsnrYng frera thelitra75% RH and 25 C?6094 RH chambers at .
oue,ffiree, eed six months or threaand six months, respectively. Sachets are observed for.
= 1,emiria1elp1ite1s,.and the 1:42-methylprupyl)-1ffimidazo[4,5-clquinolin-4:amine-= containing:memo, measureci fer.methylparaben and propylparaben stability.
Preferably, = a laminate fails testing if it shows at least one defect and a laminate passes iesthig Wit ' does not show any laminate defects. =
Methylparaben and propylparaben content of the creams are measured using reverse-phase:HPLC. A diluent of 250 mL acetonitrile (ACN. HPLC grade), 740 ml, of water (EIPLC.grade),.and 10 ml. Of hydrochloric acid (lid), reagent grade) is made a minimum of one day before the ilf;LC run. A mobile phi:in solution Is made by adding 2.0 grams of o.ctyl sodium sulfate (OSS, greater than 95% content) to 990 mi.
of HPLC
grade water and 10ØinL of triethylaMine (TEA, reagent grade). The aqueous solution is.
migrated and stirred for five minutes, 85% phosphoric acid (113PO4, HPLC
grade) is added to adjust the pH to 7...0 and then filtered through a 0.45-micron filter. The aqueous solution is mixed with ACN to the ratio of 72:28 (aqueous:ACN) by volume or is mixed to this ratio by using a binary solvent capabilities on the lint. Mixing SOO
milligrams of methylparaben and 50 milligrams of propylparaben with 250 ml. of the diluent makes a parable solution. A standard steak solution for the HPLC run is made by Mhting milligrums of.1-(2-reethylpropyl)-1H-irnidazo[4,5-e]quinolin-4-amine (3M
Pharmaceuticals, Si. Paul, MN), 206 rng oibenzyl alcohol, 10.0 ml. oldie parabra solution, and diluent solution volumetrically to 100 mi.,. Diluting 3.0,ML of the; standard . =
stock solution to 100 ML volume with the diluent solution makes a standard solution.
, . .
=
Samples are prepared by mbrjag 300 mg of th^ e l7(2-methy1propyi)-1:1iimid8z44,5-clquinolip=441nine-0ontalnigg cream from multiple sachets with apprindmately 50-60 niL
Of :111W* an df O3thhiti1y dhe = ,sbiedfbath1nhiOiiiifb1fM Minutes;
= = cooled to room temperature, brought to ;00 mi. volerne with the diluem, and filtered =
through a 0:4;5 mIcron fitte.r. Appro.ximaftly 20.mier!iliters oldie sample and rdar4 are Injected in,t5r the HPLC for;41ysip. Tilit.14:PiC parameters include:: a Zorbax RX-Ce . = "
-ii -*Trademark colutim (Agilent Technologies; Palo Alto, CA), UV; detector set at 258 mu, flew rate of .
teleantite, and an approximate run lime of twelve minutes. Typical retention times.
on the HPI.0 for methYlparaben,.propylparaberwand 1-(2-methylpropy1)1H-imidazo[4,5-c]quiriolin-4-amine peaks are 3.3 minutes, 10.5 minutes, and 6.1 minutP4, respectively, . The permit (*eight:weight) methyIparaben and propylparaben ofthe creams from the sachets are calculated by using the following equation:
%X={11-14-11-14--"-fttlx I x IttmL x 3"IL x100 wherein;
W 2.50mL 100nat- 100na = methrparaban or propylparaben;
.# I h and..4õi= peak area ofXin sample and standard, respectively; and WA.* and Waandardm weight in milligrams ofXin sample and standard, respectively. Preferably, the cream In laminate sachets tasted pass testing lithe tnethYlParaben and ProPYlparaben.contertare.within the ranges, haling:iv; of 0.18% to 0.22% and 6.018% to 0.022% by weight, respectively.
The-emoillents, emulsifiers, and/or thicken= and the preferred amounts therebf described;
above in connection with creams are also generally suitable *ruse in an ointment of the.
invention.
An-ointment can be prepared, for example, by combining 1-(2-methylprqpy1)-12T-imidazo[4,5-ejqtanolin-4-tanine with one or more Any acids and heating with occasional stirring to a tenirmture of 65 C. When the 1-(2-methylpropy1)-1H-imidazo[4,5-clquinolin-4-sanine appears to be completely dissolved, the remaining ingredients are added and heated to 65 C. The resulting mixture is mixed with a suitable mixer while being allowed to cool to room temperature.
TEST PROCDDRR
The structure of a laminated packaging material (e.g., laminate) is tested in a two-step process. First, a 5.08 centimeter by 5.08 centimeter sachet of each laminate is formed by folding a 5.08 centimeter by 10.16 centimeter strip of laminate in half and sealing 6.35 .
millimeter wide semis on the two open sides perpendicular to the bottom fold.
Laminates * =
are sealed using a Sencorp (HYamds, MA) heat sealer with either a double heated jaw configuration (260-300 C, 206.8-241.3 iPa, dwell time of 0.4-0.7 seconds) or a single heated jaw configuration (375-400 C, 206.8-240 kPa, dwelltirne of 1.0-2.0 seconds).
The Ouches are filled with approximately two milliliters of 1-(2-methylprepy1)-114Litnidazo(4,5-elquinolin-4-amine-ebntaining cream available front 3M
Company under the trade designation ALDARA (imiquimod 5% cream) and sealed at the top with a 6.35 millhneter seam creating a sachet. The sachets are transferred into a 60 C/ambient relative humidity (RH) storage oven and stored up to six weeks. One sachet of each laminate is removed from the storage oven each week, out open with a scissors and visually inspected for deIarnbuition, perforations, wrinkles, discoloration.
and Other laminate defects. Preferably, a laminate failt testing if it shows at least one defbet after at lemt 4 weeks Ofteiting,, And a laminate passes testing if it does not show any laminate defects. ' . =
' If a laminate passes the above method, the laminate is then further tested in the following Method. The laminate is Used to create sachets with an outer dimensions of 4.7.6 =
centimeters by &35 centimeters with a bottled shape area containing 250 rag of 1-(2- =
- to..
*Trademark meAMPEoPY.07ifFilaidt0i4;k9tOOM'aminct-gontpining mew.. The sachet is fninialaci).4114,81/4444190 01% anEe04413exteiells, EPSia) Packaging =Gigue using verg.gatlitwtoMP817140 qf Ma. C..enti an upper jaw temperature of 160 C.
Sachets,are placed in 40 C175% RH or 25 C(60% .R11 chambers. After initial placement in the S 490,1eTs .are rlsnrYng frera thelitra75% RH and 25 C?6094 RH chambers at .
oue,ffiree, eed six months or threaand six months, respectively. Sachets are observed for.
= 1,emiria1elp1ite1s,.and the 1:42-methylprupyl)-1ffimidazo[4,5-clquinolin-4:amine-= containing:memo, measureci fer.methylparaben and propylparaben stability.
Preferably, = a laminate fails testing if it shows at least one defect and a laminate passes iesthig Wit ' does not show any laminate defects. =
Methylparaben and propylparaben content of the creams are measured using reverse-phase:HPLC. A diluent of 250 mL acetonitrile (ACN. HPLC grade), 740 ml, of water (EIPLC.grade),.and 10 ml. Of hydrochloric acid (lid), reagent grade) is made a minimum of one day before the ilf;LC run. A mobile phi:in solution Is made by adding 2.0 grams of o.ctyl sodium sulfate (OSS, greater than 95% content) to 990 mi.
of HPLC
grade water and 10ØinL of triethylaMine (TEA, reagent grade). The aqueous solution is.
migrated and stirred for five minutes, 85% phosphoric acid (113PO4, HPLC
grade) is added to adjust the pH to 7...0 and then filtered through a 0.45-micron filter. The aqueous solution is mixed with ACN to the ratio of 72:28 (aqueous:ACN) by volume or is mixed to this ratio by using a binary solvent capabilities on the lint. Mixing SOO
milligrams of methylparaben and 50 milligrams of propylparaben with 250 ml. of the diluent makes a parable solution. A standard steak solution for the HPLC run is made by Mhting milligrums of.1-(2-reethylpropyl)-1H-irnidazo[4,5-e]quinolin-4-amine (3M
Pharmaceuticals, Si. Paul, MN), 206 rng oibenzyl alcohol, 10.0 ml. oldie parabra solution, and diluent solution volumetrically to 100 mi.,. Diluting 3.0,ML of the; standard . =
stock solution to 100 ML volume with the diluent solution makes a standard solution.
, . .
=
Samples are prepared by mbrjag 300 mg of th^ e l7(2-methy1propyi)-1:1iimid8z44,5-clquinolip=441nine-0ontalnigg cream from multiple sachets with apprindmately 50-60 niL
Of :111W* an df O3thhiti1y dhe = ,sbiedfbath1nhiOiiiifb1fM Minutes;
= = cooled to room temperature, brought to ;00 mi. volerne with the diluem, and filtered =
through a 0:4;5 mIcron fitte.r. Appro.ximaftly 20.mier!iliters oldie sample and rdar4 are Injected in,t5r the HPLC for;41ysip. Tilit.14:PiC parameters include:: a Zorbax RX-Ce . = "
-ii -*Trademark colutim (Agilent Technologies; Palo Alto, CA), UV; detector set at 258 mu, flew rate of .
teleantite, and an approximate run lime of twelve minutes. Typical retention times.
on the HPI.0 for methYlparaben,.propylparaberwand 1-(2-methylpropy1)1H-imidazo[4,5-c]quiriolin-4-amine peaks are 3.3 minutes, 10.5 minutes, and 6.1 minutP4, respectively, . The permit (*eight:weight) methyIparaben and propylparaben ofthe creams from the sachets are calculated by using the following equation:
%X={11-14-11-14--"-fttlx I x IttmL x 3"IL x100 wherein;
W 2.50mL 100nat- 100na = methrparaban or propylparaben;
.# I h and..4õi= peak area ofXin sample and standard, respectively; and WA.* and Waandardm weight in milligrams ofXin sample and standard, respectively. Preferably, the cream In laminate sachets tasted pass testing lithe tnethYlParaben and ProPYlparaben.contertare.within the ranges, haling:iv; of 0.18% to 0.22% and 6.018% to 0.022% by weight, respectively.
Claims (30)
1. A packaged composition containing an imiquimod formulation and a durable laminated packaging material for storing the imiquimod formulation therein, the packaged composition comprising:
(a) the durable laminated packaging material forming a pouch comprising:
(i) a contact layer comprising an acrylonitrile-methyl acrylate copolymer;
(ii) an outer layer; and (iii) a moisture barrier layer disposed between the contact layer, and outer layer; and (b) the imiquimod formulation comprising: 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine; and a fatty acid;
wherein the imiquimod is enclosed within the pouch of the durable laminated packaging material and is in direct contact with the contact layer;.
wherein the imiquimod formulation, when enclosed within the pouch and in direct contact with the contact layer, is stable for at least about 6 weeks at about 60°C and at ambient relative humidity (RH); and wherein the durable laminated packaging material, when stored in direct contact with the imquimod formulation at about 40°C and at about 75% RH, remains durable over a period of at least about 1 month.
(a) the durable laminated packaging material forming a pouch comprising:
(i) a contact layer comprising an acrylonitrile-methyl acrylate copolymer;
(ii) an outer layer; and (iii) a moisture barrier layer disposed between the contact layer, and outer layer; and (b) the imiquimod formulation comprising: 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine; and a fatty acid;
wherein the imiquimod is enclosed within the pouch of the durable laminated packaging material and is in direct contact with the contact layer;.
wherein the imiquimod formulation, when enclosed within the pouch and in direct contact with the contact layer, is stable for at least about 6 weeks at about 60°C and at ambient relative humidity (RH); and wherein the durable laminated packaging material, when stored in direct contact with the imquimod formulation at about 40°C and at about 75% RH, remains durable over a period of at least about 1 month.
2. The packaged composition of claim 1 wherein an adhesive is disposed between the contact layer and the moisture barrier layer.
3. The packaged composition of claim 1 wherein the outer layer and the moisture barrier layer are bonded together by extrusion bonding with a polymer tie layer.
4. The packaged composition of claim 3, wherein the tie layer is polyethylene.
5. The packaged composition of claim 1 wherein the contact layer is 25 microns to 80 microns thick.
6. The packaged composition of claim 1 wherein the moisture barrier layer is 5 microns to 15 microns thick.
7. The packaged composition of claim 1 wherein the outer layer is 5 millimeters to 20 millimeters thick.
8. The packaged composition of claim 1 wherein the moisture barrier layer comprises a metal foil.
9. The packaged composition of claim 1 wherein the moisture barrier layer comprises aluminum.
10. The packaged composition of claim 1 wherein the outer layer comprises an organic polymer.
11. The packaged composition of claim 1 wherein the outer layer comprises polyethylene terephthalate.
12. The packaged composition of claim 1 wherein the fatty acid is selected from the group consisting of isostearic acid, oleic acid, myristic acid, palmitic acid, palmitoleic acid, margaric acid, stearic acid, linoleic acid, linolenic acid, and mixtures thereof.
13. The packaged composition of claim 12 wherein the fatty acid is isostearic acid, oleic acid, or mixtures thereof.
14. The packaged composition of claim 1 wherein the fatty acid is present in an amount of at least 15% by weight based on the total weight of the formulation.
15. The packaged composition of claim 1 wherein the fatty acid is present in an amount of at least 20% by weight based on the total weight of the formulation.
16. The packaged composition of claim 1 wherein the fatty acid is present in an amount of about 25% by weight based on the total weight of the formulation.
17. The packaged composition of claim 14 wherein the fatty acid is selected from the group consisting of isostearic acid, oleic acid and mixtures thereof.
18. The packaged composition of claim 17, wherein 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine is present in an amount of 5% by weight of the formulation.
19. The packaged composition of claim 18, wherein the fatty acid is isostearic acid.
20. The packaged composition of claim 18, wherein the fatty acid is oleic acid.
21. The packaged composition of claim 1 wherein the 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine-containing formulation further comprises a preservative.
22. The packaged composition of claim 21 wherein the preservative is selected from the group consisting of methylparaben, propylparaben, benzyl alcohol, and mixtures thereof.
23. The packaged composition of claim 1 wherein the 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine formulation further comprises an emollient, an emulsifier, a thickener, a solubilizing agent, or mixtures thereof.
24. The packaged composition of claim 1, wherein the imiquimod formulation, when enclosed within the pouch and in direct contact with the contact layer, is stable for at least about 6 months at about 40°C and at about 75% RH.
25. The packaged composition of claim 1, wherein the imiquimod formulation, when enclosed within the pouch and in direct contact with the contact layer, is stable for at least about 1 year at about 30°C and at about 65% RH.
26. The packaged composition of claim 1, wherein the imiquimod formulation, when enclosed within the pouch and in direct contact with the contact layer, is stable for at least about 2 years at about 25°C and at about 60% RH.
27. The packaged composition of claim 1, wherein the durable laminated packaging material, when stored in direct contact with the imquimod formulation at about 40°C and at about 75% RH, remains durable over a period of at least about 3 months.
28. The packaged composition of claim 1, wherein the durable laminated packaging material, when stored in direct contact with the imquimod formulation at about 25°C and at about 60% RH, remains durable over a period of at least about 3 months.
29. The packaged composition of claim 1, wherein the durable laminated packaging material, when stored in direct contact with the imquimod formulation at about 40°C and at about 75% RH, remains durable over a period of at least about 6 months.
30. The packaged composition of claim 1, wherein the durable laminated packaging material, when stored in direct contact with the imquimod formulation at about 25°C and at about 60% RH, remains durable over a period of at least about 6 months.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/US2006/049518 WO2008082382A1 (en) | 2006-12-29 | 2006-12-29 | Packaging for 1-(2-methylpropyl)-1h-imidazo[4,5-c]quinolin-4-amine containing formulation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2664548A1 CA2664548A1 (en) | 2008-07-10 |
| CA2664548C true CA2664548C (en) | 2014-04-08 |
Family
ID=39588894
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2664548A Expired - Fee Related CA2664548C (en) | 2006-12-29 | 2006-12-29 | Packaging for 1-(2-methylpropyl)-1h-imidazo[4,5-c]quinolin-4-amine-containing formulation |
Country Status (2)
| Country | Link |
|---|---|
| CA (1) | CA2664548C (en) |
| WO (1) | WO2008082382A1 (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4686125A (en) * | 1984-09-28 | 1987-08-11 | Baxter Travenol Laboratories, Inc. | Film laminate for sterile flexible containers |
| US5008110A (en) * | 1988-11-10 | 1991-04-16 | The Procter & Gamble Company | Storage-stable transdermal patch |
| CA2134320C (en) * | 1993-10-26 | 2001-01-09 | Toshiyuki Hirose | Polyolefin multilayer laminate and use thereof |
| DK1450804T3 (en) * | 2001-11-29 | 2009-01-05 | 3M Innovative Properties Co | Pharmaceutical formula rings comprising an immune response modifier |
-
2006
- 2006-12-29 CA CA2664548A patent/CA2664548C/en not_active Expired - Fee Related
- 2006-12-29 WO PCT/US2006/049518 patent/WO2008082382A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| CA2664548A1 (en) | 2008-07-10 |
| WO2008082382A1 (en) | 2008-07-10 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20161229 |