HK1055584B - A terminally sterilized topical patch preparation and the methods of producing the same - Google Patents
A terminally sterilized topical patch preparation and the methods of producing the same Download PDFInfo
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Description
Introduction to the design reside in
Technical Field
The field of the invention is the production of transdermal drug delivery, in particular topical patch formulations for transdermal drug delivery.
Background
Transdermal delivery devices, such as topical patches, wound dressings, and the like, are used to administer a wide variety of therapeutic agents, such as pharmaceutically active agents. These devices are typically applied to the surface of the skin, allowing the therapeutically active agent contained therein to be delivered into the systemic circulatory system via absorption through the skin. Advantages of transdermal delivery of therapeutic agents over oral or parenteral administration include improved bioavailability (avoiding first pass hepatic metabolism), and more controlled (e.g., sustained, continuous) delivery, topical formulations for transdermal delivery, such as topical patch formulations, typically containing an active agent dissolved or dispersed in an aqueous-based adhesive gel composition coated or spread onto a fibrous material.
Sterile topical patch formulations for transdermal delivery are currently commercially produced from sterilized parts using clean room manufacturing processes. This process requires specially designed facilities, specialized equipment, clean room personnel protective clothing made of specialty materials (e.g., Tyvek ), and strict environmental control and maintenance of air quality, pressure, temperature, and humidity. Clean room manufacturing processes are therefore expensive.
Therefore, the development of a method for producing a terminally sterilized topical patch preparation for transdermal delivery would be of great benefit in terms of drug delivery.
Relevant documents
Interesting patents include the following: 6,030,554, respectively; 6,028,242, respectively; 5,782,914, respectively; 5,730,933, respectively; 5,496,302; 5,011,660, and 4,652,763. See also U.S. Pat. Nos. 5,827,529; 5,480,649, respectively; 5,242,951, respectively; 5,116,621, and 5,082,663.
Summary of The Invention
Methods of producing terminally sterilized topical patch preparations are provided. In the method of the present invention, a topical patch preparation is exposed to electron beam radiation, preferably low level electron beam radiation, for a period of time sufficient to terminally sterilize the topical patch preparation. Also provided are terminally sterilized topical patch preparations produced by the methods of the invention, as well as methods of using the preparations.
Description of the preferred embodiments
Methods of producing terminally sterilized topical patch preparations are provided. In the method of the present invention, a topical patch preparation is exposed to electron beam radiation, preferably low level electron beam radiation, for a period of time sufficient to terminally sterilize the topical patch preparation. Also provided are terminally sterilized topical patch preparations produced by the methods of the invention, as well as methods of using the preparations. In further disclosing the present invention, the method of producing the topical patch of the present invention and the patch itself will first be described in more detail, followed by a review of a representative method of use of the topical patch.
Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments of the invention described below, as such embodiments may be varied and still fall within the scope of the appended claims. It is also to be understood that the terminology used is for the purpose of describing particular embodiments only, and is not intended to be limiting. Rather, the scope of the invention is to be determined by the appended claims.
In this specification and the appended claims, a single reference includes a plurality unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
Method for producing terminally sterilized topical patch preparation
As outlined above, the present invention provides a method of producing a terminally sterilized topical patch formulation. The method of the present invention is applicable to terminal sterilization of a wide variety of different types of topical patch formulations. By topical patch preparation, it is meant a composition comprising an active ingredient in a topical delivery vehicle, i.e., a vehicle suitable for application to the skin surface (or epidermal surface) of an animal. A wide variety of different topical patch formulations are known to those skilled in the art. Representative topical patch formulations that can be terminally sterilized according to the methods of the present invention are provided below. In many embodiments, the topical patch formulation is present in a hermetically sealed packaging means, i.e., it is hermetically sealed, as described in more detail below.
A feature of the method of the present invention is that the topical patch preparation, which in many embodiments is sealed in a packaging means, is exposed to electron beam radiation for a period of time sufficient to terminally sterilize the composition while maintaining the activity of the active agent present therein. The topical patch preparation may be exposed to electron beam radiation using any convenient protocol and apparatus, with representative protocols and apparatus for exposing the relevant composition to electron beam radiation being disclosed in U.S. patent nos. 6,030,554; no.6,028,242; no.5,989,498; and No.5,807,491; the disclosures of these patents are incorporated herein by reference. In many embodiments, the topical patch composition is exposed to low levels of electron beam radiation. By low level electron beam radiation, it is meant electron beam radiation having an intensity in the range of about 5 to 19kGy, and in many embodiments, about 8 to 15 kGy.
In practicing the methods of the present invention, the topical patch preparation is exposed to electron beam radiation for a period of time sufficient to terminally sterilize the topical patch preparation without adversely affecting the performance of the preparation to an unacceptable degree. Generally, the topical patch preparation is exposed to the electron beam radiation for a period of time of at least about 1 minute, typically at least about 1-2 minutes, and more typically at least about 2 minutes, wherein the period of time can be as long as 3 minutes or longer but typically no more than about 5 minutes, more typically no more than about 3 minutes. In many embodiments, the time period ranges from about 1 to 3 minutes, typically from about 1 to 2 minutes.
The process described above results in a terminally sterilized topical patch formulation. By "terminal (sterilization)" is meantThe topical patch preparation is substantially free, if not completely free, of viable microorganisms, wherein by "substantially free" is meant that no more than about 100 viable microorganisms, typically no more than about 10 viable microorganisms, and more typically no more than about 5 viable microorganisms are present in the patch preparation after the treatment described above, and by "completely free" is meant that no viable microorganisms are present in the topical patch preparation. Thus, the patch of the present invention is substantially, if not completely, free of microorganisms selected from the group consisting of: staphylococcus aureus (S.) (Staphylococcus aureus) (ii) a Pseudomonas aeruginosa (A)Pseudomonas aeruginosa) (ii) a Escherichia coli (E.coli) ((Escherichia coli) (ii) a Candida albicans (C., (C.))Candida albicans) (ii) a Aspergillus nigerAspergillus niger) And the like.
The method of the present invention is applicable to sterilization of a wide variety of topical patch preparations. Examples of different types of topical patch formulations that can employ the sterilization method of the present invention include U.S. Pat. nos. 5,827,529; no.5,480,646; no.5,242,951; no.5,116,621; and those described in No.5,082,663; the disclosures of these patents are incorporated herein by reference.
Representative topical patch formulations described in at least some of the above-mentioned patents which may be terminally sterilized according to the present invention are comprised of an active agent retaining layer present on a support, wherein the active agent retaining layer is comprised of one or more active agents present, for example, dissolved or dispersed, in an adhesive gel base comprised of a water-soluble high molecular weight material, water and a water retaining agent.
Water soluble high molecular weight materials include water soluble polymers, wherein useful polymers include, but are not limited to: gelatin, starch, agar, mannan, alginic acid, polyacrylic acid, polyacrylate salt, dextrin, methyl cellulose, sodium carboxymethyl cellulose, carboxyvinyl polymer, polyvinyl alcohol, polyvinyl pyrrolidone, gum arabic, tragacanth gum, karaya gum, and starch acrylate copolymer. Metal salts of these, and products of crosslinking these with the aid of organic or inorganic crosslinking agents, are also advantageous. These water-soluble polymers may be used to develop the properties and characteristics of other starting materials used in the adhesive gel composition, and may be used alone or in combination of 2 or more. The water soluble high molecular weight material is generally present in the adhesive gel base in an amount ranging from about 0.5 to 50% by weight, usually from about 5 to 25% by weight.
The amount of water present in the gel adhesive is sufficient to impart the desired physical properties to the gel adhesive and is generally in the range of about 10 to 70 weight percent, usually about 20 to 50 weight percent.
The water retaining agent or agent of the adhesive gel composition of the present invention is any agent that at least reduces the evaporation of water contained in the adhesive gel base, thereby maintaining the water content in the adhesive gel base at an at least substantially constant, if not constant, level during storage and use of the formulation. One or more water retention agents may be employed in the compositions of the present invention, wherein the water retention agent is generally present in the adhesive gel base in an amount ranging from about 1 to 70% by weight, preferably 10 to 60% by weight. Examples of suitable water retention agents or agents include, but are not limited to, one or more types of polyols, such as glycerol, sorbitol, propylene glycol, 1, 3-butanediol, and ethylene glycol, and the like.
Furthermore, in addition to the above-mentioned ingredients, various additives commonly used in topical water-soluble patch preparations may also be appropriately compounded as needed, including inorganic substances such as kaolin, bentonite, and titanium dioxide; preservatives such as p-hydroxybenzoic acid; anionic, cationic, and nonionic surfactants; metallic aluminum crosslinking agents such as aluminum chloride, dried aluminum hydroxide gel, and dihydroxyaluminum aminoacetate; oils such as jojoba oil and castor oil; solubilizers such as crotamiton; chelating agents such as EDTA; pH adjusters such as malic acid, tartaric acid, and diisopropanolamine; alcohols such as ethanol; humectants such as hyaluronic acid, aloe vera extract, and urea; and other flavoring and coloring agents.
In the topical patch formulation of the present invention, a diverse group of active agents or ingredients may be present in the adhesive gel base described above. Depending on the nature of the active agent, the active agent is generally present in the composition in an amount ranging from about 0.2% to about 10%, typically from about 0.2% to about 5%, more typically from about 0.5% to about 5%. Representative specific active agents of interest include, but are not limited to: dl-camphor, capsaicin, eucalyptus oil, nonivamide, methyl salicylate, glycol salicylate, dipotassium glycyrrhizinate, 1-menthol, and tocopheryl acetate; salts and derivatives of non-steroidal anti-inflammatory drugs such as ketoprofen, flurbiprofen, felbinac, and diclofenac; and local anesthetics such as lidocaine, tetracaine, and sarucaine.
In many embodiments, the active agent present in the composition is a local anesthetic. Although two or more local anesthetics may be present in the compositions of the present invention, generally, the compositions of the present invention will comprise a single local anesthetic. Beneficial local anesthetics are those that can rapidly penetrate the keratinized skin surface when administered in a topical formulation. In many embodiments, beneficial local anesthetics have a molecular weight and melting point compatible with delivery via keratinized skin surfaces. Generally, the local anesthetic will not have a molecular weight in excess of about 300 daltons, and more typically will not have a molecular weight in excess of about 250 daltons. The local anesthetic will have a melting point below about 100 ℃. In many embodiments, the local anesthetic will be a compound comprising a secondary or tertiary amine linked by a bond or via a linking group to an aromatic group. The local anesthetic will generally be an alkanoyl compound having about 9 to 20 carbon atoms. Since the composition is applied topically, the local anesthetic will generally be present in the composition as a free base to facilitate penetration of the active agent through the skin surface. Numerous local anesthetics are known in the art, many of which are suitable for local administration. Suitable local anesthetics include lidocaine, butamben, butadocaine, ethyl aminobenzoate, fomocaine, hydroxyprocaine, isobutyl p-aminobenzoate, nanoecaine, otacaine, p-ethoxycaine, lidocaine, prilocaine, procaine, lignocaine, tolicaine, trimecaine, tetracaine, selocaine, ethyl aminobenzoate (benzocaine); and the like.
As noted above, the adhesive gel composition containing one or more active ingredients is typically present on a support. The support is typically made of a flexible material that is capable of fitting the human body and includes, for example, various nonwoven fabrics, woven fabrics, spandex, flannel, or laminates of these materials with polyethylene films, polyethylene terephthalate films, polyvinyl chloride films, ethylene-vinyl acetate copolymer films, polyurethane films, and the like.
In many embodiments, the topical formulation or patch to be sterilized, as described above, is present in a sealed package prior to exposure to electron beam radiation. Generally, the sealed package is made from a packaging material comprising a layer made of a material that prevents the passage of moisture, oxygen and other agents, i.e. the package is enclosed in a moisture/oxygen barrier material. Any suitable barrier material may be used, wherein a beneficial barrier material comprises a metal layer such as aluminum, wherein in many embodiments the barrier layer is an aluminum layer having a thickness sufficient to provide a barrier function, wherein the thickness typically ranges from about 5 to 15, typically from about 6 to 10 μm. In many embodiments, the package is a laminate of the barrier layer in combination with one or more additional layers such as polymer layers, paper layers, and the like. A representative aluminum-containing package that can be used with the patch preparation of the present invention is sold by japan printing company (kyoto, japan).
Topical patch preparations which can be terminally sterilized according to the methods of the present invention can be prepared by any convenient protocol. A convenient manufacturing protocol for such patches includes: a gel-adhesive paste is prepared by uniform mixing of the above-mentioned components, then the paste is applied to a support, and the resultant product is subsequently cut into a prescribed size to obtain a desired topical patch preparation. The resulting topical patch preparation is then heat sealed as described above with a packaging material containing an aluminum layer, typically several sheets, in a package to obtain a sealed topical patch. For a more detailed description of this fabrication scheme, see U.S. Pat. Nos. 5,827,529; the disclosure of this patent is incorporated herein by reference.
Terminally sterilized topical patch preparation
Also provided by the present invention is a terminally sterilized patch preparation, wherein in many embodiments the patch preparation is a terminally sterilized packaged patch preparation, i.e. a patch preparation sealed with a package, e.g. an aluminum foil containing package or pocket, as described above. Due to the processes employed in the methods of the present invention, the topical formulations of the present invention are characterized by the presence of non-viable microorganisms and substantially non-viable microorganisms, wherein in certain embodiments the terminally sterilized topical patch formulations of the present invention do not include viable microorganisms. Where the terminally sterilized topical patch formulations of the present invention contain some viable microorganisms, they will not contain so much of the organisms that they cannot be referred to as terminally sterilized. Thus, in these embodiments, the number of microorganisms will not exceed about 100, typically will not exceed about 10, and more typically will not exceed about 1-10. Since the compositions of the present invention are prepared from non-sterile parts and then terminally sterilized, as opposed to formulations prepared under clean room conditions and protocols, the number of non-viable or radiation-killed microorganisms present in the compositions of the present invention is important and can range from about 1 to 100, typically from about 1 to 50, and more typically from about 1 to 10.
Method of using patch preparation
The terminally sterilized patch formulation of the present invention finds use in the topical delivery of an active agent to a host, wherein by topical delivery is meant delivery via absorption through the skin. In topically administering an active agent to the skin using the terminally sterilized topical patch preparation of the present invention, the topical preparation is applied to the skin surface and maintained at the site of application for a period of time sufficient to deliver the desired amount of active agent to the host, wherein the period of time typically ranges from about 1 hour to 24 hours, usually from about 1 hour to 12 hours.
Whole set medicine box (Kits)
Kits of parts are also provided, wherein a kit of parts according to the invention comprises at least one or more terminally sterilized topical patch preparations as described above. The topical patch preparation of the present invention in the kit of parts may be present in a package as described above. Kits of parts according to the invention will also generally include instructions for how to use the patch to deliver an active agent to a host. Such instructions are generally described on a suitable recording medium. For example, the instructions may be printed on a substrate such as paper or plastic, etc. Thus, the instructions may be present in the kit of parts as a package insert, labeling of the containers of the kit of parts or components thereof (i.e., components associated with the package or sub-package), and the like. In other embodiments, the instructions are presented as an electronically stored data file on a suitable computer readable storage medium, such as a CD-ROM, floppy disk, or the like.
The following examples and comparative examples are provided by way of illustration and not by way of limitation.
Experiment of
I. Compositions of the examples
TABLE 1 compositions of examples 1-6
| Composition (I) | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 |
| Indometacin | 0.5 | |||||
| Biphenylacetic acid | 0.5 | |||||
| Lidocaine | 5.0 | |||||
| Salicylic acid diol ester | 1.0 | |||||
| 1-menthol | 0.5 | 0.5 | 0.02 | |||
| dl-camphor | 0.5 | |||||
| Tocopheryl acetate | 0.2 | 0.2 | ||||
| Hyaluronic acid | 2.0 | |||||
| Clomiton (a kind of medicine) | 2.0 | 0.5 | ||||
| Sorbitol | 30.0 | 25.0 | 20.0 | 10.0 | 20.0 | |
| Kaolin clay | 5.0 | 1.5 | 2.0 | 1.0 | ||
| Urea | 3.0 | |||||
| Gelatin | 2.0 | 1.0 | 0.5 | |||
| EDTA disodium salt | 0.2 | 0.1 | 0.1 | 0.07 | 0.05 | 0.08 |
| Diisopropanolamine | 3.0 | |||||
| Tartaric acid | 2.3 | 0.2 | 1.5 | 1.0 | 1.4 | 1.5 |
| Castor oil | 1.0 | 0.2 | 2.0 | 2.0 | 1.0 |
| Composition (I) | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 |
| Tween-80 | 0.2 | 0.2 | 0.1 | |||
| P-hydroxybenzoic acid methyl ester | 0.2 | 0.2 | 0.2 | 0.2 | 0.15 | 0.2 |
| Dihydroxyaluminum aminoacetate | 0.2 | 0.5 | 0.25 | 0.08 | 0.05 | 0.07 |
| Carboxycarbonyl polymers | 1.6 | 0.8 | 0.5 | |||
| Polyacrylic acid | 10.0 | 10.0 | 5.0 | |||
| Polyacrylamide sodium salt | 5.0 | 3.0 | 5.0 | 7.0 | 7.0 | 5.0 |
| Sodium carboxymethylcellulose | 4.0 | 5.0 | 4.0 | 3.0 | 5.0 | |
| Polyvinyl alcohol | 2.0 | 1.0 | 2.0 | 1.0 | ||
| Glycerol | 15.0 | 17.0 | 23.0 | 20.0 | 30.0 | 20.0 |
| Distilled water | 31.9 | 47.2 | 21.45 | 40.25 | 53.33 | 39.05 |
| Total up to | 100.00 | 100.00 | 100.00 | 100.00 | 100.00 | 100.00 |
The units are all by weight%
Example II
Example 1
A water-soluble polymer gel topical patch preparation was prepared in which indomethacin, a nonsteroidal anti-inflammatory drug, was compounded as an active ingredient. All ingredients were blended together to produce a homogeneous paste. The paste is at a concentration of 1200kg/m2The content of (A) was spread on a PET-nonwoven fabric, and then, the resulting product was covered with a PP film and cut into a size of 10cm by 14 cm. The sheets were then packaged into 2 packs by heat sealing with a packaging material containing an aluminium layer. The resulting hermetically sealed packaged product was then sterilized by irradiation with a 12kGy electron beam for 2 minutes.
Example 2
A water-soluble polymer gel topical patch preparation is prepared in which felbinac, a non-steroidal anti-inflammatory drug, is compounded as an active ingredient. All ingredients were blended together to produce a homogeneous paste. The paste is at a concentration of 1200kg/m2The content of (A) was spread on a PET-nonwoven fabric, and then, the resulting product was covered with a PP film and cut into a size of 10cm by 14 cm. The sheets were then packaged into 2 packs by heat sealing with a packaging material containing an aluminium layer. The resulting hermetically sealed packaged product was then sterilized by irradiation with a 12kGy electron beam for 2 minutes.
Example 3
A water-soluble polymer gel topical patch preparation was prepared in which the local anesthetic lidocaine was compounded as an active ingredient. All ingredients were blended together to produce a homogeneous paste. The paste is at a concentration of 1200kg/m2The content of (A) was spread on a PET-nonwoven fabric, and then, the resulting product was covered with a PP film and cut into a size of 10cm by 14 cm. The sheets were then packaged into 2 packs by heat sealing with a packaging material containing an aluminium layer. The resulting hermetically sealed packaged product was then sterilized by irradiation with a 12kGy electron beam for 2 minutes.
Example 4
An anti-inflammatory analgesic water-soluble polymer gel topical patch preparation was prepared in which glycol salicylate, 1-menthol, dl-camphor, and tocopheryl acetate were compounded as active ingredients. All ingredients were blended together to produce a homogeneous paste. The paste is at a concentration of 1200kg/m2The content of (A) was spread on a PET-nonwoven fabric, and then, the resulting product was covered with a PP film and cut into a size of 10cm by 14 cm. The sheets were then packaged into 2 packs by heat sealing with a packaging material containing an aluminium layer. The resulting hermetically sealed packaged product was then sterilized by irradiation with a 12kGy electron beam for 2 minutes.
Example 5
A water-soluble moisturizing topical patch preparation in which hyaluronic acid and tocopheryl acetate are compounded as active ingredients was prepared. All ingredients were blended together to produce a homogeneous paste. The paste is at a concentration of 1200kg/m2The content of (A) was spread on a PET-nonwoven fabric, and then, the resulting product was covered with a PP film and cut into a size of 10cm by 14 cm. The sheets were then packaged into 2 packs by heat sealing with a packaging material containing an aluminium layer. The resulting hermetically sealed packaged product was then sterilized by irradiation with a 12kGy electron beam for 2 minutes.
Example 6
A placebo. All ingredients were blended together to produce a homogeneous paste. The paste is at a concentration of 1200kg/m2The content of (A) was spread on a PET-nonwoven fabric, and then, the resulting product was covered with a PP film and cut into a size of 10cm by 14 cm. The sheets were then packaged into 2 packs by heat sealing with a packaging material containing an aluminium layer. The resulting hermetically sealed packaged product was then sterilized by irradiation with a 12kGy electron beam for 2 minutes.
Comparative example III
Comparative example 1
The water-soluble polymer gel topical patch formulation according to example 1, has not been subjected to sterilization by means of electron beam irradiation.
Comparative example 2
The water-soluble polymer gel topical patch formulation according to example 2, has not been subjected to sterilization by means of electron beam irradiation.
Comparative example 3
The water-soluble polymer gel topical patch formulation according to example 3, has not been subjected to sterilization by means of electron beam irradiation.
Comparative example 4
The water-soluble polymer gel topical patch formulation according to example 4, has not been subjected to sterilization by means of electron beam irradiation.
Comparative example 5
The water-soluble, water-retaining topical patch formulation according to example 5, has not been subjected to sterilization by electron beam irradiation.
Comparative example 6
The placebo according to example 6 has not been subjected to sterilization by electron beam irradiation.
Comparative example 7
To the water-soluble polymer gel topical patch preparation according to example 1, methylparaben was added as a preservative at a content of 0.2%, and the resulting product was packaged into 2 pieces per pack by heat-sealing with a packaging material containing an aluminum layer. The resulting product has not been subjected to sterilization by means of electron beam irradiation.
Comparative example 8
To the water-soluble polymer gel topical patch preparation according to example 2, methylparaben was added as a preservative at a content of 0.2%, and the resulting product was packaged into 2 pieces per pack by heat-sealing with a packaging material containing an aluminum layer. The resulting product has not been subjected to sterilization by means of electron beam irradiation.
Comparative example 9
To the water-soluble polymer gel topical patch preparation according to example 3, methylparaben was added as a preservative at a content of 0.2%, and the resulting product was packaged into 2 pieces per pack by heat-sealing with a packaging material containing an aluminum layer. The resulting product has not been subjected to sterilization by means of electron beam irradiation.
Comparative example 10
To the water-soluble polymer gel topical patch preparation according to example 4, methylparaben was added as a preservative at a content of 0.2%, and the resulting product was packaged into 2 pieces per pack by heat-sealing with a packaging material containing an aluminum layer. The resulting product has not been subjected to sterilization by means of electron beam irradiation.
Comparative example 11
To the water-soluble water-retaining topical patch preparation according to example 5, methylparaben was added as a preservative at a content of 0.2%, and the resulting product was packaged into 2 pieces per package by heat-sealing with a packaging material containing an aluminum layer. The resulting product has not been subjected to sterilization by means of electron beam irradiation.
Comparative example 12
To the placebo according to example 6, methylparaben was added as a preservative at a content of 0.2%, and the resulting product was packaged into 2 sheets per packet by heat-sealing with a packaging material containing an aluminum layer. The resulting product has not been subjected to sterilization by means of electron beam irradiation.
Results IV
TABLE 2Comparison of microbial levels in the compositions of examples 1-6 and comparative examples 1-6
Results
| First comparison | Second comparison | Third comparison | |
| Example 1 | - | - | - |
| Comparative example 1 | + | + | + |
| Example 2 | - | - | - |
| Comparative example 2 | + | + | + |
| Example 3 | - | - | - |
| Comparative example 3 | + | + | + |
| Example 4 | - | - | - |
| Comparative example 4 | + | + | + |
| Example 5 | - | - | - |
| Comparative example 5 | + | + | + |
| Example 6 | - | - | - |
| Comparative example 6 | + | + | + |
+ with a low level of microorganisms
Complete sterilization
As shown in Table 2, the sterilization by electron beam irradiation was complete, indicating that sufficient sterilization effect was obtained even by irradiation at 12kGy for 2 minutes.
Examples 1 to 6 and comparative examples 7 to 12 were prepared, and each was stored in a room maintained at 40 ℃. These examples and comparative examples were compared for formulation discoloration and off-flavor after 1 week, after 1 month, after 3 months, and after 6 months (table 3). The content of active ingredient was also measured and compared for example 1 and comparative example 7, and for example 3 and comparative example 9 (table 4).
The values shown represent the differences between the examples and the comparative examples and represent the sensory differences experienced by the healthy individuals of each of the examples in 10 comparisons.
TABLE 3Comparison of discoloration and off-flavors
| After 1 week | After 1 month | After 3 months | After 6 months | |||||
| Color change | Peculiar smell | Color change | Peculiar smell | Color change | Peculiar smell | Color change | Peculiar smell | |
| Example 1 | - | - | - | - | + | + | + | + |
| Example 2 | - | - | - | - | + | - | + | - |
| Example 3 | - | - | - | - | - | + | + | + |
| Example 4 | - | - | - | - | - | - | - | + |
| Example 5 | - | - | - | - | - | - | + | + |
| Example 6 | - | - | - | - | - | - | - | - |
3+ rather big difference
2+ difference
+ slight difference
No difference
As shown in table 3, the topical patch preparation sterilized by electron beam irradiation actually showed the same external characteristics as the topical patch preparation not sterilized by electron beam irradiation. Thus, long-term storage leads to minimal decomposition of the water-soluble polymer gel, for example, due to electron irradiation.
The results shown are all obtained by comparison with n-3 and are the average thereof.
TABLE 4Results of active ingredient measurement and comparison of example 1 and comparative example 7, and example 3 and comparative example 9
| After 1 week | After 1 month | After 3 months | After 6 months | ||
| Indometacin | Example 1 | 4.98 | 4.94 | 4.88 | 4.72 |
| Comparative example 7 | 4.99 | 4.96 | 4.87 | 4.75 | |
| Lidocaine | Example 3 | 48.7 | 48.3 | 47.9 | 47.1 |
| Comparative example 9 | 49.2 | 48.9 | 48.5 | 47.7 | |
The units are mg/active/g of composition.
Table 4 shows that as far as the stability of the active ingredient is concerned, there is practically no decomposition caused by electron beam irradiation, and the stability is well within the range of ± 10%.
Stability of V
A. Introduction to the design reside in
Three small batches of lidocaine topical patches (5%, as described in example 3 above) (batch No. 2024) received low electron beam irradiation doses of 0.5 megarads (or 5.0kGy), 0.9-1.0 megarads (or 9-10 kGy), and 1.3-1.4 megarads (13-14 kGy), respectively.
These three stability lot numbers are recorded as follows:
stable lot number radiation dose
001-9A 0.5 megarad
001-9B 0.9 to 1.0 megarad
001-9C 1.3 to 1.4 megarads
B. Specific batch number
1. Stability #001-9A, exposed to 5.0kGy (kilogray) or 0.5 megarad beam
| Tests carried out | Initial | 40 deg.C for 3 months | 40 deg.C for 6 months | Description of the invention |
| Microbiology | ||||
| Sterility test (USP24) | Qualified | Qualified | Qualified | Qualified |
| Chemistry | ||||
| Physical appearance | Qualified | Qualified | Qualified | White to light yellow, faint characteristic odor |
| Lidocaine hydrochloride | 96.4％ | 101.3％ | 101.4％ | 90.0-110.0% of each plaster 700mg |
| Dissolving lidocaine | 324.2mg | 321.5mg | 348.0mg | NLT 280 mg/patch, 30 minutes |
| P-hydroxybenzoic acid methyl ester | 13.2mg | 13.6mg | 13.6mg | 14.0+/-1.4mg per patch |
| Propyl p-hydroxybenzoate | 6.70mg | 6.95mg | 7.12mg | 7.0+/-0.7mg per patch |
| 2, 6-dimethylaniline as a related compound | Not detected | Not detected | Not detected | < 700 mcgs/patch |
| pH | 6.80 | 6.95 | 6.82 | 6.0-7.5 |
| Adhesive strength | 38 seconds | 27 seconds | > 5 seconds | NLT 5 seconds |
| Mean value of weight variation (20) RSD | 16.354g2.04g | 16.280g1.41g | 16.390g1.62g | Deviation NMT 10% |
2. Stability #001-9B, irradiated with 9-10 kGy (kilogray) or 0.9-1.0 mrad of electron beam
| Tests carried out | Initial | 40 deg.C for 3 months | 40 deg.C for 6 months | Description of the invention |
| Microbiology | ||||
| Sterility test (USP24) | Qualified | Qualified | Qualified | Qualified |
| Chemistry | ||||
| Physical appearance | Qualified | Qualified | Qualified | White to light yellow, faint characteristic odor |
| Lidocaine hydrochloride | 96.7％ | 103.2％ | 100.8％ | 90.0-110.0% of each plaster 700mg |
| Dissolving lidocaine | 344.6mg each patch | 328.8mg each patch | 349.7mg per patch | The NLT is 280mg per patch, |
| p-hydroxybenzoic acid methyl ester | 13.5mg | 13.9mg | 13.4mg | 14.0+/-1.4mg per patch |
| Propyl p-hydroxybenzoate | 6.51mg | 7.09mg | 7.04mg | 7.0+/-0.7mg per patch |
| 2, 6-dimethylaniline as a related compound | Not detected | Not detected | Not detected | < 700 mcg/patch |
| pH | 6.81 | 7.10 | 6.83 | 6.0-7.5 |
| Adhesive strength | 39 seconds | 22 seconds | > 5 seconds | NLT 5 seconds |
| Mean value of weight variation (20) RSD | 16.389g1.54g | 16.470g1.71g | 16.504g1.45g | Deviation NMT 10% |
3. Stability #001-9C, irradiated with 13-14 kGy (kilogray) or 1.3-1.4 mrad of electron beam
| Tests carried out | Initial | 40 deg.C for 3 months | 40 deg.C for 6 months | Description of the invention |
| Microbiology | ||||
| Sterility test (USP24) | Qualified | Qualified | Qualified | Qualified |
| Chemistry | ||||
| Physical appearance | Qualified | Qualified | Qualified | White to light yellow, faint characteristic odor |
| Lidocaine hydrochloride | 96.6％ | 98.3％ | 97.7％ | 90.0-110.0% of each plaster 700mg |
| Dissolving lidocaine | 328.5mg | 334.5mg | 332.9mg | The NLT is 280mg per patch, |
| p-hydroxybenzoic acid methyl ester | 13.5mg | 13.5mg | 13.3mg | 14+/-1.4mg per patch |
| Propyl p-hydroxybenzoate | 6.52mg | 6.85mg | 6.97mg | 7+/-0.7mg per patch |
| 2, 6-dimethylaniline as a related compound | Not detected | Not detected | Not detected | < 700mcgs per patch |
| pH | 6.79 | 7.00 | 6.81 | 6.0-7.5 |
| Adhesive strength | 60 seconds | 46 seconds | > 5 seconds | NLT 5 seconds |
| Mean value of weight variation (20) RSD | 16.409g1.33g | 16.290g1.88g | 16.389g1.58g | Deviation NMT 10% |
C. Results
Storage of 5% of lidocaine patches receiving electron beam radiation at a dose of 0.5-1.4 mrads under accelerated conditions (6 months, 40 ℃, 75% relative humidity) showed no effect on the stability and sterility of the product.
As is apparent from the above results and discussion, the present invention provides for efficient, complete sterilization of topical patch formulations using electron beam radiation (even with low levels of irradiation), resulting in a stable, terminally sterilized topical patch formulation. Thus, the present invention provides a more convenient method of manufacturing a terminally sterilized topical patch. Furthermore, the terminally sterilized patch preparation of the present invention has a wide variety of applications due to its ultimate sterility, including application to open wounds, among others. Thus, the present invention represents a significant contribution to the industry.
All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.
Claims (25)
1. A method of producing a terminally sterilized topical patch preparation, the method comprising:
exposing a topical patch preparation to electron beam radiation for a period of time sufficient to terminally sterilize said topical patch preparation, wherein said topical patch preparation comprises: (i) an active agent retaining layer comprising a pharmaceutically active agent; and
(ii) a support layer of the active agent retaining layer,
to produce a terminally sterilized topical patch preparation.
2. The method of claim 1, wherein said topical patch preparation is sealed with a packaging material comprising an aluminum layer.
3. The method of claim 2, wherein said sealed topical patch preparation is produced by the steps of:
(a) providing a topical patch formulation;
(b) packaging said topical patch preparation in a packaging material comprising an aluminum layer; and
(c) sealing the packaged topical patch preparation.
4. The method of claim 1, wherein the electron beam radiation is a low level electron beam radiation.
5. The method of claim 4, wherein the low level electron beam radiation is about 5-19 kGy.
6. The method of claim 4, wherein the low level electron beam radiation is about 8-15 kGy.
7. The method of claim 1, wherein the formulation is exposed for a period of time ranging from about 40 to 80 seconds.
8. A method of producing a sealed, terminally sterilized topical patch preparation, the method comprising:
(a) producing a sealed topical patch preparation by a process comprising the steps of:
(i) providing a topical patch formulation produced by the method of claim 1;
(ii) packaging said topical patch preparation in a packaging material comprising an aluminum layer; and
(iii) sealing the packaged topical patch preparation; and
(b) exposing the sealed topical patch preparation to low level electron beam radiation for a time sufficient to terminally sterilize the topical patch preparation;
thereby producing a sealed, terminally sterilized topical patch formulation.
9. The method of claim 8, wherein the low level electron beam radiation is about 5-19 kGy.
10. The method of claim 8, wherein the low level electron beam radiation is about 8-15 kGy.
11. The method of claim 8, wherein the formulation is exposed for a period of time ranging from about 40 to 80 seconds.
12. A terminally sterilized topical patch preparation produced by exposing a topical patch preparation to electron beam radiation for a time sufficient to terminally sterilize said topical patch preparation, wherein said topical patch preparation comprises:
(i) an active agent retaining layer comprising a pharmaceutically active agent; and
(ii) a support layer of the active agent retaining layer.
13. A terminally sterilized topical patch preparation produced by the method of any one of claims 1-11, the preparation comprising:
a fibrous material; and
an adhesive gel composition;
wherein the formulation contains non-viable microorganisms.
14. The formulation of claim 13, wherein the adhesive gel composition comprises:
an active agent;
a water-soluble polymer gel;
water; and
a water-holding agent.
15. The formulation of claim 14, wherein the active agent is a local anesthetic.
16. The formulation of claim 13, wherein the formulation is sealed with a packaging material.
17. The formulation of claim 16, wherein the packaging material comprises an aluminum layer.
18. The formulation of claim 14, wherein the non-viable microorganisms are electron beam irradiated microorganisms.
19. A method of delivering an active agent to a subject, said method comprising:
applying a terminally sterilized topical patch preparation comprising an active agent produced by the method of any one of claims 1-11 to a skin surface of said subject;
thereby delivering the active ingredient to a subject.
20. The method of claim 19, wherein the formulation is the formulation of claim 14.
21. A kit of parts for transdermal delivery of an active agent to a subject in need thereof, said kit of parts comprising:
(a) a terminally sterilized topical patch preparation comprising an active agent produced by the method of any one of claims 1-11; and
(b) instructions for using said formulation to perform the method of claim 19.
22. A method of producing a sealed, terminally sterilized topical patch preparation, the method comprising:
(a) producing a sealed topical patch preparation by a process comprising the steps of:
(I) providing a topical patch formulation comprising:
(a) an active agent retaining layer comprising a pharmaceutically active agent; and
(b) a support for the active agent retaining layer;
(ii) packaging said topical patch preparation in a packaging material comprising an aluminum layer; and
(iii) sealing the packaged topical patch preparation; and
(b) exposing the sealed topical patch preparation to low level electron beam radiation for a time sufficient to terminally sterilize the topical patch preparation;
thereby producing a sealed, terminally sterilized topical patch formulation.
23. The method of claim 22, wherein the low level electron beam radiation is about 5-19 kGy.
24. The method of claim 22, wherein the low level electron beam radiation is about 8-15 kGy.
25. The method of claim 22, wherein the formulation is exposed for a period of time ranging from about 40 to 80 seconds.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US19160800P | 2000-03-23 | 2000-03-23 | |
| US60/191,608 | 2000-03-23 | ||
| US21822000P | 2000-07-14 | 2000-07-14 | |
| US60/218,220 | 2000-07-14 | ||
| PCT/US2001/009567 WO2001070577A1 (en) | 2000-03-23 | 2001-03-22 | Methods of producing a terminally sterilized topical patch preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1055584A1 HK1055584A1 (en) | 2004-01-16 |
| HK1055584B true HK1055584B (en) | 2006-01-13 |
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