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WO1990009809A1 - Systeme de liberation percutanee d'un medicament - Google Patents

Systeme de liberation percutanee d'un medicament Download PDF

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Publication number
WO1990009809A1
WO1990009809A1 PCT/US1990/000998 US9000998W WO9009809A1 WO 1990009809 A1 WO1990009809 A1 WO 1990009809A1 US 9000998 W US9000998 W US 9000998W WO 9009809 A1 WO9009809 A1 WO 9009809A1
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WO
WIPO (PCT)
Prior art keywords
skin
drug
papain
localized area
patch
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1990/000998
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English (en)
Inventor
Robert V. Petersen
Tsung-Min Hsu
Han-Chen Lee
Don Christy
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University of Utah
Original Assignee
University of Utah
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by University of Utah filed Critical University of Utah
Publication of WO1990009809A1 publication Critical patent/WO1990009809A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein

Definitions

  • This invention pertains to drug delivery systems generally and is more particularly directed to transdermal drug delivery systems and methods.
  • Devices for transdermal or percutaneous drug delivery are known in the art. Such devices include “patches” such as the Nitro-Dur R nitroglycerin transdermal infusion system marketed by Key Pharmaceutical of Kenilsworth, New Jersey. This system consists of a "patch” containing nitroglycerin in
  • acrylic-based polymer adhesives with a resinous crosslinking agent to provide a continuous source of
  • nitroglycerin to the patient.
  • the patches are available in various dosage strengths for delivering various amounts of nitroglycerin to the patient over a twentyfour hour period. These patches vary in size from five to thirty square centimeters (cm 2 ). The rated release of the drug is dependent upon the area of the patch with 0.5 milligram (mg) being released for every square centimeter of patch per 24 hours.
  • the patch is applied to any convenient skin area, especially the arm or chest.
  • transdermal patch is marketed by Noven Pharmaceutical of Miami, Florida.
  • the Noven patch has been used with nitroglycerin and estrogen. It consists of a non-occlusive backing layer, a drug reservoir for containing the drug, a microporous rate controlling membrane which contacts the skin of the patient, and an adhesive formulation for keeping the patch in contact with the skin. Drug passes from the reservoir through the membrane, through the patient's skin, and into the bloodstream.
  • Transderm SCOP R is used by CIBA Consumer Pharmaceutical Co. of Summit, New Jersey. It is a film 0.2 mm thick and 2.5 cm 2 , with four layers. Proceeding from the visible surface towards the surface attached to the patient's skin (FIG. 12), these layers are: (a) a backing layer of tan-colored,
  • aluminized, polyester film (b) a drug reservoir of scopolamine, mineral oil, and polyisobutylene; (c) a microporous polypropylene membrane that controls the rate of delivery of scopolamine from the system to the skin surface; and (d) an adhesive formulation of mineral oil (12.4 mg), polyisobutylene (11.4 mg) and scopolamine (1.5 mg).
  • a protective peel strip of siliconized polyester, which covers the adhesive layer, is removed before the system is used. The inactive components, mineral oil and polyisobutylene, are not released from the system.
  • the system is "programmed" to deliver 0.5 mg of scopolamine at an approximately constant rate of the systemic
  • the rate controlling membrane is an ethylene/vinyl acetate copolymer membrane that is
  • the adhesive used is a hypoallergenic silicone adhesive.
  • SUBSTITUTE SHEET various excipients.
  • the enzymatic penetrating agents disclosed include alpha-chymotrypsin and hyaluronidase.
  • Drugs disclosed for use with these sticks include
  • Excipients disclosed include sodium glycerol stearate.
  • penetrating agent and excipient can be mixed together to form a homogeneous mixture.
  • the various components of the stick can be separated from one another in a manner that brings one component (e.g., enzymatic penetrating agent) immediately after the other (e.g., drug) in contact with the local application zone of the patient's skin for treatment (e.g. a solid stick can make up two
  • the enzymatic penetrating agents increase the penetration of the desired drug through the patient's skin or mucous membrane.
  • transdermal drug delivery system is disclosed in French Patent No. 2,448,903.
  • This system consists of at least one antibiotic, an enzyme, an antiinflammatory agent, and/or a local anesthetic agent, and/or a heteratolytic agent, and/or a mucolytic agent, and/or an emulsifying agent.
  • Enzymes disclosed include hyaluronidase, streptokinase, streptodornase, trypsin, chymotrypsin, ⁇ -chymotrypsin; ⁇ -amylase, bromelain, papain, deoxyribonuclease, collagenase, and sutilain. This system is used to provide localized antibiotic therapy.
  • the invention includes a method of delivering a drug to an animal having skin, comprising: 1) applying and keeping in contact a proteolytic enzyme preparation to a localized area of the animal's skin in a sufficient quantity to enhance that area of skin's permeability to a selected drug over a predetermined amount of time; 2) occluding the area of skin with occlusion means for an amount of time sufficient to allow the enzymatic
  • the skin may be 5) occluded again after the application of the selected drug.
  • animal includes human beings.
  • the invention includes a percutaneous permeation enhancer which
  • a non-enzymatic penetration enhancer such as a lactam compound.
  • Both the enzyme preparation and the non-enzymatic penetration enhancer are present in sufficient quantities and concentrations so that when they are applied to an area of the skin for a selected period of time, they enhance the penetration of chemical agents through the skin.
  • skin refers to the outer body integument as well as those tissues which are histologically related, such as nails and the like.
  • the percutaneous permeation enhancer may further include solubilizers for assisting in the admixture of the components into a liquid solvent such as water.
  • the enhancer may also include other chemical agents, such as propylene glycol, which enhance the penetration of a chemical agent through the skin.
  • Non-enzymatic penetration enhancers are compositions which enhance the permeation of biologically active agents (e.g. drugs) through the skin of an animal.
  • Such compositions include alcohols, such as ethanol and isopropanol; polyols, such as n-alkanols (C 6 -C 8 ), limonene, terpenes, dioxolane, propylene glycol, ethylene glycol, other glycols, and glycerol; sulfoxides, such as dimethylsulfoxide (“DMSO”) and methyl dodecyl sulfoxide; esters such as isopropyl.
  • DMSO dimethylsulfoxide
  • esters such as isopropyl.
  • myristate/palmitate ethyl acetate, butyl acetate, methyl propionate, and capric/caprylic triglycerides
  • ketones such as 2-alkyl cyclohexanones, t-butyl cyclohexanones, and various C 8 derivatives
  • amides such as acetamides
  • oleates such as triolein
  • surfactants such as Brij 96, Tweens (Atlas Chemical Company), myrjs, and sodium lauryl sulfate
  • various alkanoic acids such as caprylic acid (C 6 - C 10 )
  • lactam compounds such as
  • Azone alkanols, such as oleyl alcohol; and admixtures thereof. These compositions are believed to enhance permeation of biologically active agents by acting at the lipid matrix of the stratum corneum (i.e. by enhanced intercellular matrix diffusion).
  • Lactam compound is an organic compound containing the -NR-CO-group in a ring.
  • the R group of this compound should be free from the lactam ring, unlike the penicillins and cephalosporins wherein the R group is bonded to another portion of the lactam ring to form a bucolic compound.
  • Lactam compounds useful in the invention have the following typical structural formula :
  • R is an alkyl, aryl, or phenyl group.
  • R is an alkyl, aryl, or phenyl group.
  • These compounds as disclosed in U.S. Patent Nos. 3,989,816 and 4,316,893 enhance the penetration of chemical agents through the skin. Similar permeation enhancing compounds are disclosed in U.S. Patent Nos. 4,405,616; 4,415,563; 4,423,040; 4,424,210; 4,444,762; 4,525,199; 4,562,075; 4,801,586; and 4,806,341, the contents of which are incorporated by this reference. Concentrations of these agents effective to enhance the skin's permeability to drugs are disclosed throughout these patent references. A synergistic permeation enhancement effect is achieved when a potentiating amount of these compounds is in admixture with an enzyme.
  • the percutaneous permeation enhancers of the present invention are used as an aid in delivering a drug percutaneously to an animal, including humans.
  • the percutaneous permeation enhancer is first applied to a localized area of the skin in a sufficient quantity and concentration to enhance eventually the permeability of the skin to a drug.
  • the enhancer is kept in contact with the skin for a sufficient amount of time to enhance the skin's permeability to the drug.
  • the area of skin may optionally be occluded during the time in which the enhancer is in contact with the skin.
  • the drug is then applied to the localized area of skin and permeates through the skin to be delivered to the animal.
  • the invention further includes a drug delivery system.
  • This drug delivery system includes an enzyme preparation, means for applying the enzyme preparation to an area of skin, a membrane for occluding the area of skin after the enzyme preparation has been applied; a drug; and means for applying the drug to the area of skin.
  • the drug delivery system can be a dual patch percutaneous drug delivery device which includes: a first patch sized and adapted to contact a localized area of skin. This first patch contains, in a reservoir, an effective amount of a proteolytic enzyme.
  • the drug delivery device further includes a second patch attached to the first patch in a common structure. This second patch is also adapted to contact the localized area of skin after the first patch has been removed from the skin. This second patch contains an effective amount of a preselected drug in liquid form for administration percutaneously.
  • the drug delivery system of the present invention can also be a dual-patch, percutaneous drug delivery kit.
  • This kit includes: 1) a first patch containing enzyme, enzymes or a permeation enhancer preparation; 2) a second patch containing drug or drugs, and 3) structure adapted to receive the first and second patches serially, i.e. sequentially, so that the second patch is removable from the structure only after the first patch removed.
  • FIG. 1 is a graph comparing the percentage urinary recovery of 14 C-TEAB with papain treatment, seven days after papain treatment, and without papain
  • FIG. 2 is a graph comparing the percentage urinary recovery of 14 C-Citric acid with papain
  • FIG. 3 is a graph comparing the percentage urinary recovery of 14 C-glucose with papain treatment; five days after papain treatment; seven days after papain treatment; and without papain pretreatment per Example 1.
  • FIG. 4 is graph comparing the percentage urinary recovery of the 14 C-protein lysozyme with papain
  • FIG. 5 is a graph comparing the percentage urinary recovery of the 14 C-protein insulin with papain treatment and seven days after treatment per Example 1.
  • FIG. 6 is a graph comparing the percentage urinary recovery of 14 C-protein albumin with papain treatment and seven days after treatment per Example 1.
  • FIG. 7 is a graph comparing the percentage urinary recovery of H 3 -Hydrocortisone with papain
  • FIG. 8 shows the saturation coefficient of citric acid, and the flux, permeability coefficient, and graph for citric acid first day (immediately following 24-hour exposure to papain), second day (24 hours following 24-hour exposure to papain) and third day (48 hours
  • FIG. 9 shows the saturation coefficient of hydrocortisone, and the flux, permeability coefficient and graph for hydrocortisone first day (immediately following 24-hour exposure to papain), second day (24 hours following 24-hour exposure to papain), and third day (48 hours following 24-hour exposure to papain) as per Example 2.
  • FIG. 10 shows the saturation coefficient of TEAB and the flux, permeability coefficient, and graph for
  • TEAB first day immediately following 24-hour exposure to papain
  • second day 24 hours following 24-hour exposure to papain
  • third day 48 hours following 24-hour exposure to papain
  • FIG. 11 shows the saturation coefficient of glucose, and the flux, permeability coefficient, and graph for glucose first day (immediately following 24-hours exposure to papain), and third day (48 hours following 24-hour exposure to papain) as per Example 2.
  • FIG. 12 stylistically depicts a side view of a prior art patch useful in the practice of the invention.
  • FIG. 13 stylistically depicts the side view of a dual patch drug delivery device according to the invention.
  • FIG. 14 stylistically depicts the side view of one embodiment of a dual patch percutaneous drug delivery kit according to the invention.
  • FIG. 15 depicts the side view of a patch useful in the practice of the invention.
  • FIG. 16 depicts the side view of a patch useful in the practice of the invention.
  • FIG. 17 depicts the enhancement of
  • TEAB tetraethylammonium bromide
  • FIG. 18 depicts the enhancement of TEAB
  • FIG. 19 depicts the enhancement of TEAB
  • FIG. 20 depicts the percentage of drug (citric acid, an anionic substance) which penetrated through mouse skin at varying times and using various sources of papain in the enzyme preparation as per Example 8.
  • Enzymes useful in the enzyme preparations, and in the percutaneous permeation enhancers ("enhancers") of the alternate embodiment are enzymes capable of altering structures of the skin of the particular animal to be treated so as to enhance the skin's permeability to a selected drug or drugs. Enzymes preferred for these purposes do not substantially react detrimentally with the selected drug or non-enzymatic penetration enhancer, do not degrade substantially to an inactive state at body temperature or in solution; do not cause unacceptable discoloration or scarring of the skin, and react in sufficiently small concentrations to be useful over a relatively small area of skin.
  • a preferred enzyme is papain, which is readily available from Sigma Chemical Company of St. Louis, Missouri or other sources.
  • pancreatin (actually a mixture of enzymes), ficin, bromelain, elastase, and pepsin.
  • a non-specific proteolytic enzyme is one that alters a protein's
  • proteolytic enzyme breaking down disulfide bonds, which can result in complete denaturation of the skin protein.
  • a specific proteolytic enzyme is one that merely alters the protein under conditions not sufficiently severe to alter protomer configuration. Papain and pancreatin, are preferred in the practice of this invention; although other proteolytic enzymes, such as bromelain and ficin, will also work.
  • Some enzyme preparations will also include “activating agents.” These activating agents enhance the percutaneous delivery of the drug(s) through the skin.
  • papain from Sigma Chemical may be activated with the chelating agent ethylene-diaminetetraacetic acid ("EDTA") in admixture with cysteine.
  • EDTA ethylene-diaminetetraacetic acid
  • TEAB tetraethylammonium bromide
  • Other possible sources of papain include papain from Allergan. Allergan papain is contained in a contact lens cleaning product (tablets for dissolution in water) wherein activators are included. Amounts of EDTA in a papain enzyme preparation will vary from 2 mg/ml to about 20 mg/ml.
  • An especially preferred activating agent for use with papain is 0.10 molar cysteine in combination with 0.0375 molar EDTA which activates the papain to achieve greater penetration of drug through the skin.
  • each is typically admixed with a liquid, such as water or ethanol to form an enzyme preparation.
  • a liquid such as water or ethanol
  • the concentration of enzyme (s) in liquid will be of a sufficient quantity to increase the skin's permeability to selected drugs over a predetermined time period.
  • the concentration of enzyme(s) in the enzyme preparation will be great enough to alter the skin's permeability to the selected drug in less than 24 hours for practical reasons.
  • Concentrations of papain in water will generally be greater than about 0.019 milligrams/milliliter (mg/ml). Preferred concentrations of papain in water will be less than about 0.093 mg/ml. Pretreatment of skin samples with papain concentrations greater than 0.093 mg/ml at pH 7.4 leads to greater drug penetration, but also damages the skin, possibly leading to bleeding.
  • the enzyme preparations are compounded to retain stability for long periods of time.
  • Various factors such as composition, pH and ionic strength of the solution, and the chosen solvent, influence the stability of the enzyme preparations.
  • the enzyme preparation should be dissolved in water, and have a pH of from about 3 to about 10.
  • an alternative embodiment of the invention includes the admixture of enzyme and non-enzyme components to enhance permeation of the skin in
  • each is typically admixed with a non-enzyme penetration enhancer such as a lactam compound, (e.g. AzoneTM), and a liquid, such as propylene glycol, to form an enhancer.
  • a non-enzyme penetration enhancer such as a lactam compound, (e.g. AzoneTM)
  • a liquid such as propylene glycol
  • Azone is 1-N-dodecylazacycloheptan-2-one, available from Nelson Research &
  • lactam compounds which are chemically related to AzoneTM may be useful in the practice of this invention. Enzymes are believed to potentiate the ability of lactam compounds to enhance percutaneous penetration of chemical agents. Lactam compounds useful in the instant invention are disclosed in the
  • the enzyme and lactam compound act to potentiate one another forming a synergistic effect. That is, the permeation enhancement is greater than would be
  • non-enzyme penetration enhancers which can be used in the admixture include various alcohols, polyols, sulfoxides, esters, ketones, amides, oleates, various surfactants, alkanoic acids, and alkanols which demonstrate a capability for enhancing permeation. More than one non-enzyme enhancer may be used in combination as a penetration enhancer. As shown by Example 11, studies indicate that these other nonenzyme compounds, in admixture with an enzyme such as papain, can be very effective in increasing permeation of the skin. Those non-enzyme compounds which are watersoluble tend to be more effective in permeation
  • the concentration of enzyme(s) in the enhancer will be great enough to increase the skin's permeability to the selected drug in less than 24 hours, for practical reasons.
  • Concentrations of papain in water will generally be greater than about 0.019
  • Preferred concentrations of papain in water will be less than about 0.093 mg/ml.
  • Pretreatment of skin samples with papain concentrations greater than 0.093 mg/ml at pH 7.4 lead to greater drug penetration, but also damage the skin, possibly leading to bleeding.
  • Solubilizers such as Spans and Tweens increase the solubility of various components of the enhancers into the liquid solvent.
  • the percutaneous permeation enhancers are compounded to retain stability for long periods of time. Again, various factors, such as composition, pH of the solution, and choice of solvent, influence the stability of an enzyme preparation.
  • the enzyme preparation should be dissolved in water when papain or bromelain are used, and should have a pH of from about 3 to about 10.
  • the enhancers are also preferably refrigerated before use and kept at temperatures of 3-5°C.
  • the enzyme or drug preparation may also be stabilized with various preservatives. Considerations in selecting an agent for use as a preservative in the system, as with most pharmaceutical preparations,
  • agent's spectrum of activity include: a) the agent's spectrum of activity; b) the agent's stability over time; c) the agent's relative toxicity; d) the agent's allergenic potential; e) the agent's compatibility with the other constituents of the preparation, and f) the agent's odor.
  • Various alcohols e.g. ethanol or isopropanol, quaternary ammonium
  • permeation enhancer will vary from 5.8 to 8.0, with the preferred pH being about 7.4. (See Example 6)
  • concentrations of either proteolytic enzyme or enhancers may be decreased if contact time is to be increased, it is generally preferred that certain concentrations be used inasmuch as treatment time may be minimized by use of such concentrations. Long treatment times may be annoying to patients and discourage them from employing a therapeutically necessary treatment.
  • the preparation of enzyme alone or enhancer preparation can be applied using any of several wellknown techniques for applying a liquid to a surface. For example, a brush, swab, or spray container containing the enhancer preparation may be used to apply the preparation to the skin.
  • the enhancer preparation is an admixture of a non-enzymatic
  • the enzyme alone or the enhancement preparation is contained within a reservoir of a "patch" which is placed on the animal's skin.
  • the patch would include a backing 20, a reservoir 22 to contain the enzyme preparation, a membrane 24 to contain and release the contents of the reservoir, and a protective peel strip 26 or strips.
  • Patches are typically round or oblong when viewed from above, and are preferably sized to affix neatly to the animal's skin.
  • the membrane 24 is typically ratecontrolling or semi-permeable to the contents of the reservoir 22.
  • Adhesive 28 is located around the outer circumference of the patch adjacent to the membrane 24, and a separate, removable, protective peel strip 26 is positioned over the adhesive for removal prior to
  • Adhesives are preferably hypoallergenic substances which are useful in retaining the protective peel strips to the patch and the patch to the animal's skin.
  • Preferred adhesives include silicone adhesive formulations and other adhesives well known to those skilled in the art.
  • a patch is particularly preferred because the occlusion means are included as part of the system, i.e., the backing 20.
  • Other occlusion means include aluminized plastic, plastic film such as Saran WrapTM, and
  • BioclusiveTM tape Important factors to consider when selecting occlusion means are a) non-reaction with the contents of the reservoir, b) adequate containment of the contents to the desired localized area of skin, and c) non-reaction with the skin to a detrimental degree.
  • the backing In the case of use with humans, the backing is preferably skin-colored for cosmetic reasons.
  • the protective peel strip is removed from the patch, and the patch is applied to the skin.
  • the enzyme preparation or the enhancement preparation permeates through the
  • the patch containing the enhancement preparation or the enzyme preparation is removed.
  • the selected drug or drug preparation also preferably in a liquid form, is then applied to the skin.
  • the drug or drug preparation is then applied in a similar way as previously described for application of the enzyme or the enhancement preparation.
  • a drug may be contained within the reservoir 22 of a patch which is then applied to the same localized area of skin
  • the drug preferably contain the drug in a sufficient concentration to allow therapeutic levels of the drug to pass through the skin to the animal's circulatory system.
  • an impermeable membrane 40 can be constructed into the reservoir 22 of the patch to divide the reservoir into two distinct compartments 42, 44.
  • One compartment 42 contains the active ingredient in a dry, stable form, while the other compartment 44 contains the solvent with which the active ingredient is to be admixed.
  • the dry active ingredient or solvent could be contained within a breakable impermeable container 46 such as a capsule, within the reservoir 22, separating it from the other component.
  • a breakable impermeable container 46 such as a capsule
  • the impermeable membrane or capsule wall could then be purposely
  • the patch is applied to the selected localized area of skin or administration of the particular active
  • FIG. 13 depicts an alternate patch for use with the invention. It, like the patch depicted in FIG. 12, has a protective peel strip 26 which is removed to expose a membrane 24 and backing 20 containing an enzyme
  • the patch depicted in FIG. 13 may be applied to the localized area of skin of the animal for the amount of time needed to increase the skin's permeability to the drug preparation contained within the other reservoir 24.
  • Adhesive 28 serves both to keep the entire patch together, and to keep the respective portions of the patch attached to the patient's skin.
  • Drug contained within the drug preparation in reservoir 23 passes through the membrane 25 and onto the patient's enzyme-treated skin. The drug then passes through the skin and into the patient ' s circulatory system.
  • hormones such as progesterone
  • quaternary compounds such as acetylcholine; and anionic chemicals such as coumadin.
  • Therapeutic classes of drugs for use in the system include anti-hypertensive agents such as beta-blockers, anti-nauseants such as
  • chlorpromazine and anti-arrythmics, and analgesics.
  • Polypeptides such as hormones and the like, are particularly aided in percutaneous delivery by the permeation enhancer invention.
  • Tests performed on pretreated mouse skin indicate that polypeptides of lower molecular weight, ranging from about 800 to about 15,000 in molecular weight, are successfully used in combination with an enzyme/non-enzyme enhancement compound. (See Example 12)
  • polypeptides of higher molecular weight tend to be fractionated when applied to skin pretreated with papain. The exact mechanism of fractionation is unclear, but gel
  • polypeptides of lower molecular weight which can be used are insulin and synthetic growth hormones .
  • active ingredients i.e., enzymes, lactam compounds or drugs
  • active ingredients i.e., enzymes, lactam compounds or drugs
  • the enzyme, enzymes, drug or drugs can be mixed with solvent and then injected with a syringe, or otherwise introduced, into the
  • the invention allows for the controlled and timed non-invasive release of drugs to the animal.
  • the invention allows for the penetration of larger molecular weight compounds than was previously attainable.
  • the localized area of the skin to which the enzyme/non-enzyme compounds and drug preparations are applied is preferably a relatively thin layer of skin; other areas of typically thicker skin, such as the sole of the foot, should be avoided. Furthermore, hairy areas of skin should be avoided, or the hair should first be removed.
  • the system may be present in a kit form. Included in this kit are means for applying the
  • percutaneous permeation enhancers percutaneous permeation enhancers, occlusion means, and means for applying the selected drug.
  • Means for applying the enhancer and selected drug may be differently marked patches, one patch containing the enzyme preparation and the other patch containing the drug. Different patch marking may include different coloration of the patches and/or the protective peel strips. All components of the kit are contained within a convenient package for use by a medical or veterinary practitioner or patient.
  • the kit may include means for mixing the enzyme with solvent such as a small glass container containing a solvent selected for the enzyme; means for mixing the selected drug(s) with solvent such as a small glass container containing a solvent selected for the drug; and means for introducing active ingredient preparations into the patches such as a needle-bearing syringe.
  • solvent such as a small glass container containing a solvent selected for the enzyme
  • solvent such as a small glass container containing a solvent selected for the drug
  • active ingredient preparations into the patches such as a needle-bearing syringe.
  • FIG. 14 One embodiment of a percutaneous drug delivery kit is shown in FIG. 14. It includes a first patch 30 containing an enzyme preparation; and a second patch 32 containing a drug selected to be delivered
  • flaps 36A, 36B Associated with the container are flaps 36A, 36B for retaining the patches 30, 32 within the container 34.
  • the container may contain extension means such as spring 38 to press the patches 30, 32 against the flaps 36A, 36B.
  • a person using the kit removes the first patch 30 from the container 34 through the flaps 36A, 36B.
  • the flaps 36A, 36B may be made of any material which is flexible, yet strong enough to retain the patches 30,32 within the container 34 against the force of the spring 38.
  • the first patch is then applied to a localized area of the patient's skin for a predetermined time as
  • the person using the system removes the first patch 30 from the skin.
  • the second patch 32 is then removed from the container 34 and the second patch 32 is then applied to the localized area of the skin for administration of the drug.
  • the kit for the permeation enhancer As with the kit provided for a preparation of enzyme alone, the kit for the permeation enhancer
  • preparation may include means for mixing the enzyme and non-enzyme components with solvent such as a small glass container containing a solvent selected for optimal use with the enzyme and non-enzyme components; means for mixing the selected drug(s) with solvent such as a small glass container containing a solvent selected for the drug; and means for introducing active ingredient
  • preparations into the patches such as a needle-bearing syringe.
  • patches such as a needle-bearing syringe.
  • these various means would typically be included in the kit when any, or all, active ingredients or constituents thereof are not stable for sufficient lengths of time when premixed in solution.
  • the model chemicals included: 14 C-labeled tetraethylammonium bromide (TEAB), a cationic substance; 14 C-labeled citric acid, an anionic substance; 14 C-labeled glucose, a highly polar nonionic substance; and 3- H-labeled
  • Enzyme preparations were prepared by dissolving one papain-containing tablet (Allergan, 144 mg) in 2 ml Phosphate Buffer Saline (PBS) solution. Two hundred ⁇ l of this solution was applied to 1 cm 2 areas on the back of congenitally athymic hairless mice. The 1 cm 2 areas were covered with folded gauze pads to absorb the excess papain solution, then the areas were occluded with a transparent dressing (Bioclusive Tape) and an adhesive tape. Each mouse was individually housed in separate cages for 24 hours. At the end of this time, residual papain on the surface of the mouse's skin was removed by washing.
  • PBS Phosphate Buffer Saline
  • radio labeled material was applied separately on each marked area of mouse skin and covered with gauze sponge and Bioclusive tape and adhesive tape. Mice were kept in metabolism cages, one animal per cage, and urine samples collected for scintillation counting to determine the quantity of radio labeled materials being excreted.
  • mice were maintained separately in metabolism cages for varying periods of time prior to the application of the labeled model compounds. After various time intervals, 150 ⁇ l of radio labeled chemicals were applied separately on the 1 cm 2 marked areas on the backs of the mice where papain had previously been applied. The mice were then kept in separate metabolism cages, and at time intervals of 17, 41, and 65 hours, urine was collected and counted using a scintillation counter.
  • FIGS. 8-11 show the saturation concentration of each substance tested, and the flux, permeability coefficient, and graph for each of the substances at the first day (immediately following 24 hours exposure to papain), second day (24 hours following 24-hour exposure to papain), and third day (48 hours following 24-hour exposure to papain).
  • Hairless mouse skin was pretreated with papain at a concentration of 0.093 mg/ml at pH 7.4 for 24 hours. Afterwards, TEAB was applied. The pretreated skin demonstrated a 33-fold increase in absorption of the TEAB in comparison to normal, untreated mouse skin.
  • An enzyme preparation especially useful with ionic drugs has the following composition, with a pH adjusted to 7.4:
  • Drug penetration through a skin barrier is thought to be a process of passive diffusion and may be described by Fick's First Law:
  • J is the flux of a drug through a skin barrier
  • D is the diffusion constant of a drug in the skin barrier
  • dC/dX is the concentration gradient of a drug between the vehicle and the skin barrier.
  • K is the partition coefficient of drug between a skin barrier and the vehicle
  • C v is the concentration of drug dissolved in the vehicle
  • h is the thickness of the skin barrier
  • P is the permeability of a drug through the skin barrier.
  • FIG. 18 TEAB penetration through mouse skin increases as the amount of papain in the enzyme preparation used to pretreat the skin increases .
  • FIG. 18 also shows that very small amounts of an enzyme in the enzyme preparation are useful in enhancing drug
  • TEAB penetration is further enhanced by even greater levels of papain in the enzyme preparation pretreatment solution.
  • Sigma papain of 0.170 mg, 0.113 mg, and 0.057 mg in 0.4-0.6 ml of water were first applied to mouse skin, each with cysteine and EDTA as activating agents.
  • each enzyme preparation contained 0.170 mg of papain dissolved in 0.1 ml of water.
  • One sample of papain was obtained from Allergan. The other was obtained from Sigma
  • the Tween 20 was used to solubilize the AzoneTM in the admixture.
  • stratum corneum cells It is postulated that a shift from a random form of protein to the more organized beta sheet structure occurs.
  • the alpha-helix structures of skin protein could be fractionated, uncoiled, or both.
  • FTIR absorbance spectra of pure cast papain showed slight, but significantly different peak positions than papain treated skin and included a peak at 1516 cm -1 which did not appear in the treated stratum corneum.
  • AzoneTM was tested as a permeation enhancer with and without the presence of papain. When papain was present the changes in protein FTIR areas were not significantly different than those observed with papain alone. AzoneTM by itself did not change protein FTIR areas. When AzoneTM was present it apparently caused a lengthening of both symmetric and asymmetric CH stretch lines but did not change their peak positions.
  • polypeptides were diffused through the pretreated mouse skin using the same concentration and pH values for each test. Pure buffer solution was also diffused through the pretreated skin of the mouse to determine if any endogenous proteins diffused into the diffusate. This showed that the compounds measured originated only from the polypeptides.
  • polypeptides, diffused polypeptides and diffused buffer solutions were made using gel electrophoresis.
  • the system used for these determinations was sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), a procedure well-known in the art. These comparisons determined if fragmentation of the diffused polypeptide molecules occurred.
  • the BSA that diffused through the pretreated mouse skin was fractionated to a great extent.
  • BSA showed a distinct stained band within the gel while the diffused BSA showed small extended bands indicating compounds of smaller and varying molecular weights. There were no detectable endogenous compounds that diffused out of the papain-treated skin when buffer solution was used as the only diffusing medium.
  • Insulin (regular, bovine)
  • Electrophoresis of a solution of insulin and the diffused insulin produced extended stained areas in the gel. It would seem that the electrophoretic process caused considerable agglutination and the determination of molecular fragmentation due to the permeation would be very difficult if not impossible.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Dermatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Media Introduction/Drainage Providing Device (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Procédé pour libérer un médicament à travers la peau d'un animal, qui consiste à appliquer une préparation enzymatique sur une région localisée de la peau pendant un intervalle de temps prédéterminé, en une quantité suffisante pour altérer la structure de la région localisée de la peau; à fermer cette région localisée de la peau à l'aide d'un moyen d'occlusion (20) pendant cet intervalle de temps prédéterminé; à enlever ce moyen d'occlusion (20) et à appliquer une quantité efficace du médicament sur la région localisée de la peau. L'invention porte en outre sur un système de libération percutanée de médicament, comprenant un moyen de mise en contact (30) pour mettre en contact une préparation enzymatique avec une région localisée de la peau; elle porte aussi sur un moyen d'occlusion pour fermer cette région localisée de la peau mise en contact avec ce moyen de contact (30); et sur un moyen (32) pour appliquer un médicament sur ladite région localisée de la peau une fois que le moyen de mise en contact et le moyen d'occlusion en ont été enlevés; ce moyen de mise en contact et ce moyen d'application du médicament sont des pièces différentes (30, 32). L'invention porte également sur un procédé pour libérer un médicament à travers la peau d'un animal, qui consiste à appliquer un stimulateur de pénétration percutanée, comprenant des quantités efficaces d'une combinaison de stimulateurs de pénétration enzymatiques et non enzymatiques, sur une région localisée de la peau de cet animal pendant un intervalle de temps prédéterminé, en une quantité suffisante pour rendre cette région localisée de la peau plus perméable au médicament; à fermer la région localisée de la peau avec un moyen d'occlusion (20) pendant cet intervalle de temps prédéterminé; à enlever ce moyen d'occlusion (20); et à appliquer une quantité efficace du médicament sur cette région localisée de la peau de manière à ce qu'au moins une partie du médicament pénètre à travers la peau.
PCT/US1990/000998 1989-02-23 1990-02-23 Systeme de liberation percutanee d'un medicament Ceased WO1990009809A1 (fr)

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US31481989A 1989-02-23 1989-02-23
US314,819 1989-02-23
US35292689A 1989-05-18 1989-05-18
US352,926 1989-05-18

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0857488A3 (fr) * 1996-11-18 1999-08-25 Bristol-Myers Squibb Company Procédés et compositions pour augmenter la perméation cutanée de médicaments en utilisant des promoteurs de la perméation
WO2000074762A1 (fr) * 1999-06-07 2000-12-14 Evgeny Filippovich Soloviev Procede permettant de traiter un patient et/ou d'exercer une action therapeutique sur celui-ci
WO2003047629A3 (fr) * 2001-11-29 2003-08-28 Molecular Skincare Ltd Traitement de maladies
US6756052B1 (en) 1999-05-21 2004-06-29 Lts Lohmann Therapie-Systeme Ag Device and method for increasing the transdermal permeation of medicaments
EP2399607A4 (fr) * 2009-02-18 2013-08-21 Hisamitsu Pharmaceutical Co Préparation transdermique
CN114557928A (zh) * 2022-03-01 2022-05-31 上海联衡生物科技有限公司 一种美白祛黄护肤品及其制备方法
CN114569513A (zh) * 2022-03-24 2022-06-03 上海联衡生物科技有限公司 一种祛痘抑菌护肤品及其制备方法

Families Citing this family (4)

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DE59906392D1 (de) * 1998-12-23 2003-08-28 Esparma Gmbh Hyaluronatlyase als penetrationsförderer in topischen mitteln
US20100113348A1 (en) * 2007-03-01 2010-05-06 Fumio Kamiyama Percutaneously absorbable preparation, process for production thereof and method for percutaneous absorption
JP5700810B2 (ja) * 2011-03-24 2015-04-15 リンテック株式会社 経皮吸収型貼付剤キット
WO2018222213A1 (fr) * 2017-06-02 2018-12-06 Casemed Engineering Applicateur sans contact multi-usage avec réservoir

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US4690683A (en) * 1985-07-02 1987-09-01 Rutgers, The State University Of New Jersey Transdermal varapamil delivery device
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US3029187A (en) * 1958-02-20 1962-04-10 Steinhardt Amos Gelating adhesive pharmaceutical preparations
US4600574A (en) * 1984-03-21 1986-07-15 Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte Method of producing a tissue adhesive
US4668228A (en) * 1985-03-12 1987-05-26 Johnson & Johnson Products, Inc. Debriding tape
US4867981A (en) * 1987-11-19 1989-09-19 Henry Greenwald Tape releasing composition and method of using same

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0857488A3 (fr) * 1996-11-18 1999-08-25 Bristol-Myers Squibb Company Procédés et compositions pour augmenter la perméation cutanée de médicaments en utilisant des promoteurs de la perméation
AU742996B2 (en) * 1996-11-18 2002-01-17 Bristol-Myers Squibb Company Methods and compositions for enhancing skin permeation of drugs using permeation enhancers, when drugs and/or permeation enhancers are unstable in combination during long-term storage
US6756052B1 (en) 1999-05-21 2004-06-29 Lts Lohmann Therapie-Systeme Ag Device and method for increasing the transdermal permeation of medicaments
WO2000074762A1 (fr) * 1999-06-07 2000-12-14 Evgeny Filippovich Soloviev Procede permettant de traiter un patient et/ou d'exercer une action therapeutique sur celui-ci
WO2003047629A3 (fr) * 2001-11-29 2003-08-28 Molecular Skincare Ltd Traitement de maladies
EP2399607A4 (fr) * 2009-02-18 2013-08-21 Hisamitsu Pharmaceutical Co Préparation transdermique
US8702664B2 (en) 2009-02-18 2014-04-22 Hisamitsu Pharmaceutical Co., Inc. Transdermal preparation
CN114557928A (zh) * 2022-03-01 2022-05-31 上海联衡生物科技有限公司 一种美白祛黄护肤品及其制备方法
CN114557928B (zh) * 2022-03-01 2023-09-29 上海联衡生物科技有限公司 一种美白祛黄护肤品及其制备方法
CN114569513A (zh) * 2022-03-24 2022-06-03 上海联衡生物科技有限公司 一种祛痘抑菌护肤品及其制备方法
CN114569513B (zh) * 2022-03-24 2023-10-13 上海联衡生物科技有限公司 一种祛痘抑菌护肤品及其制备方法

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EP0418341A1 (fr) 1991-03-27
AU5190790A (en) 1990-09-26
CA2027590A1 (fr) 1990-08-24
EP0418341A4 (en) 1992-02-19
JPH03505835A (ja) 1991-12-19

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