CA1280974C - Transdermal delivery system - Google Patents
Transdermal delivery systemInfo
- Publication number
- CA1280974C CA1280974C CA000524665A CA524665A CA1280974C CA 1280974 C CA1280974 C CA 1280974C CA 000524665 A CA000524665 A CA 000524665A CA 524665 A CA524665 A CA 524665A CA 1280974 C CA1280974 C CA 1280974C
- Authority
- CA
- Canada
- Prior art keywords
- oleic acid
- carrier
- weight
- delivery system
- transdermal delivery
- 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.)
- Expired - Fee Related
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Classifications
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- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0014—Skin, i.e. galenical aspects of topical compositions
Abstract
ABSTRACT OF THE DISCLOSURE
Pharmaceutical preparations comprised of a pharmaceutically active ingredient and a carrier which comprises a percutaneous penetration enhancer comprised of 2-ethyl-1, 3-hexanediol and/or oleic acid is disclosed. The 2-ethyl-1, 3-hexanediol may be present in an amount in the range of about 50% to 100% based on the weight of the carrier. The oleic acid may be used in combination with 2-ethyl-1, 3-hexanediol in an amount of about 1 to 40% based on the weight of the carrier to provide a synergistic effect with respect to percutaneous penetration enhancement. The compound 2-ethyl-1, 3-hexanediol as used alone and/or in combination with the oleic acid has been found to significantly enhance the delivery of a drug, to a patient, from a transdermal delivery system.
Pharmaceutical preparations comprised of a pharmaceutically active ingredient and a carrier which comprises a percutaneous penetration enhancer comprised of 2-ethyl-1, 3-hexanediol and/or oleic acid is disclosed. The 2-ethyl-1, 3-hexanediol may be present in an amount in the range of about 50% to 100% based on the weight of the carrier. The oleic acid may be used in combination with 2-ethyl-1, 3-hexanediol in an amount of about 1 to 40% based on the weight of the carrier to provide a synergistic effect with respect to percutaneous penetration enhancement. The compound 2-ethyl-1, 3-hexanediol as used alone and/or in combination with the oleic acid has been found to significantly enhance the delivery of a drug, to a patient, from a transdermal delivery system.
Description
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TransDermal Delivery Svstem The present invention relates to the field of pharmaceutical preparations which are applied to the skin in order to obtain transdermal delivery of a pharmaceutically active drug from the preparation to the patient. More specifically, the invention relates to such preparations which utilize as a percutaneous penetration enhancer 2-ethyl-1, 3-he~anediol and/or oleic acid.
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It is well known that many drugs taken orallY, are destroyed on the first pass through the liver. It is also well known that when many drugs are taken orally, their rate of absorption into the body is not constant. In view of such difficulties, a number of different drug delivery systems have been developed. Recently, the use of transdermal delivery systems have met with increasing interest by researchers in the pharmaceutical drug delivery field.
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U.S. Patent 4,291,015 to Keith, et al., discloses the use of a polymeric diffusion matrix for the sustained release of pharmaceutically active drugs. The matrix is covered by a backing laver and applied to the skin where diffusion of the pharmaceutically active arug occurs and the drug is transdermaley delivered to the patient. Althoug~ U.S. Patent 4,291,015 discloses transdermal deliverv of nitroglycerine, other drugs may be delivered by utili~ing the same or a-similar matri~, as ~isclosed in U;S; Patents 4,292,820;`
4,292,302; and 4,29', 303.
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U.S. Patent 4,490,206 discloses the use of a different tvpe of transdermal delivery system whereby the pharmaceutically active druq is disperse~ within àn adhesive (see also U.S. Patent 4,390,52Q). In accordance with such systems, the pharmaceutically active drug is dispersed in a pressure-sensitive adhesive which is adhered to the skin. The drug then diffuses from the adhesive through the skin for delivery to the patient. Other types of transdermal delivery systems are also known and each has various advantages and disadvantages with respect to the transdermal delivery of different types of pharmaceutically active drugs.
One of the problems with utilizing transdermal delivery systems _ is one of efficacy. More specifically, the aevice must supply a sufficient amount of the pharmaceutically active ingredient to the patient to obtain the desired pharmaceutical effect on the patient , ~ , .. '' , , , : . '', , ' ' ' .. .. ' - ' ' . .
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over a given period of time. Different means may be employed in order to obtain the desired efficacy over that period of time.
One means of at.empting to increase the amount of drug delivery might be to include a higher concentration of the pharmaceutically active dru~ in the delivery system. By simply increasing the concentration of the drug,' the amount of the drug delivered to the patient would hopefully be increased. This concept might work well to a cer_ain e~tent but would be limited by the amount of drug which can be delivered through the skin barrier, ie., the skin acts as a rate limitation means.
Another means for increasing the amount of drug delivered and obtaininq the desired efficacy, might involve increasing the surface area contact of the delivery system with the skin. Althougl: en increase in the surface area will increase the amount o drug delivered to the patient, there are, of course, practical limitations with respect to increasing this surface are~. The cost of producing very large delivery systems might be prohibitive. Patients would be unlikely to ware a delivery system which had a surEace such that it covered the entire back and/or front of the patient.
-A completely different concept for increasing transdermaldelivery of a pharmaceutically active drug is the 'utilization of a penetration enha~cer to be used in combination with the drug delivery .
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' 09~ , svstem. Utilization cf such enhancers is subject to certain linitations such as the fac~ that the enhancer must be de'er~atologically acceptable, and compatible with the pharmaceutically active drug as well as the ~elivery system which it is used in connection with.
Perhaos the most famous of such penetration enhance_s is "DMSO
~Dimethyl sulfoxide1". However, DMSO has not received FDA approval for use on hu;mans. Another well known penet_ation enhar.c~r is AZONE~
s~e U.S. Patents 3,909,816; 4,311,481; and 4,316,893 as we1l as the correspondinq foreign patents.
~ ore recently, there has been some teachinSs with respect to the use o~ olei- acid as a penet~ation enhancer. (See Coo~er, EugenQ, R., ~Inc-eased Skin Permeability for LITOTHILIC Molecules" Journa7 of Pharn7aceutical Sciences, volume 73, number 8, Aucust 1984.) Cooper discloses the use of oleic acid in different concentrations in the presence of propylene glycol as a solid. The oleic acid does apcear to enhance penetration of the active ingredient SALICYLIC acid.
Cooper also discloses the use of oleic acid in combination with 1,2-butanediol. The article specifically indicates that "other diols also e~hibit this synerqism with lipids, hut the effect is less pronouncea às the cha-n lenSth is increased~. Coocer teaches that the treat~ent of the skin with surfactants can have a substantial influence on increasiDg the penetratioD of polar molecules. ~owever, .
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such surfactants do not generally increase the transdermal penetration of the non-polar molecules. Accordingly, Cooper concludes that the enhanced transdermal penetration of non-polar molecules such as salicylic acid can be obtained by the addition of small amounts O r fatty acids or alcohols to the formulation. More specifically transdermal penetration of salicylic acid can be greatly enhanced by the addition of small amounts of oleic acid. Accordinc,ly, Cooper appears to teach only the use of small amounts of oleic acid either alone or in combination with diols of short chain length and contains no teachings with respèct to the use of large amounts of oleic acid alone or in combination with long chain diols and actually teaches against the use of such long chain diols.
U.S. Patent 4,305,936 discloses a solution for topical or local application comprised of a corticos~eroid in a carrier. The carrier is comprised of 1 to 4~ by weight of solubilizing agents of a glyceral ester of a fatty acid containing 6 to 22 carbon atoms, 10 to 50% by weight of an alkanol cosolvent and from 20 to 50~ by weight of water.
The patent also indicates that the carrier can include a carrier a "suitable auxiliary adjuvant in an amount of up to 10% bv weight;:' Oleic acid is mentioned as a suitable auxiliary adjuvant. The patent does not appear to contain any teaching with respect to the effect oleic àcid might have on enhancing penetration and does ~ot appear to contain any teachings with respect to the use of large amounts of oleic acid alone or in combination with a long chain diol.
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U.S. Patent 4,45;,146 discloses a plaster comprised Gf a thermalplastic elastomer, an oil or higher fatty acid, a tack-providing resin and an active ingredient. The "higher fatty acid" may be present in the range of 25 to 370 parts by weight per 100 parts by weight of the thermalplastic elastomer. The active ingredient may be present in an amount in the range of 0.09 to 110 parts by weight per 100 parts by weight of the thermalplast-c elastomer, (see column 4, lines 3-35). Oleic acid is mentioned 2S
. "ohe of the preferred" highèr fatty acids, (seë column i, lines 16-17).
Although percutaneous penetration enhancers are known, there remains a need for an enhancer which is dermatologically acceptable has PD~ approval for use on human skin and has a substantial effect cr.
increasing in the rate of tr~nsdermal delivery of a pharmaceutically active drug to a patient.
The present invention provides a pharmaceutical preparation in the form of a transdermal delivery system comprised of a carrier having dispersed therein a pharmaceutically active drug. The carrie~
is comprised of a percutaneous penetration enhancer which includes 2-ethyl-1, 3-hexanediol (hereinafter ~HD) and/or oleic acid. The present inventor has found that the use of high '; . ~, ', ' : ' , . .
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concentrations of EHD as a carrier can have a substantial effect on increasing in the ratc of aelivery of pharmaceutically active drugs and has further found that rate of delivery is further enhanced, and a synergistic effect is obtained, when the oleic acid is used in combination with EHD. The percutaneous penetration enhancement of this combination has been found to work particularly well in connection with pharmaceutically active drugs such as vasodiolators eg, nitroqlycerine, anti-arythmias eg, lidocane; sterioids eg, estrogen and corticosteroids.
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Hence one aspect of this invention is a transdermal delivery system, comprising:
a pharmaceutically active ingredient; and a carrier wherein the carrier is comprised of Z-ethyl-l, 3-hexanediol in an amount of 1 to 40% based on the weight of the carrier. ~he carrier may also be comprised almost totally of 2-ethyl-1,3-hexanediol. In a preferred embodiment of this aspect o the invention, the carrier contains about 5% by weight of oleic acid and the active ingredient is nitroglycerine. In another preferred embodiment, the carrier comprises l to 40~ oleie acid and the active ingredient is estradiol.
Another aspect of this invention is a transdermal delivery system, comprising:
nitroglycerine; and 8 ~ 3~
a carrier which includes 1 to 10% by weight of oleic acid based on the weight of the carrier.
The use of the transdermal delivery system for preparinq compositions useful for treatlng illnesses treatable by the active ingredient is another aspect of this invention.
It is a primary object of this invention to provide a percutaneous penetration enhancer ~or use in connection with a transdermal delivery system.
Another object of this invention is to provide such a penetration enhancer which is comprised of a large percentage of EHD alone and/or in combination with oleic acid.
Still anotner object of this invention is to provide a transdermal delivery system using EHD in an amount of 50% to 100 based on the weight of the carrier as a penetration enhancer.
Anoth`er object of this invention is to provide a transdermal delivery system comprised of a pharmaceutically active ingred7ent and a carrier which carrier is comprised of E~D in an amount of 50~ or . .
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Yet another object of this invention is to provide a transdermal delivery system comprised of nitroglycerine and a carrier wherein the carrier is comprised of 50~ or more by weight of E~D and about 5~ by weight of oleic acid.
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In order for 2 compound to be useful as a percutaneous penetration enhancer the compound must meet a number of different requirements. Firstly, the compound must be a aetermatologically acceptable compound which when used topically on the skin does no' cause adverse side effects. Secondly, the compound must be compatible with the active ingredient within the transdermal delivery system. If ehe compound and the active ingredient are incompatible then a separation will take place or a reaction could occur which would destroy the pharmacoloqical activity of the ac~ive ingredient.
Thirdly, it is pre~erable for the compound to have been approved for use on humans by the Fooa And Drug Administration of the United States. Further, the compound must of course have a sub~tantial _ effect on increasing the transdermal rate of delivery of the pharmaceutically active drug.
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The present inventor ir.vestigated a large number of compounds in order to find one or more compounds which would meet the above referred to criteria and be useful as a percutaneous penetration enhancer. One such compound investigated was EHD which is known to be useful as an insect repellent. In addition to being used as an insec' repellent, EHD has been used in an antibacterial and an antifungal composition as disclosed by Minuto in U.S. Patent 4,~41,084. This patent discloses a pharmaceutical composition which includes an antibacterial - antifungal composition dispersed in ot'her camponerts which may include EHD. The composition mav be applied to the skin for the topical application of the antibacterial and antifungal compositions.
Another compound investigated by the present inventor was oleic acid. Oleic acid has been used as a vehicle in which salicylic acid and carbinoxamine have been incorporated. See "Percutaneous Absorption Of Drugs From Oily Vehicles~ Washitake, et al., Journal of Pharmaceutical Sciences, volume 64, number 3, pages 397-401. Further, oleic acid has been disclosea as being used in connection with a salicylic acid as indicated above by Cooper. The publication by Washitake, et al., demonstrates that the effect of oleic acid varies depending on the active ingredient which is included with the oleic acid. Therefore, it is not possible to accurately predict which pharmaceutically active compounds might have their skin penetration enhanced b-y the use of oleic acid.
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Nineteen different compositions were prepared containing 10~
nitroqlycerine each. The composition of the carrier within each of the nineteen different compositions is shown belo~ in Table I.
TABLE I
Diffusion of Nitroalvcerine Throuqh Hairless Mouse Skin Vehicle Composition, ml 103 NTG/PG2 PG DET D~SO DTP EHD FSB H2O OA UREA
1. 2 2 2 2. 1 4 -3. 4 . 2 5. 2 6. 2 0.5 1 0.5 100mg 7. 2 1 200mg 8. 2 1.8 55mg 0.2 g. 2 1.8 0.2 410~q 10. 1 2 11. 1 1 2 12. 1 1 2 1 300mg 13. 1 3 1~. 1 1 2 100mg 15. 1 0.8 0.2 16. 1 0.9 0.1 17. 1 0.7 0-3 18. 1 0.8 0.2 19. 1 0.8 0.2 1 except for the oleic acid experiments when 0.5 ml was used, 1 ml donor phase was applied to each skin.
10~ NTG/PG = Lot SDM no. 27, A 27-4, ICI
PG = propylene glycol DET = N,N-diethyl-m-toluamide DTP = 1,3-dimethyl-3,4,5,6 tetrahydro-2(lH) pryimidinone .
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After preparing each of these nineteen different compositions the cornpositions were tested to deterrnine the effect of all of the compounds on enhancing the percutaneous penetration o' nitroglycerine through hairless rat skin. The results of these test for all nineteen compositions are shown within Table II.
TAcLE II
~ N.G/skin Lag Time N
1. 0.05 0.044 + 0.032 2 7 + 0 56 6 2. 0.02 0.0074 + 0.006 1 86 + 1 38 5 3. 0.1 0.022 + 0.003 1.85 + 0.28 4 ~. 0.05 0.021 2.23 2 5. 0.05 0.007 2.57 2 6. 0.05 0.010 1.41 2 7. 0.05 0.032 , 2 8. 0.05 0.012 2 9. 0.05 0.012 2 10. 0.02 0.019 1.52 2 11. 0.02 0.015 + 0.005 1.48 + 0.47 6 12. 0.02 0.024 1.85 2 13. 0.02 0.022 + 0.003 1.51 + 0.06 4 14. 0.02 0.017 + 0.003 1.51 + 0.13 4 15. 0.05 0.306 + 0.084 1.11 + 0.41 8 16. 0.05 0.360 + 0.089 1.65 + 0.46 6 17. 0.05 0.351 + 0.034 1.70 + 0.08 3 18. 0.05 0.032 + 0.004 2.84 + 0.81 3 19. 0,05 0.039 + 0.019 2.53 + 0.23 3 1 flu~ measured in mg~cm2hr for times up to 10 hours The data within Table II clearly shows that the oleic acid utilized ~s the percutaneous penetration enhancer in compositions 15, 16, and 17 greatly increased the flux through the hairless mouse skin.
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After determining that oleic acid had a substantial in~luence on enhancing the penetration of nitroglycerine through hairless mice skir;
the present inventor had experiments carried out in order to determine the amount of oleic acid which could be utilized in order to most efficiently enhance the penetration. The results of those experiments are summarized in Table III.
Oleic Acid Concentration In Vehicle:
Nitroqlycerine~Flux throuqh E1airless ~1ouse Skin Oleic Acid Flux, mq/cm2hr n 0 0.046 + 0.021 9 0.360 + 0.089 6 - lO 0.306 + 0.~134 8 0.351 + 0.034 3 The results shown within Table III indicate that the flux of the nitroglycerine across the hairless mouse skin is not increased much bv increasing the amount of oleic acid beyond 5~ by weight based on the total weight of composition.
After determining the usefulness of oleic acid as a percutaneous penetration enhancer the present inventor carried out experimenta-tion . ' ' ' . - :, :. :
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in order to determine if the combination of two or more different com?ounds might have some synergistic effect with respect to enhancing ?er~tration of one or more active ingredients. As a result, the present inventor did find that the addition of minor amounts of olelc acid to major amounts of EHD had a synergistic effect with respect to the percutaneous penetration enhancement of pharmaceutically active ingredients. Information describing experiments and the results obtained weFe put forth below-- EXAMPLE III
Diffusion of Triamcinolone Acetonide Throuqh Hairless Mouse Skin Solutions of Triamcinolone Acetonide (TA) (RD-2K-0537) in propylene glycol (PG), 2-ethyl, 1,3 hexanediol (EHD), and 5% oleic acid (OA) in EHD were used to measure the flux in mg/cm2hr of the compound through hairless mouse skin. When a 0.5% solution of the compound in 5% OA/EHD was applied, the flux was about four time, greater than that from a 0.5~ solution in PG and twice that of a 0.590 solution in EHD. Similarly, 5% OA/EHD was almost twice as effective as EHD alone when a 0.19~ solution was used. This solvent gave results about twelve times better than PG alone at this concentration.
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~xperimental SXins from female hairles, mice, stra n SX~lHR-l (Temple University) were placed over circular te lon holders and secured with 0-rincs. The holders were at'ached to Plexiglas reservoirs filled with a receptor phase consisting of 39 ml of 2% Brij 58~
(polyoxethylene 20 cetyl either, Sigmz) dissolvec. in pH 7.4 isotonic phosphate bu-fer and 0.4 ml formalin. The solut on was deaassed . .
before use. 500 l alicuots of the .test solutions were spread over each s'~in. The di~~fusion cells were stirred or 48 hrs in a 35 incubator and l ml samples were removed at intervals and frozen until analyzed.
The samples were analyzed by HPLC using a Waters 481 vari-.~le wavelength UV detector set at 20 nm, LDC constametric III pump at l ml/min flow, and Fisher ~ecordall recorcer at chart speed 0.25 cm/min. Usinq a C-18 column and 50~ acetonitr-le in distillea water triamcinolone had a retention of l.4 cm.
~esults TA~3LE IV
- .The Flux of TA in Each of Three Solvents 0.1~ TA 0.5~ TA
PG 2.04 + 1.4 xl0 4 2.4g + 0.88x'0 4 EHD 1.49 + 0.39:c10 4 5.35 ~ 2.00x10 5~ OA/E~D 2.57 + 0.56xl0 1.06 + C.39~10 3 ~' .
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D,FFUSION OF ESTRADIOL THROUGH HAIRLESS MOUSE SXIN
Est_adiol was mixed with an assortment of diffusion enhancing substances in an attempt to increase its flux throush skin. The compound was also mixed with its ester, estradiol 17- cypionate, to achieve the same result. Since estradiol is not especially water soluble the r~ceptor phase was varied to include different amounts Oc a surfactant o_ plasma to better dissolve any diffused estradiol which might be attached to the underside of the skin.
Ex~erimental . . .
Female hairless mice, strain SXHI-~-1 (Temple University) wer-Xilled by cervical dislocation. The skins were remo~ed, placed carefully over a circular teflon holder, and held in place with an O-ring. This ~vielded a 7.07cm2 sXin surface which was suspended over a plexiglas reservoir (Kersco Engineering, Palo Alto, CA.) containinc 39ml of receptor phase: ph 7.4 phosphate buffer with or without 2 Brij-58 (polyoxyethylene 20 cetyl ether) or plasma. The receptor phase was filtered under a vacuum to remove dissolved air. Estradiol 100mg, or 100mg estradiol plus 100mg estradiol 17- -cypionate, was powdered and mixed with 2ml of the desired vehicle. The resulting suspension was sonicated and 0.Sml spread over each skin. The cells were stirred overnisht in a 35C incubator and lml samples taken at 6 hr intervals. Samples were pipetted into lml CH3CN to dissolve all diffused estradiol.
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The samples were analyzed by HPLC using a 8eckman model 160 detector at 280nm. Mobile phase was 55~ CH3CN in distilled water. At a flow of lml/min and chart speed 0.5cm/min estraZiol retention was 2.9Scm.
~ESULTS:
Table I su~marizAs 33 experiments ùsinq estradiol alone mixed with different combinations of 15 vehicle additives. Fair res~lts were obtained with vehicles which contained 2-ethvl-1,3-hexanediols (EHD) or, N,N'-diethyl-m-toluamide ~DET) and oleic acid tOA) or methy~
salicylate (m-Sal); total flux through skin was 1.1-1.6 x 10 3mq/cm hr.
Several experiments were conducted using a combination of estradiol and its 17- cypionate ester using combinations of nine vehicle additives (Table 2). Total flux was not changed dramatically over that found when estradiol alone was used. The flux of estradiol observed when estradiol 17- cypionate alone was applied to skin was considerably lower (Table III).
The results using different receptor phases are shown in Table IV. None of the conditions are significantly different from the others.
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Conclusion:
Using DET, E~D, m-Sal or OA in the vehicle seems to give best results for the diffusion of estradiol through hairless mouse skin.
~ttempts to increase the flux by a~ding an ester to the donor phase or by making the receptor phase more lipophilic were not successful.
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TABLE V
Vehicle Composition and Flux of Estradiol throuqh Skin after A~lication of Estradiol-Estradiol CYpionate Mixture ~ of Vehiclel .. . .. . ..
D~T DMSO DTP E'HD IPM _OA m-Sal MO PMS Flux,mq/cm hr N
100 l-.49x10 3 + 0.4 1-~
~` ` ` ` 95 - 5 9.23x10 4 + 0.2~ 9 2.15x10 + 0.23 3 1.27x10 3 + 0.1~ 3 1.36x10 3 + 0.8' 3 57 43 6.08x10 4 + 0.39 12 1.14x10 3 + 0.17 3 33 50 17 3.22x10 4 + 1.12 8 7.68x10 4 + 1.14 6 10 90 9.89x10 4 + 0.16 5 1.41x10 3 + 0.62 6 100 2.9 x10 5 + 3.03 3 4.2gx10 4 + 0.81 3 1.34x10 3 + 0.06 3 DET, N,Nldiethyl-m-toluamide DMSO, dimethyl sulfoxide DTP, 1,3-dimethyl-3,4,5,6 tetrahydro-2(IH)pyrimidinone EEID, 2-ethyl-1,3-hexanediol IPM, isopropyl myristate OA, oleic acid m-Sal, methyl salicylate ~IO, mineral oil PMS, polymethionine sulfoxide :
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The present inventor determined that olei.c acid could not be utilized in connection with pharmaceutically active ingredients which ingredients were a base. Accordingly, the present inventor carried out experiments in order to test the ability of EHD on enhancing the penetration of a pharmaceutically active ingredient which acted as a base such as local anesthetics. The results of these experiments are shown below within Example 4.
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TABLE VI
Local Anes~hetics: Experimental Conditions % of vehicleJ
10 N Vol Exp. Drugl mg on KOH/ Ap?. of mq s~in IPM n-p PG DE~ DET EDH MEOH Sal ml* ar L-l 39.3L 5.24 100 .20 4 L-2 136L 34.067 33 .15* 4 L-3 151.5E 37-9 67 33 .15* 2 L-4 -155.6B 38.9 67 - 33 .15 2 L-5 200.9E 50.2 34 33 33 .15 2 L-S 204-5B 27-9 64 18 18 .15 2 L-7 152E 45.6 100 .18 2 L-8 128.6B 38.6 100 .18* 2 L-9 206.8B 41.4 43 43 14 .18 3 L-10 205.1E 52.7 43 43 14 .18 3 L-ll 406.3E 110.8 32 38 8 15 .3 4 L-12 428.7B 98.9 38 38 8 15 .3 L-13 207.1E 53.3 8614 .18 3 L-14 208.8~3 53.7 8614 .18 3 B, Bupivacaine HCl 3IPM, isoprypyl myristate E, Etidocaine HCl n-p, normal propanol L~ Lidocaine HCL-H2O PG, propylene glycol ` ~ DEA, diethanolamine 10~ IPM in acetone DET, N,N-diethyl-m-toluamide EHD, 2-ethyl-1,3-hexanediol ~suspension KOH/MeOH, potassiumhydroxide/methanol m-Sal, methyl salicylate : . .
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T~BLE VII
Local Anesthetics: Results Exp.
.Flux + S.D. mg/cmZhr Lag time + S.D., hrs L-12 9.67 + .295 x 10 1 5.6 + 0.2 L-ll 4.7 + .179 x 10 1 3.8 + 1.6 L-9 1.46 + 0.01 x 10 1 6.5 + 0.2 L-3 1.43 x 10 1 3.2 L-10 - 6.97 + 0.49 x .10 2 6.6 + 0.1 L-2 5.62 + 0.01 x 10 2 2.9 L-14 3.09 + 1.46 x 10 9.1 + 0.2 L-13 2.66 + 0.65 x 10 2 6.3 + 0.1 L-4 1.55 x 10 2 4.3 T~ - ~ } .45 x ~ ~,2 L-? 4.14 x 10 3 6.4 L-8 3.15 x 10 3 5.2 L-5 1.01 x 10 3 3.4 L-l 4.65 + 0.1 x 10 4 0 Further experimentation was then carried out in order to test the ability of-certain compounas to enhance the penetration of estradio~,.
The results of these experiments are put forth below in Taole VIII.
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The results shown within Table VIII clearly indicate that oleic acid and E~ can increase the flu~ of estradiol through skin.
The present invention has been disclosed and described herein in what is believed to be its preferred embodiments. It is recogni~ed, however, that those skilled in the art may contemplate variations thereof which are not specifically disclosed herein, which variations are intended to be encompassed by the scope of the present invention.
~Acco`rdingly, the scope- of: the present invention should not be construed as being limited to the above description.
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TransDermal Delivery Svstem The present invention relates to the field of pharmaceutical preparations which are applied to the skin in order to obtain transdermal delivery of a pharmaceutically active drug from the preparation to the patient. More specifically, the invention relates to such preparations which utilize as a percutaneous penetration enhancer 2-ethyl-1, 3-he~anediol and/or oleic acid.
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It is well known that many drugs taken orallY, are destroyed on the first pass through the liver. It is also well known that when many drugs are taken orally, their rate of absorption into the body is not constant. In view of such difficulties, a number of different drug delivery systems have been developed. Recently, the use of transdermal delivery systems have met with increasing interest by researchers in the pharmaceutical drug delivery field.
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U.S. Patent 4,291,015 to Keith, et al., discloses the use of a polymeric diffusion matrix for the sustained release of pharmaceutically active drugs. The matrix is covered by a backing laver and applied to the skin where diffusion of the pharmaceutically active arug occurs and the drug is transdermaley delivered to the patient. Althoug~ U.S. Patent 4,291,015 discloses transdermal deliverv of nitroglycerine, other drugs may be delivered by utili~ing the same or a-similar matri~, as ~isclosed in U;S; Patents 4,292,820;`
4,292,302; and 4,29', 303.
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U.S. Patent 4,490,206 discloses the use of a different tvpe of transdermal delivery system whereby the pharmaceutically active druq is disperse~ within àn adhesive (see also U.S. Patent 4,390,52Q). In accordance with such systems, the pharmaceutically active drug is dispersed in a pressure-sensitive adhesive which is adhered to the skin. The drug then diffuses from the adhesive through the skin for delivery to the patient. Other types of transdermal delivery systems are also known and each has various advantages and disadvantages with respect to the transdermal delivery of different types of pharmaceutically active drugs.
One of the problems with utilizing transdermal delivery systems _ is one of efficacy. More specifically, the aevice must supply a sufficient amount of the pharmaceutically active ingredient to the patient to obtain the desired pharmaceutical effect on the patient , ~ , .. '' , , , : . '', , ' ' ' .. .. ' - ' ' . .
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over a given period of time. Different means may be employed in order to obtain the desired efficacy over that period of time.
One means of at.empting to increase the amount of drug delivery might be to include a higher concentration of the pharmaceutically active dru~ in the delivery system. By simply increasing the concentration of the drug,' the amount of the drug delivered to the patient would hopefully be increased. This concept might work well to a cer_ain e~tent but would be limited by the amount of drug which can be delivered through the skin barrier, ie., the skin acts as a rate limitation means.
Another means for increasing the amount of drug delivered and obtaininq the desired efficacy, might involve increasing the surface area contact of the delivery system with the skin. Althougl: en increase in the surface area will increase the amount o drug delivered to the patient, there are, of course, practical limitations with respect to increasing this surface are~. The cost of producing very large delivery systems might be prohibitive. Patients would be unlikely to ware a delivery system which had a surEace such that it covered the entire back and/or front of the patient.
-A completely different concept for increasing transdermaldelivery of a pharmaceutically active drug is the 'utilization of a penetration enha~cer to be used in combination with the drug delivery .
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' 09~ , svstem. Utilization cf such enhancers is subject to certain linitations such as the fac~ that the enhancer must be de'er~atologically acceptable, and compatible with the pharmaceutically active drug as well as the ~elivery system which it is used in connection with.
Perhaos the most famous of such penetration enhance_s is "DMSO
~Dimethyl sulfoxide1". However, DMSO has not received FDA approval for use on hu;mans. Another well known penet_ation enhar.c~r is AZONE~
s~e U.S. Patents 3,909,816; 4,311,481; and 4,316,893 as we1l as the correspondinq foreign patents.
~ ore recently, there has been some teachinSs with respect to the use o~ olei- acid as a penet~ation enhancer. (See Coo~er, EugenQ, R., ~Inc-eased Skin Permeability for LITOTHILIC Molecules" Journa7 of Pharn7aceutical Sciences, volume 73, number 8, Aucust 1984.) Cooper discloses the use of oleic acid in different concentrations in the presence of propylene glycol as a solid. The oleic acid does apcear to enhance penetration of the active ingredient SALICYLIC acid.
Cooper also discloses the use of oleic acid in combination with 1,2-butanediol. The article specifically indicates that "other diols also e~hibit this synerqism with lipids, hut the effect is less pronouncea às the cha-n lenSth is increased~. Coocer teaches that the treat~ent of the skin with surfactants can have a substantial influence on increasiDg the penetratioD of polar molecules. ~owever, .
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such surfactants do not generally increase the transdermal penetration of the non-polar molecules. Accordingly, Cooper concludes that the enhanced transdermal penetration of non-polar molecules such as salicylic acid can be obtained by the addition of small amounts O r fatty acids or alcohols to the formulation. More specifically transdermal penetration of salicylic acid can be greatly enhanced by the addition of small amounts of oleic acid. Accordinc,ly, Cooper appears to teach only the use of small amounts of oleic acid either alone or in combination with diols of short chain length and contains no teachings with respèct to the use of large amounts of oleic acid alone or in combination with long chain diols and actually teaches against the use of such long chain diols.
U.S. Patent 4,305,936 discloses a solution for topical or local application comprised of a corticos~eroid in a carrier. The carrier is comprised of 1 to 4~ by weight of solubilizing agents of a glyceral ester of a fatty acid containing 6 to 22 carbon atoms, 10 to 50% by weight of an alkanol cosolvent and from 20 to 50~ by weight of water.
The patent also indicates that the carrier can include a carrier a "suitable auxiliary adjuvant in an amount of up to 10% bv weight;:' Oleic acid is mentioned as a suitable auxiliary adjuvant. The patent does not appear to contain any teaching with respect to the effect oleic àcid might have on enhancing penetration and does ~ot appear to contain any teachings with respect to the use of large amounts of oleic acid alone or in combination with a long chain diol.
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U.S. Patent 4,45;,146 discloses a plaster comprised Gf a thermalplastic elastomer, an oil or higher fatty acid, a tack-providing resin and an active ingredient. The "higher fatty acid" may be present in the range of 25 to 370 parts by weight per 100 parts by weight of the thermalplastic elastomer. The active ingredient may be present in an amount in the range of 0.09 to 110 parts by weight per 100 parts by weight of the thermalplast-c elastomer, (see column 4, lines 3-35). Oleic acid is mentioned 2S
. "ohe of the preferred" highèr fatty acids, (seë column i, lines 16-17).
Although percutaneous penetration enhancers are known, there remains a need for an enhancer which is dermatologically acceptable has PD~ approval for use on human skin and has a substantial effect cr.
increasing in the rate of tr~nsdermal delivery of a pharmaceutically active drug to a patient.
The present invention provides a pharmaceutical preparation in the form of a transdermal delivery system comprised of a carrier having dispersed therein a pharmaceutically active drug. The carrie~
is comprised of a percutaneous penetration enhancer which includes 2-ethyl-1, 3-hexanediol (hereinafter ~HD) and/or oleic acid. The present inventor has found that the use of high '; . ~, ', ' : ' , . .
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concentrations of EHD as a carrier can have a substantial effect on increasing in the ratc of aelivery of pharmaceutically active drugs and has further found that rate of delivery is further enhanced, and a synergistic effect is obtained, when the oleic acid is used in combination with EHD. The percutaneous penetration enhancement of this combination has been found to work particularly well in connection with pharmaceutically active drugs such as vasodiolators eg, nitroqlycerine, anti-arythmias eg, lidocane; sterioids eg, estrogen and corticosteroids.
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Hence one aspect of this invention is a transdermal delivery system, comprising:
a pharmaceutically active ingredient; and a carrier wherein the carrier is comprised of Z-ethyl-l, 3-hexanediol in an amount of 1 to 40% based on the weight of the carrier. ~he carrier may also be comprised almost totally of 2-ethyl-1,3-hexanediol. In a preferred embodiment of this aspect o the invention, the carrier contains about 5% by weight of oleic acid and the active ingredient is nitroglycerine. In another preferred embodiment, the carrier comprises l to 40~ oleie acid and the active ingredient is estradiol.
Another aspect of this invention is a transdermal delivery system, comprising:
nitroglycerine; and 8 ~ 3~
a carrier which includes 1 to 10% by weight of oleic acid based on the weight of the carrier.
The use of the transdermal delivery system for preparinq compositions useful for treatlng illnesses treatable by the active ingredient is another aspect of this invention.
It is a primary object of this invention to provide a percutaneous penetration enhancer ~or use in connection with a transdermal delivery system.
Another object of this invention is to provide such a penetration enhancer which is comprised of a large percentage of EHD alone and/or in combination with oleic acid.
Still anotner object of this invention is to provide a transdermal delivery system using EHD in an amount of 50% to 100 based on the weight of the carrier as a penetration enhancer.
Anoth`er object of this invention is to provide a transdermal delivery system comprised of a pharmaceutically active ingred7ent and a carrier which carrier is comprised of E~D in an amount of 50~ or . .
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- ' , ' ' ' ' ' ' ' -more by weight and oleic acid in an amount of 1 to 40% by weight basedon the weight of the carrier.
Yet another object of this invention is to provide a transdermal delivery system comprised of nitroglycerine and a carrier wherein the carrier is comprised of 50~ or more by weight of E~D and about 5~ by weight of oleic acid.
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In order for 2 compound to be useful as a percutaneous penetration enhancer the compound must meet a number of different requirements. Firstly, the compound must be a aetermatologically acceptable compound which when used topically on the skin does no' cause adverse side effects. Secondly, the compound must be compatible with the active ingredient within the transdermal delivery system. If ehe compound and the active ingredient are incompatible then a separation will take place or a reaction could occur which would destroy the pharmacoloqical activity of the ac~ive ingredient.
Thirdly, it is pre~erable for the compound to have been approved for use on humans by the Fooa And Drug Administration of the United States. Further, the compound must of course have a sub~tantial _ effect on increasing the transdermal rate of delivery of the pharmaceutically active drug.
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The present inventor ir.vestigated a large number of compounds in order to find one or more compounds which would meet the above referred to criteria and be useful as a percutaneous penetration enhancer. One such compound investigated was EHD which is known to be useful as an insect repellent. In addition to being used as an insec' repellent, EHD has been used in an antibacterial and an antifungal composition as disclosed by Minuto in U.S. Patent 4,~41,084. This patent discloses a pharmaceutical composition which includes an antibacterial - antifungal composition dispersed in ot'her camponerts which may include EHD. The composition mav be applied to the skin for the topical application of the antibacterial and antifungal compositions.
Another compound investigated by the present inventor was oleic acid. Oleic acid has been used as a vehicle in which salicylic acid and carbinoxamine have been incorporated. See "Percutaneous Absorption Of Drugs From Oily Vehicles~ Washitake, et al., Journal of Pharmaceutical Sciences, volume 64, number 3, pages 397-401. Further, oleic acid has been disclosea as being used in connection with a salicylic acid as indicated above by Cooper. The publication by Washitake, et al., demonstrates that the effect of oleic acid varies depending on the active ingredient which is included with the oleic acid. Therefore, it is not possible to accurately predict which pharmaceutically active compounds might have their skin penetration enhanced b-y the use of oleic acid.
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Nineteen different compositions were prepared containing 10~
nitroqlycerine each. The composition of the carrier within each of the nineteen different compositions is shown belo~ in Table I.
TABLE I
Diffusion of Nitroalvcerine Throuqh Hairless Mouse Skin Vehicle Composition, ml 103 NTG/PG2 PG DET D~SO DTP EHD FSB H2O OA UREA
1. 2 2 2 2. 1 4 -3. 4 . 2 5. 2 6. 2 0.5 1 0.5 100mg 7. 2 1 200mg 8. 2 1.8 55mg 0.2 g. 2 1.8 0.2 410~q 10. 1 2 11. 1 1 2 12. 1 1 2 1 300mg 13. 1 3 1~. 1 1 2 100mg 15. 1 0.8 0.2 16. 1 0.9 0.1 17. 1 0.7 0-3 18. 1 0.8 0.2 19. 1 0.8 0.2 1 except for the oleic acid experiments when 0.5 ml was used, 1 ml donor phase was applied to each skin.
10~ NTG/PG = Lot SDM no. 27, A 27-4, ICI
PG = propylene glycol DET = N,N-diethyl-m-toluamide DTP = 1,3-dimethyl-3,4,5,6 tetrahydro-2(lH) pryimidinone .
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After preparing each of these nineteen different compositions the cornpositions were tested to deterrnine the effect of all of the compounds on enhancing the percutaneous penetration o' nitroglycerine through hairless rat skin. The results of these test for all nineteen compositions are shown within Table II.
TAcLE II
~ N.G/skin Lag Time N
1. 0.05 0.044 + 0.032 2 7 + 0 56 6 2. 0.02 0.0074 + 0.006 1 86 + 1 38 5 3. 0.1 0.022 + 0.003 1.85 + 0.28 4 ~. 0.05 0.021 2.23 2 5. 0.05 0.007 2.57 2 6. 0.05 0.010 1.41 2 7. 0.05 0.032 , 2 8. 0.05 0.012 2 9. 0.05 0.012 2 10. 0.02 0.019 1.52 2 11. 0.02 0.015 + 0.005 1.48 + 0.47 6 12. 0.02 0.024 1.85 2 13. 0.02 0.022 + 0.003 1.51 + 0.06 4 14. 0.02 0.017 + 0.003 1.51 + 0.13 4 15. 0.05 0.306 + 0.084 1.11 + 0.41 8 16. 0.05 0.360 + 0.089 1.65 + 0.46 6 17. 0.05 0.351 + 0.034 1.70 + 0.08 3 18. 0.05 0.032 + 0.004 2.84 + 0.81 3 19. 0,05 0.039 + 0.019 2.53 + 0.23 3 1 flu~ measured in mg~cm2hr for times up to 10 hours The data within Table II clearly shows that the oleic acid utilized ~s the percutaneous penetration enhancer in compositions 15, 16, and 17 greatly increased the flux through the hairless mouse skin.
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After determining that oleic acid had a substantial in~luence on enhancing the penetration of nitroglycerine through hairless mice skir;
the present inventor had experiments carried out in order to determine the amount of oleic acid which could be utilized in order to most efficiently enhance the penetration. The results of those experiments are summarized in Table III.
Oleic Acid Concentration In Vehicle:
Nitroqlycerine~Flux throuqh E1airless ~1ouse Skin Oleic Acid Flux, mq/cm2hr n 0 0.046 + 0.021 9 0.360 + 0.089 6 - lO 0.306 + 0.~134 8 0.351 + 0.034 3 The results shown within Table III indicate that the flux of the nitroglycerine across the hairless mouse skin is not increased much bv increasing the amount of oleic acid beyond 5~ by weight based on the total weight of composition.
After determining the usefulness of oleic acid as a percutaneous penetration enhancer the present inventor carried out experimenta-tion . ' ' ' . - :, :. :
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in order to determine if the combination of two or more different com?ounds might have some synergistic effect with respect to enhancing ?er~tration of one or more active ingredients. As a result, the present inventor did find that the addition of minor amounts of olelc acid to major amounts of EHD had a synergistic effect with respect to the percutaneous penetration enhancement of pharmaceutically active ingredients. Information describing experiments and the results obtained weFe put forth below-- EXAMPLE III
Diffusion of Triamcinolone Acetonide Throuqh Hairless Mouse Skin Solutions of Triamcinolone Acetonide (TA) (RD-2K-0537) in propylene glycol (PG), 2-ethyl, 1,3 hexanediol (EHD), and 5% oleic acid (OA) in EHD were used to measure the flux in mg/cm2hr of the compound through hairless mouse skin. When a 0.5% solution of the compound in 5% OA/EHD was applied, the flux was about four time, greater than that from a 0.5~ solution in PG and twice that of a 0.590 solution in EHD. Similarly, 5% OA/EHD was almost twice as effective as EHD alone when a 0.19~ solution was used. This solvent gave results about twelve times better than PG alone at this concentration.
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~xperimental SXins from female hairles, mice, stra n SX~lHR-l (Temple University) were placed over circular te lon holders and secured with 0-rincs. The holders were at'ached to Plexiglas reservoirs filled with a receptor phase consisting of 39 ml of 2% Brij 58~
(polyoxethylene 20 cetyl either, Sigmz) dissolvec. in pH 7.4 isotonic phosphate bu-fer and 0.4 ml formalin. The solut on was deaassed . .
before use. 500 l alicuots of the .test solutions were spread over each s'~in. The di~~fusion cells were stirred or 48 hrs in a 35 incubator and l ml samples were removed at intervals and frozen until analyzed.
The samples were analyzed by HPLC using a Waters 481 vari-.~le wavelength UV detector set at 20 nm, LDC constametric III pump at l ml/min flow, and Fisher ~ecordall recorcer at chart speed 0.25 cm/min. Usinq a C-18 column and 50~ acetonitr-le in distillea water triamcinolone had a retention of l.4 cm.
~esults TA~3LE IV
- .The Flux of TA in Each of Three Solvents 0.1~ TA 0.5~ TA
PG 2.04 + 1.4 xl0 4 2.4g + 0.88x'0 4 EHD 1.49 + 0.39:c10 4 5.35 ~ 2.00x10 5~ OA/E~D 2.57 + 0.56xl0 1.06 + C.39~10 3 ~' .
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D,FFUSION OF ESTRADIOL THROUGH HAIRLESS MOUSE SXIN
Est_adiol was mixed with an assortment of diffusion enhancing substances in an attempt to increase its flux throush skin. The compound was also mixed with its ester, estradiol 17- cypionate, to achieve the same result. Since estradiol is not especially water soluble the r~ceptor phase was varied to include different amounts Oc a surfactant o_ plasma to better dissolve any diffused estradiol which might be attached to the underside of the skin.
Ex~erimental . . .
Female hairless mice, strain SXHI-~-1 (Temple University) wer-Xilled by cervical dislocation. The skins were remo~ed, placed carefully over a circular teflon holder, and held in place with an O-ring. This ~vielded a 7.07cm2 sXin surface which was suspended over a plexiglas reservoir (Kersco Engineering, Palo Alto, CA.) containinc 39ml of receptor phase: ph 7.4 phosphate buffer with or without 2 Brij-58 (polyoxyethylene 20 cetyl ether) or plasma. The receptor phase was filtered under a vacuum to remove dissolved air. Estradiol 100mg, or 100mg estradiol plus 100mg estradiol 17- -cypionate, was powdered and mixed with 2ml of the desired vehicle. The resulting suspension was sonicated and 0.Sml spread over each skin. The cells were stirred overnisht in a 35C incubator and lml samples taken at 6 hr intervals. Samples were pipetted into lml CH3CN to dissolve all diffused estradiol.
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The samples were analyzed by HPLC using a 8eckman model 160 detector at 280nm. Mobile phase was 55~ CH3CN in distilled water. At a flow of lml/min and chart speed 0.5cm/min estraZiol retention was 2.9Scm.
~ESULTS:
Table I su~marizAs 33 experiments ùsinq estradiol alone mixed with different combinations of 15 vehicle additives. Fair res~lts were obtained with vehicles which contained 2-ethvl-1,3-hexanediols (EHD) or, N,N'-diethyl-m-toluamide ~DET) and oleic acid tOA) or methy~
salicylate (m-Sal); total flux through skin was 1.1-1.6 x 10 3mq/cm hr.
Several experiments were conducted using a combination of estradiol and its 17- cypionate ester using combinations of nine vehicle additives (Table 2). Total flux was not changed dramatically over that found when estradiol alone was used. The flux of estradiol observed when estradiol 17- cypionate alone was applied to skin was considerably lower (Table III).
The results using different receptor phases are shown in Table IV. None of the conditions are significantly different from the others.
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Conclusion:
Using DET, E~D, m-Sal or OA in the vehicle seems to give best results for the diffusion of estradiol through hairless mouse skin.
~ttempts to increase the flux by a~ding an ester to the donor phase or by making the receptor phase more lipophilic were not successful.
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TABLE V
Vehicle Composition and Flux of Estradiol throuqh Skin after A~lication of Estradiol-Estradiol CYpionate Mixture ~ of Vehiclel .. . .. . ..
D~T DMSO DTP E'HD IPM _OA m-Sal MO PMS Flux,mq/cm hr N
100 l-.49x10 3 + 0.4 1-~
~` ` ` ` 95 - 5 9.23x10 4 + 0.2~ 9 2.15x10 + 0.23 3 1.27x10 3 + 0.1~ 3 1.36x10 3 + 0.8' 3 57 43 6.08x10 4 + 0.39 12 1.14x10 3 + 0.17 3 33 50 17 3.22x10 4 + 1.12 8 7.68x10 4 + 1.14 6 10 90 9.89x10 4 + 0.16 5 1.41x10 3 + 0.62 6 100 2.9 x10 5 + 3.03 3 4.2gx10 4 + 0.81 3 1.34x10 3 + 0.06 3 DET, N,Nldiethyl-m-toluamide DMSO, dimethyl sulfoxide DTP, 1,3-dimethyl-3,4,5,6 tetrahydro-2(IH)pyrimidinone EEID, 2-ethyl-1,3-hexanediol IPM, isopropyl myristate OA, oleic acid m-Sal, methyl salicylate ~IO, mineral oil PMS, polymethionine sulfoxide :
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The present inventor determined that olei.c acid could not be utilized in connection with pharmaceutically active ingredients which ingredients were a base. Accordingly, the present inventor carried out experiments in order to test the ability of EHD on enhancing the penetration of a pharmaceutically active ingredient which acted as a base such as local anesthetics. The results of these experiments are shown below within Example 4.
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TABLE VI
Local Anes~hetics: Experimental Conditions % of vehicleJ
10 N Vol Exp. Drugl mg on KOH/ Ap?. of mq s~in IPM n-p PG DE~ DET EDH MEOH Sal ml* ar L-l 39.3L 5.24 100 .20 4 L-2 136L 34.067 33 .15* 4 L-3 151.5E 37-9 67 33 .15* 2 L-4 -155.6B 38.9 67 - 33 .15 2 L-5 200.9E 50.2 34 33 33 .15 2 L-S 204-5B 27-9 64 18 18 .15 2 L-7 152E 45.6 100 .18 2 L-8 128.6B 38.6 100 .18* 2 L-9 206.8B 41.4 43 43 14 .18 3 L-10 205.1E 52.7 43 43 14 .18 3 L-ll 406.3E 110.8 32 38 8 15 .3 4 L-12 428.7B 98.9 38 38 8 15 .3 L-13 207.1E 53.3 8614 .18 3 L-14 208.8~3 53.7 8614 .18 3 B, Bupivacaine HCl 3IPM, isoprypyl myristate E, Etidocaine HCl n-p, normal propanol L~ Lidocaine HCL-H2O PG, propylene glycol ` ~ DEA, diethanolamine 10~ IPM in acetone DET, N,N-diethyl-m-toluamide EHD, 2-ethyl-1,3-hexanediol ~suspension KOH/MeOH, potassiumhydroxide/methanol m-Sal, methyl salicylate : . .
, ~ . .. ~ . --: .. - . .. .. ~ ~ -, . . : .-. . - ., 22 ~ 7~
T~BLE VII
Local Anesthetics: Results Exp.
.Flux + S.D. mg/cmZhr Lag time + S.D., hrs L-12 9.67 + .295 x 10 1 5.6 + 0.2 L-ll 4.7 + .179 x 10 1 3.8 + 1.6 L-9 1.46 + 0.01 x 10 1 6.5 + 0.2 L-3 1.43 x 10 1 3.2 L-10 - 6.97 + 0.49 x .10 2 6.6 + 0.1 L-2 5.62 + 0.01 x 10 2 2.9 L-14 3.09 + 1.46 x 10 9.1 + 0.2 L-13 2.66 + 0.65 x 10 2 6.3 + 0.1 L-4 1.55 x 10 2 4.3 T~ - ~ } .45 x ~ ~,2 L-? 4.14 x 10 3 6.4 L-8 3.15 x 10 3 5.2 L-5 1.01 x 10 3 3.4 L-l 4.65 + 0.1 x 10 4 0 Further experimentation was then carried out in order to test the ability of-certain compounas to enhance the penetration of estradio~,.
The results of these experiments are put forth below in Taole VIII.
.' . : :
, ~ ' ' ' ,, `' ~ - :
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7~
~ O O O O O O O O O O O G O C O O O O O
X E X X X X X X X X X X X X X X X x X X X
I) r ~ ~ o~ ~D ~ N ~ C~
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1~
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~ ,~
,~
.
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~ ~0 O E~ ~ ~ u~ o o u~ u~ o PE' . ~ ~ N
O U~ O U~
~ ~ N N (~
',C 2 . E
~,~
Ll U~ :
t~
o Lrl o o U~ o o U7 o CO o o C
~:: O 1-- ~ 117 N CO tt~ N ~ ~ U7 L'l 11') ~ ~` O C ~ C O
H ~D IJl Ul U~ Ir.
': - ' ' ~, , ' - . . .
' ~ . ~` ' .
37~
oooooooooooooo E .1::
X E x X x x x x X x x X X X x X
V
r~ ~ ~ ~D ~ U~ U'~ ~ ~ U~ O r~ O
E r o o _~ O O Q) . ul u~ ~1 ~1 ~: :1 O R c ~,~ ~ ~ E ~a ,~ a~
r~
E~ u~ ~ V X O ~a u :r U C~
O
~ ~ r~ o o ~ ~7 ~ ~ o o ~ ~ r( .c O ~ o o r~
~ ,~ ,~
~i Ql U~
O ~ ~ e ,~a~ E E ~ S ~ V J
r~ ~ u~ In O ~
C` ~ ~1 ~1 1 O ~1 0 ~ tq~1 O
.,~ ~ O ~ u) ~ ~ ~
;~ ~ u~ ~ ,~
O O ~ u~
V X E _ o O
~ O ~ . u~
~: V
u~
O
O ~ Q h .,~ O
~ . ~ a '~ ~ O ~ r~ C~
U g ' o V ~ 0 ~ ~1 .,~ Q ~ ~ O
.~: ~ 0 g ~
h~ ~ ~ E
"_~ O
~1 ~ h ~) ~ ~, h ~ ~ G ~: V 0 ul ' O ~I ~ X
. a.~e ~
t~ o r r~ 7 O L~ O ~ c~ Z
P. u~ ul ~ ~) ~ ~ ul O h 0~
; Z
co r~ o o r~ u~
f~J ~ Nf`l ,~
" h ~ E~
H S~ Q Q
H _~
iZ
. . .
` ' '~ ' ` ' ' . .
.' -' , ' .~ ' . :
- . '- ` ' ~ :' ` ' ' '' ' .' ''' ' ' ". ~ ~ ' . `' ` ' . ~ . .
1~ 7~
The results shown within Table VIII clearly indicate that oleic acid and E~ can increase the flu~ of estradiol through skin.
The present invention has been disclosed and described herein in what is believed to be its preferred embodiments. It is recogni~ed, however, that those skilled in the art may contemplate variations thereof which are not specifically disclosed herein, which variations are intended to be encompassed by the scope of the present invention.
~Acco`rdingly, the scope- of: the present invention should not be construed as being limited to the above description.
- .: . . : : . . . . .
. : . . - ............................ : . .
.: - : .' ' :. . ' . - , ' ' , ,:
Claims (6)
1. A transdermal delivery system, comprising:
a pharmaceutically active ingredient; and a carrier wherein the carrier is comprised of 2-ethyl-1, 3-hexanediol in an amount of 50% or more based on the weight of the carrier.
a pharmaceutically active ingredient; and a carrier wherein the carrier is comprised of 2-ethyl-1, 3-hexanediol in an amount of 50% or more based on the weight of the carrier.
2. A transdermal delivery system as claimed in claim 1, wherein the carrier is further comprised of oleic acid in an amount of 1 to 40% by weight based on the weight of the carrier.
3. A transdermal delivery system as claimed in claim 1, wherein a carrier is comprised almost totally of 2-ethyl-1, 3-hexanediol.
4. A transdermal delivery system, comprising:
nitroglycerine; and a carrier which includes 1 to 10% by weight of oleic acid based on the weight of the carrier.
nitroglycerine; and a carrier which includes 1 to 10% by weight of oleic acid based on the weight of the carrier.
5. A transdermal delivery system as claimed in claim 1, wherein the carrier is further comprised of about 5% by weight of oleic acid and the pharmaceutically active ingredient is nitroglycerine.
6. A transdermal delivery system as claimed in claim 2, wherein the pharmaceutically active ingredient is estradiol.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US806,257 | 1985-12-06 | ||
| US06/806,257 US4764381A (en) | 1985-12-06 | 1985-12-06 | Percutaneous penetration enhancer of oleic acid and 2-ethyl-1, 3-hexanediol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1280974C true CA1280974C (en) | 1991-03-05 |
Family
ID=25193671
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000524665A Expired - Fee Related CA1280974C (en) | 1985-12-06 | 1986-12-05 | Transdermal delivery system |
Country Status (11)
| Country | Link |
|---|---|
| US (2) | US4764381A (en) |
| EP (2) | EP0393727A3 (en) |
| JP (1) | JPS63502108A (en) |
| KR (1) | KR900002653B1 (en) |
| AT (1) | ATE86870T1 (en) |
| AU (2) | AU602324B2 (en) |
| CA (1) | CA1280974C (en) |
| DE (1) | DE3688075T2 (en) |
| DK (1) | DK407587A (en) |
| MY (1) | MY102378A (en) |
| WO (1) | WO1987003490A2 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11872199B2 (en) | 2019-11-06 | 2024-01-16 | Smartech Topical, Inc. | Topical formulations of cyclooxygenase inhibitors and their use |
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-
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- 1985-12-06 US US06/806,257 patent/US4764381A/en not_active Expired - Lifetime
-
1986
- 1986-12-05 JP JP62500191A patent/JPS63502108A/en active Pending
- 1986-12-05 AT AT87900446T patent/ATE86870T1/en not_active IP Right Cessation
- 1986-12-05 WO PCT/US1986/002584 patent/WO1987003490A2/en active IP Right Grant
- 1986-12-05 DE DE8787900446T patent/DE3688075T2/en not_active Expired - Fee Related
- 1986-12-05 AU AU67336/87A patent/AU602324B2/en not_active Ceased
- 1986-12-05 KR KR1019870700681A patent/KR900002653B1/en not_active IP Right Cessation
- 1986-12-05 EP EP19900110514 patent/EP0393727A3/en not_active Withdrawn
- 1986-12-05 CA CA000524665A patent/CA1280974C/en not_active Expired - Fee Related
- 1986-12-05 EP EP87900446A patent/EP0250542B1/en not_active Expired - Lifetime
-
1987
- 1987-08-05 DK DK407587A patent/DK407587A/en not_active Application Discontinuation
- 1987-09-29 MY MYPI87002301A patent/MY102378A/en unknown
-
1988
- 1988-05-25 US US07/198,798 patent/US4885174A/en not_active Expired - Lifetime
-
1990
- 1990-08-20 AU AU61158/90A patent/AU625830B2/en not_active Ceased
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11872199B2 (en) | 2019-11-06 | 2024-01-16 | Smartech Topical, Inc. | Topical formulations of cyclooxygenase inhibitors and their use |
Also Published As
| Publication number | Publication date |
|---|---|
| KR880700675A (en) | 1988-04-11 |
| DE3688075D1 (en) | 1993-04-22 |
| AU625830B2 (en) | 1992-07-16 |
| WO1987003490A2 (en) | 1987-06-18 |
| WO1987003490A3 (en) | 1987-07-30 |
| MY102378A (en) | 1992-06-17 |
| AU602324B2 (en) | 1990-10-11 |
| EP0393727A3 (en) | 1990-11-22 |
| EP0250542A1 (en) | 1988-01-07 |
| EP0393727A2 (en) | 1990-10-24 |
| AU6115890A (en) | 1991-02-07 |
| JPS63502108A (en) | 1988-08-18 |
| DK407587D0 (en) | 1987-08-05 |
| DE3688075T2 (en) | 1993-06-24 |
| DK407587A (en) | 1987-08-05 |
| AU6733687A (en) | 1987-06-30 |
| KR900002653B1 (en) | 1990-04-21 |
| US4764381A (en) | 1988-08-16 |
| ATE86870T1 (en) | 1993-04-15 |
| US4885174A (en) | 1989-12-05 |
| EP0250542B1 (en) | 1993-03-17 |
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