JPH07500114A - Transdermal azidothymidine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Transdermal azidothymidine field of invention The present invention provides a permeation enhancer that facilitates transdermal delivery and transdermal absorption delivery of azidothymidine. The present invention relates to a method for transdermal delivery of azidothymidine using a sensor.

Background of the invention Azidothymidine (AZT) is a compound of cytopsin and 3-azido-3-deoxythymidine. Also known as gin. It is an antiviral agent. It is acquired immunodeficiency syndrome ( Symptomatic human immunotherapy, including AN) S) and progressive AIDS-related syndrome (ARC). Used to treat patients infected with HIV infection. Azidothymidine is currently It has been administered orally or by intravenous infusion.

The present invention applies azidothymidine directly to the skin or via a transdermal patch. The present invention provides a novel method for administering the drug by formulating it into a transdermal absorbable pharmaceutical composition. It is something that This pharmaceutical composition includes an active ingredient that is effective in the treatment of AIDS and ARC. A permeation enhancer is included to achieve dothymidine blood levels.

Transdermal delivery of azidothymidine has advantages over Ike's delivery method of azidothymidine. be. One advantage is the ease of application and removal of transdermal formulations. In use This simplicity eliminates the hospital visits required when administering azidothymidine intravenously. Provides the benefit of no hindrance to style. Additionally, oral and intravenous administration Advantageous for use in pediatrics where administration is difficult.

Oral administration of azidothymidine causes a steep rise in A2711 degrees, which is toxic. may be indicated. Transdermal administration of AZT ensures that an effective amount of AZT remains in the blood for a long period of time. It also provides continuous administration of AZT that is maintained without spikes.

The outer layer of the skin, the epidermis, protects the area beneath the skin from the penetration of foreign chemicals. is known, and various enhancers are used to deliver drugs transdermally. It has been. Substances that help facilitate the diffusion of drugs through the stratum corneum and epidermis.

Skin Penetration Enhancer-2 is called an accelerator, adjuvant and absorption enhancer. B, I dson.

Cosmetics & Toi 1 etries, 95.59 (1980) The factors that influence drug penetration, and therefore often its effectiveness, are complex and unpredictable. It is said that it is impossible to measure. A vehicle that gives a certain drug the ideal penetration-enhancing effect. Kru may be unsatisfactory in other cases.

A variety of penetration enhancers are known to be useful in transdermal drug delivery.

U, S, 4.863.970. U, S, 4.722.941. U, S, 4.93 1.283 and EP 351.897 for use in transdermal compositions and topical administration. Some representative penetration enhancers that may be used are disclosed.

Summary of the invention The present invention provides a method for transdermal delivery of azidothymidine using a penetration enhancer. One we present is linalool, carvacrol, thymol, and citral.

Various compounds selected from the group consisting of menthol and t-anethole can be used transdermally. Demonstrated to be an effective penetration enhancer for delivery of azidothymidine through absorption I made it.

A primary object of the present invention is to provide a method for transdermal delivery of azidothymidine. It's there. This method involves administering an effective amount of azidothymidine along with a penetration enhancer. It is carried out by subcutaneous administration.

Yet another object of the invention is to provide a transdermal solution for effective transdermal delivery of azidothymidine. The objective is to provide absorbent compositions or patches.

Brief description of the drawing Figure 1 shows a transdermal package placed on the skin for transdermal delivery of azidothymidine. FIG.

FIG. 2 is a schematic bottom view of the embodiment illustrated in FIG.

Figure 3 illustrates a template used for topical administration of azidothymidine formulations for transdermal absorption. .

Figure 4 shows a second implementation of a transdermal patch for transdermal delivery of azidothymidine. Figure 3 illustrates a cross-sectional schematic diagram of an embodiment.

FIG. 5 illustrates a cross-sectional schematic diagram of a third embodiment of a transdermal patch.

Figure 6 shows the results of in vitro experiments using AZT compositions containing various penetration enhancers. This is a graphical representation of the results.

Figure 7 shows a graph of the results of in vitro experiments using AZT compositions containing various pharmaceutical carriers. This is a rough display.

Figure 8 shows the results of in vitro experiments using AZT compositions containing various amounts of AZT. It is a graph display.

FIG. 9 is a graphical representation of the results of in vivo experiments using various AZT formulations.

Detailed description of the invention The present invention includes a composition for transdermal absorption of azidothymidine as described above.

Azidothymidine has structural formula I.

As used herein, the term "composition J" refers to a mixture of two or more elements or components. refers to the product obtained from combining or blending.

As used herein, the term "pharmaceutically acceptable carrier" refers to involves the transport or transport of chemicals from parts of the body to other organs or parts of the body. a pharmaceutically acceptable substance 2 composition or vehicle, such as a liquid or means a solid filler, diluent, excipient, or solvent.

As used herein, the term "transdermal delivery" refers to the topical delivery of pharmaceutical compositions to the skin. topical administration, in which a therapeutically effective amount of the active ingredient, azidothymidine, is administered transdermally. will be delivered.

As used herein, the term "transdermal patch" refers to a patch containing a pharmaceutical composition. , means a dermal patch applied to the skin of a patient. Build a transdermal patch The technology used is well known in the pharmaceutical technology field.

The terms "backing layer" and "incubation layer J" used in this specification refer to the percutaneous absorption material. means the constituent elements of the chain. Suitable materials and designs for transdermal drug delivery technology is well known in For example, D. Hsieh, “Multipl e m1nation for Vol, 1. pp, 167-188.19 See 88.

As used herein, the term "penetration enhancer" refers to a drug that increases transdermal absorption of a drug. linalool, carvacrol, thymol, citral , menthol and t-anethole. effective against certain drugs The selection of permeation enhancers must be estimated experimentally to determine whether they are effective for a given drug. Penetration enhancers that work for some drugs are not necessarily effective for all other drugs.

Due to its activity as an antiviral agent, azidothymidine Useful in the treatment of RC (HIV-infection).

In the present invention, azidothymidine is used for topical application of azidothymidine compositions to the skin. It is administered transdermally depending on the application. More preferably, the azidothymidine is Administered in the form of 1. Pharmaceutical compositions and patches of the present invention that can be administered using a patch The azidothymidine is combined with a penetration enhancer and suitable pharmaceutical diluents, carriers and and excipients such as gelling agents, emollients, and preservatives. Ru. Preferably, azidothymidine is administered in combination with the penetration enhancer, thymol. the blood concentration of the drug required to be delivered, and the degree of permeability of the skin to the drug.

and the amount of skin surface area available for drug administration.

Theoretically there is no limit to the skin surface area available for drug administration, but for practical reasons to 3 usually limited to a range of about 1 square centimeter to about 100 square centimeters. available By fixing the available skin surface area within this range, the problem can be solved by providing the desired treatment. It is determined whether enough drug passes through a limited skin surface area to deliver If it passes through 9, it is possible to effectively administer the drug transdermally.

However, the skin's inherent permeability to the drug is very high or low. If only too much or too little of the drug passes through that area of the skin, then In order to put skin administration into practical use, it is necessary to control the rate of drug administration to the skin depending on the case. or the permeability of the skin to the drug must be increased.

The present invention relates to transdermal administration of drugs or drug delivery enhanced by the presence of penetration enhancers. It is about the delivery system.

For a compound to be useful as a transdermal penetration enhancer, it must be First, the compound must meet the following requirements: If used, it must be a dermatologically acceptable compound that does not cause harmful side effects. Second, the compound must be compatible with the active ingredient in its transdermal delivery system. Third, the compound should be safe for human use. 9 have been approved or can be approved by the Food and Drug Administration of the United States. Preferably, the compound further improves the transdermal delivery rate of the pharmaceutically active agent. It has to be raised.

In the present invention, a penetration enhancer is desired for transdermal delivery of azidothymidine. Something new was discovered. Suitable penetration enhancers for azidothymidine include Linaro All, carvacrol, thymol, citral, menthol and t-anetho Compounds selected from the group consisting of:

The use of non-toxic and therapeutically effective amounts of azidothymidine for the treatment of AIDS or ARC. Used or adopted. Administration for the treatment of AIDS or ARC with azidothymidine The criteria are based on a variety of factors including patient type, age, weight, gender and medical condition. 1 A doctor with ordinary skill will be able to provide the necessary information to treat the condition. Effective doses of drugs can be easily determined and prescribed.

The minimum inhibitory concentration of AZT in humans has been reported to be 0.27 mcg/ml.

The clearance of AZT in humans is approximately 1.3 L/hr/kg. delivery speed 1 mg/cm2/h is about 1 mg/cm2/h to give the minimum inhibitory concentration of AZT in humans. A 20cm” patch will be required.

5 mg/kg as an hourly infusion every 4 hours or 10 mg/kg orally every 4 hours. kg is administered to maintain therapeutic levels. Assuming a typical weight of 55 kg and this is equivalent to 1650 mg/El intravenously or 3300 mg/el orally for 7 days. According to the minimum inhibitory concentration of AZT (0,27 mcg/ml), the percutaneous absorption of AZT For delivery, a minimum of 460 mg/day of AZT is required to bring blood levels to the minimum inhibitory concentration. required to maintain it.

In order to administer the dosage set above, the concentration of azidothymidine in one composition must be It can be about 3 to about 3.096 w/v. However, azidothymidine The density is about 5 to about 2596. More preferably it is 15-2596.

The concentration of the penetration enhancer in the composition may be from about 0.5 to about 2096 w/v. can. However, the concentration of permeation enhancer is preferably from about 1 to about 1096 ．． It is more preferably about 2 to about 596.

Concentrations of azidothymidine and permeation enhancer are determined here by maximum and minimum concentrations. However, amounts above or below this limit can also be determined by those skilled in the technical field. Obviously, one can use the present invention without modification.

The agents introduced into the reservoir of the transdermal patch of the present invention to achieve the desired therapeutic effect. The amount of didothymidine and penetration enhancer is the desired dosage of azidothymidine.

Depends on the time the patch is placed on the patient's skin, as well as the area and thickness of the patch and can be varied. Therefore, what is the patient's serum concentration of azidothymidine?

The concentration of azidothymidine in the patch, the length of time the patch is placed on the patient's skin, or the This can be adjusted by changing the size of the switch.

The effective rate of release of azidothymidine from the patch to the patient's skin is H, about 24 to about 70 mg of active ingredient per day (mg-cm-'・day-ri) It can be within the range of A more preferable range is 1 square centimeter of skin per day. and about 24 somg of active ingredient. The exact amount depends on the desired dosage of active ingredient , and the treatment is performed on either an HIV asymptomatic patient or an HIV symptomatic patient. Depends on the crab.

Certain matrix materials used in patches for transdermal delivery of azidothymidine and the selected matrix material combination to allow the active drug ingredient to penetrate. The speed at which the invention occurs can be easily determined by one skilled in the art. this) as well as in the references cited therein.

The compositions and punches of the present application may contain other excipients and pharmaceutical carriers. Examples of excipients useful as gelling agents for the preparation of topical gels include Possible pharmaceutical carriers include hydroxypropyl cellulose (HPC). For example, isopropanol (IPA) and water or propylene glycol (PG) and water. Suitable for use in azidothymidine compositions for transdermal absorption The preservative of choice is paraben.

The azidothymidine compositions of the present invention are suitable for transdermal delivery of azidothymidine. Can be introduced during expropriation punch. Regarding transdermal patches for drug delivery Methodologies and designs are well known in the pharmaceutical arts.

Figure 1 shows a transdermal patch (10) designed to be placed on a patient's skin. exemplify. The transdermal absorption patch consists of (10), a backing layer (12), and a drug-retaining part ( 18), adhesive layer (16'), and removable protective covering sheet (I9) It consists of

The backing layer (12) forms the top (outer surface) of the patch. The backing layer is a component of the preservation layer. It can be made from a material or compound material that is substantially impermeable to water. The lining layer is transdermal It acts as a protective cover for the absorbent patch and prevents leakage of the components of the storage layer.

The backing layer of the transdermal patch of the present invention can be of various occlusive and non-occlusive properties.

Flexible and non-flexible backing members can be used in the transdermal patch of the present invention. Examples of suitable backing layers include cellophane, cellulose acetate, and ethyl cellulose. plasticized vinyl acetate, vinyl chloride copolymer, polyethylene terephthalate.

Nylon, polyethylene, polypropylene, polyvinylidene chloride, K cloth, pho film and aluminum foil are included.

The drug holding part (18) is in direct contact with the lower part of the lining layer (12), and contains azidothymidine for transdermal absorption. Contains a gin composition. to the reservoir of the patch of the invention to obtain the desired therapeutic effect. The amount of azidothymidine introduced depends on the desired dosage of azidothymidine, the patch It varies depending on the time of application on the person's skin, as well as the area and thickness of the patch. can be set. The patient serum concentration of azidothymidine was determined by the concentration of azidothymidine in the patch. You can change the concentration of the patch, the time the patch is placed on the patient's skin, or the size of the patch. It can be adjusted with.

An adhesive layer (16) is affixed to the backing layer around the drug reservoir. This is illustrated in Figure 2 Ta. This is clearly shown by the view of the punch from the bottom (patient side). The adhesive layer This is a means of fixing the transdermal patch to the skin. Contact adhesive compositions are often Heat-sensitive adhesives commonly used for skin absorbent patches may be selected.

Transdermal patches (1) A removable patch that completely covers the patient side of the transdermal patch. A protective covering sheet (19) may be included. Before use (the second coating sheet (19) is glued) Peel off layer (16) and discard to expose adhesive layer and drug reservoir.

Figures 3 and 4 show transdermal absorption of an azidothymidine composition formed on the skin of a patient. Figure 1 illustrates another embodiment of the patch, which is applied to an area of the patient's skin. Figure 2 illustrates an applied template (20). The inner periphery of the template (20) is azide for transdermal absorption. Determine the area of skin (22) to which the thymidine composition will be delivered. The area of the skin is Patient age, gender, and weight, and whether treatment is prophylactic or curative, as described above. Ruka.

as well as the blood level of azidothymidine to be achieved. administration The amount is determined by the factors mentioned above. The azidothymidine composition for transdermal absorption is It is applied within the inner circumference and then the template is removed from the skin.

Figure 4 shows the same image of the patient's skin after the azidothymidine composition and template were removed. - A sealing cover (36) placed over the area is shown. The sealing cover has It has the same properties and is chosen for the same reasons as described above for skin-absorbing patches. A backing layer (42) and an adhesive layer (40) can be included. The adhesive layer is azidothymidine is applied to the skin in the area determined by the template, i.e. it is the inner circumference or surrounding It can have the same radius and inner circumference as the area forming the boundary. The sealed cover is The azidothymidine composition for transdermal absorption is applied to a predetermined space on the skin (44). or held in the holding section (38).

Alternatively, the dosage of the azidothymidine composition for transdermal absorption to be administered is shown in Figure 2. Apply from the dispenser to the sealing cover (36) within the boundaries of the adhesive layer (38) shown. It can also be used. The skin of the patient to be treated with the transdermal patch formed with The method of administration described with respect to Figures 3 and 4 will vary depending on the individual patient. This is particularly advantageous as it allows dose titration to meet the needs of the individual.

FIG. 5 shows an example of another embodiment of the transdermal patch of the present invention designated as 26 in its entirety. Show. The patch for transdermal absorption (26) includes a backing layer (28) and a composition layer for transdermal absorption. (30) and an adhesive layer (34). The backing layer and the transdermal absorption composition layer are , which have the same properties as the above-mentioned backing layer and azidothymidine composition for transdermal absorption, respectively. This is selected for the reasons stated above. Furthermore, the adhesive layer (34) is must be permeable to the expropriating composition and must not constitute a significant obstacle to its passage; Must not be.

The transdermal absorption patch (2G) can also include a protective covering sheet (see the figure). (not shown), before use (the second coating sheet should be peeled off from the adhesive layer (34) and discarded). hand.

Expose the adhesive layer. The coating sheet contains azidothymidine, penetration enhancer and Substantially impermeable to other components of the transdermal composition layer and adhesive layer (34) It can be manufactured from the following materials.

The transdermal patch of the present invention can be applied to the patient's skin. transdermal patch is placed in firm contact with the patient's skin, preferably in close contact with the skin. . The azidothymidine in the patch moves from the patch to the patient's skin by diffusion.

When azidothymidine comes into contact with a patient's skin, the azidothymidine molecules It travels along the outer surface of the skin, is absorbed by the skin and enters the 2 capillary network. and enters the patient's circulation. Transdermal patches can be applied to any area of the patient's skin. Wear.

The following example describes a drug used to deliver azidothymidine by transdermal absorption. Pharmaceutical formulations are described and nine examples are given. Also regarding the results achieved by administration of this preparation A more detailed discussion of both the various aspects of the invention and its operation is provided below. Please describe as appropriate. These examples are intended to be merely illustrative of the invention. The three techniques do not limit the invention in either scope or spirit. According to those skilled in the art, there are two methods for producing the transdermal compositions and patches of the present invention.

Known variations in the manufacturing operating conditions and processes described in these examples may be used. It is easy to understand.

In the in vitro experiments described here, hairless (NU/NO) male mice Transport of azidothymidine through excised skin was measured. skin is francse between the donor and receptor compartments of the cell. Skin (1,77c +a”) contains the azidothymidine formulation to be tested and is in contact with the outside of the skin. a receptor compartment that contains saline and is in contact with the inside of the skin. Separate the components. It is maintained at a constant temperature of 37°C. Receptor aqueous medium was replaced at the following time points during the assay: 4 hours, 8 hours and 24 hours. . The concentration of azidothymidine was determined using HPLC. in in vitro tests Most formulations were tested in triplicate.

Example 凰〜l　2 Composition 1-12 was prepared by the following method except that the amounts of the ingredients were varied. sand That is, AZT was weighed and added to a vial. Next, weigh AZT and convert it to AZT. Added. Weigh IPA/water and/or PG/water into each vial and add all was added until the fine particles were dissolved.

Table■ Composition of formulation used for AZT in vitro test (g) Implementation AZT tPA/H20PG/H20 Calva Rikanal Thymol RifT J All [-7 Tall Menthol Example (60:40. (60 :40° Number v/v) v/v) 1 0.21 6.79 20.21 6.44 0.35 30.21 6.44 0.35 4 0.15 4.60 0.25 50.21 6.44 0.35 60.21 6.44 0.35 70.2 + 6.44 0.35 8 0.2 + 6.65 0.14 90.21 6.65 10 0.2 + 6.65 0.14 11 0.60 5.10 0.30 +2 1.10 6.65 0.35 Table ■ shows the results of excisional hairless (NO/NO) male mice using 9 compositions 1 to 7. These results demonstrate the consequences of AZT transport in the skin. Figure 6 shows the effect of variation on AZT transport in vitro. This is a graphical representation of the results of the experiment.

Table I in excisional hairless (NU~'') mouse skin. 37℃.

AZT transport at 5% enhancer concentration Example Cumulative AZT transport rate ■ Enhanced deposit (mg/ca+”/24h) ([/C11”/h) Average (S, D,) (1) 0.55 (0,31) 0.03 1 (2) 20.96 (0,98 ) 0.92 38.0 (3) 18.65 (1,57) 0.81 33. 8 (4) 12.82 (9°36) 0.69 24.6 (5) 14.16 (1,84) 0.57 26.7 (6) 16.40 (1,02) 0.7 8 29.7 (7) 18.73 (1,71) 0.82 33.91 These The value was calculated from the amount transported between 8 and 12 hours.

1 These values represent the transported cumulative values for the control (#1) and enhancer-containing formulations. Obtained from the ratio of the product AZT, Figure 7 shows 2 composition layers and 8~! The graph shows the results of an in vitro test using 0. ing. These results demonstrate that variations in the pharmaceutical carrier affect the in vitro transport of AZT. Show effectiveness.

Figure 8 shows 1 composition 5. ! Graphical representation of the results of in vitro tests using 1 and 12 It is. These results demonstrate that variations in AZT concentration affect the in vitro transport of AZT. This shows the effect of

In vivo experiments: In vivo transdermal absorption studies of AZT were carried out on - overnight fasted male males weighing 300-600 g. Performed in Sprague-Dawley rats. One day before the experiment, dorsal 1 approximately 5c 1 surface area 2.54cm by pricking the area II+X5cm with a pet shaver Fill the Hill Top chamber with 0.5 ml of the formulation and attach adhesive tape and sear. It was attached to the stinging area of each rat with noacrylate glue. The animals were kept during the experiment. Let them drink water freely.

After 8 hours, they were allowed to eat ad libitum. Systemic blood was collected by cardiac puncture at predetermined time points. It was collected by Animals were anesthetized with nitric oxide/isofluorene during sample collection. Ta. Plasma was stored at -20°C until analysis. The prescription is 150M@/■l AZT, 5% t-anethole, menthol, carvacrol or as enhancer Add 3% RPC to formulations made with Thymol with or without PG. It was added at 60°C and then allowed to cool to form a gel. At the end of each experiment, the hilltop The chamber was removed and the skin was observed for any changes.

Examples 13-16 For gel formulations (cold 13-16), heat the mixture to 60”C after all particles have dissolved. 3% RPC was weighed and added to the vial, and in the same manner as in Examples 1 to 12. Manufactured by After thorough mixing, the mixture was allowed to cool and gel.

Table■ Composition of the formulation used for AZT in vivo testing AZT O, 600, 600, 7T 10.75IPA/H20 (60/40.v/v) 2.191.613. ! J 3.58+ PG/H20 (60/40.v/v) 1.011.62t- Anethole 0.20 Menthol 0.20 Carvacrol 0.25 Thymol 0.25 i) IPCO, 120, 120, IS O, 15 Figure 9 uses these compositions. Figure 2 is a graphical representation of the results of an in vivo experiment. Absolute bioavailability values are shown in Table ■ vinegar.

Table■ Absolute bioavailability percentage of transdermal AZT in rats 1, V, saline solution 1 00 Example 13 4 1.35 (0,43) Example 14 4 0.81 (0,48) Example 15 4 2.94 (0,65) The transdermal compositions and patches of the present invention provide ease of application. and that they maintain the desired amount of AZT in the blood. It is. After 24 hours, the skin that was under the gel chamber was significantly different from before the gel was applied. No noticeable changes were observed.

[2uJ0/6”], LZ’ml [Douu0/6uu) 1ZV Sentomi (Do+, u+ /6LLI) Continuation of the above zvm:t’tsim front page (81) Specified times EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, SE), 0A (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, SN, TD, TG), AT, AU, BB, BG, BR, CA, CH, C5゜DE, DK, ES, FI, GB, HU, JP, KP, KR, LK, LU, MG, MN, MW, NL, No, PL, RO, RU, SD, SE, US (72) Inventor Kerkhoff, Carol F.

North Sheridan Road, Chicago, Illinois 60660, United States 5630゜Apartment 806 (72) Inventor: Penzotti, Stanley C0. junior Saratoga Co., Green Oaks, Illinois 60048, United States 1549 (72) Inventor Schmidt, Cynthia Marie - United States of America 6 0031 6428 Lone Tree Court, Ga 121, Illinois

Claims (1)

[Claims] 1. A therapeutically effective amount of azidothymidine is administered through the skin. Linalool, Carvacrol, Thymol, Citral, Meng to deliver and the permeation enhancement amount of a compound selected from the group consisting of toll and t-anethole. A method of transdermal delivery of azidothymidine comprising topical administration of azidothymidine. 2. Claim 1: The therapeutically effective amount of azidothymidine is about 5 to about 20 mg/kg. method. 3. 9. The method of claim 8, wherein the amount of permeation enhancement of the compound is about 0.5 to about 20%. 4. Pharmaceutical active substance having a backing layer, an adhesive layer and a drug holding part containing an active drug. In the transdermal delivery patch, the active agents azidothymidine and linaloo Le, carvacrol. Thymol, citral, menthol and t-anethole A pharmaceutical composition comprising a permeation-enhancing compound selected from the group consisting of Improvements featuring: 5. A therapeutically effective amount of azidothymidine, as well as linalool, carvacrol, and thimidine. selected from the group consisting of mole, citral, menthol and t-anethole. A pharmaceutical composition for transdermal delivery of azidothymidine comprising a permeation-enhancing amount of a compound.