JP2000053588A - Composition for supplying pharmaceutically active agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition capable of topically supplying a pharmaceutically active agent to the body of a person or animal by mixing the pharmaceutically active agent with a silicone rubber and a pharmaceutical vehicle in a specific ratio. SOLUTION: This composition for supplying a pharmaceutically active agent to the body of a person or animal comprises (A) 0.1-25 wt.% of a pharmaceutically active agent (for example, a therapeutic medicine or a diagnostic medicine), (B) 0.1-3 wt.% of a silicone rubber (including dimethylpolysiloxane-terminated with dimethylhydroxysilyl groups and preferably having a mol.wt. of >=2,000,000), and (C) 72-99.8 wt.% of a pharmaceutical vehicle (preferably hexamethyldisiloxane). The composition is obtained by mixing the components A, B and C, and is preferably coated on a substrate to form a substantially thin film on the substrate. Thereby, the pharmaceutically active composition to be adhered to a substrate for a time sufficient for supplying the medicine to a body can simply be prepared.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to compositions useful for delivering pharmaceutically active agents topically to the human or animal body. In particular, the compositions of the present invention comprise a pharmaceutically active agent, a controlled amount of silicone gum to increase the substantivity of the pharmaceutically active agent, and a pharmaceutical excipient.

[0002]

BACKGROUND OF THE INVENTION Many topical compositions for delivering pharmaceutically active agents to the human or animal body are known in the art.
These include, for example, ointments, creams, gels, solutions, lotions, transdermal and topical plasters and film-like matrices. Many of these topical dosage forms use silicone in their formulation. For example, silicone oils are used in ointments and salves, volatile silicones are used as excipients in many formulations, and silicone-based substances diffuse into the body at a controlled rate with pharmaceutically active agents. It can be used as a matrix or membrane that can be used.

[0003]

SUMMARY OF THE INVENTION U.S. Pat.
No. 2,815 teaches the use of volatile silicones as carriers in drug delivery systems. The patent teaches that silicone can spray the drug composition without leaving any residual carrier on the body. However, this patent does not teach silicone rubber which forms a substantially thin film. French Patent No. 94 05272 also teaches a silicone-containing topical dosage form comprising a lipophilic active, a silicone-based adhesive polymer composition and a volatile solvent. However, this patent requires the use of large amounts of silicone-based adhesive polymer. These large amounts of polymer are not only expensive, but also make the activator more difficult to dissolve in the solvent. They also result in thin films with poor aesthetics, preventing spraying of the formulation. Further, it takes a long time to dry.

[0004]

SUMMARY OF THE INVENTION The present inventors now have a composition which avoids these prior art problems and which is useful for delivering pharmaceutically active agents topically to the human or animal body. Was found. The present invention provides, as one embodiment, 0.1.
Topically into the human or animal body, comprising -25% by weight of a pharmaceutically active agent, 0.1-3% by weight of a silicone rubber and 72-99.8% by weight of a pharmaceutical excipient. A composition for providing an active agent is provided.

[0005]

DETAILED DESCRIPTION OF THE INVENTION The composition of the present invention provides a thin film having a substantially silky feel on a human or animal body,
A pharmaceutically active agent is provided from the thin film. These compositions also prevent solidification of the formulation in which the pharmaceutically active agent is insoluble. The compositions of the present invention include a pharmaceutically active agent. Generally, the choice of the pharmaceutically active agent is not critical. The active agent can include any solid or liquid substance desired to be locally delivered to the human or animal body. As used herein, "topical" means formed not only in dermatological actives, but also in the eyes, mouth, nose, ears, vagina, or rectum, as well as in teeth or open wounds, for example. Means active agent for cavities. These active agents include therapeutic or diagnostic agents.

[0006] As the therapeutic agents used, for example, antibiotics, antiseptics, antifungals, anti-acne agents, anti-inflammatory agents, hormones, anticancer agents, smoking cessation agents, cardiovascular therapeutic agents, H ₂ blockers, bronchodilators Dilator, analgesic, arrhythmia treatment, antihistamine, alpha blocker, beta blocker, AC
E inhibitors, diuretics, anti-aggressive agents, sedatives, tranquilizers, anticonvulsants, anticoagulants, vitamins, treatments for gastric ulcer and duodenal ulcer, proteolytic enzymes, healing factors,
Contains cell growth nutrients, peptides and others. Specific examples of suitable therapeutic agents include penicillin, cephalosporin, tetracycline, macrolide, epinephrine,
Amphetamine, aspirin, barbitalate, catecholamine, benzodiazepine, thiopental, codeine, morphine, procaine, lidocaine, sulfonamide, ticonazole, pabuterol, furosamide, prazosin, prostaglandin, salbutamol, indomethacin, diclofenac, graphenin, dipyridamole and theophylline Can be
Pharmaceutically active agent mixtures can also be used in the present invention. Suitable diagnostics are also known in the art, for example, X
Line contrast agents.

[0007] The mixing ratio of the pharmaceutically active agent used in the composition according to the present invention is selected according to the concentration of the pharmaceutically active agent required to supply the required dose. This may vary widely, such as from 0.1 to about 25% by weight of the composition. However, generally, the pharmaceutically active agent will comprise from about 0.1% to about 10% by weight of the composition.

[0008] The silicone rubbers used in the present invention are known in the art, many of which are commercially available. Generally, they consist of a silicone polymer and have the following structural formula: R ₃ Si—O— [R ₂ Si—O] _n —SiR _{3 In} this structural formula, each R is independently hydrogen, hydroxy, alkoxy or methyl, ethyl, propyl, vinyl, phenyl, etc. To 20 hydrocarbon groups. Generally, the repeating units include dimethyl, methylvinyl, methylphenyl, methylhydrogen, methylhydroxy, and mixtures thereof, and have end-capping groups (end-
Polymers whose capping unit is composed of dimethylhydroxy, dimethylvinyl, trimethyl and methylvinylphenyl are preferred. Most preferred is a silicone rubber having a dimethylsiloxy repeating unit having a terminal trimethylsilyl group or dimethylhydroxysilyl group. Such substances and their preparation are described, for example, in Chemistry and Technology of Silicones.
cones), W. Noll, Academic Press, New York, 1968
It is described in.

[0009] Silicone rubber is usually 50x1 at 25 ° C.
Has a viscosity of up to 0 ⁶ mm ² / s, up to 700,000,
Alternatively, it has a higher average molecular weight (Mn).
Preferably, the rubber has a Mn of at least about 200,000, more preferably at least about 300,000, most preferably from about 200,000 to 500,000. Generally, the silicone rubber is used at a concentration of about 0.1 to about 3% by weight, preferably 0.5 to 2.85% by weight.
If less than 0.1% by weight of the reagent is used, the composition will generally be less substantial. Also, the use of more than 3% by weight of the reagent results in a poor aesthetics of the composition, hinders dissolution and spraying of the pharmaceutically active agent, and delays the drying time of the formulation.

The pharmaceutical excipient used in the present invention comprises:
It is not critical as long as it is possible to deliver the pharmaceutically active agent and the silicone rubber to the desired site by the desired means. The excipient is composed of one or more substances. Examples of such excipients include water, solvents, diluents, excipients for preparing emulsifiers, excipients for preparing gels, excipients for preparing lotions, excipients for preparing ointments, and excipients for preparing creams. Excipients and the like. These excipients are usually used in formulating pharmaceutical products and can be prepared by known methods.
Specific examples of substances used as excipients include:
Water, alcohols, polyols, ethers, esters, aldehydes, ketones, fatty acids and alcohols, fatty acid esters, mineral oils, hydrocarbon oils, oleaginous bases, silicone oils and volatiles, waxes, vegetable volatile oils, monosaccharides and Polysaccharides, natural rubber, cellulose derivatives, acrylic polymers, polyvinyl alcohol, polyvinylpyrrolidone, proteins, polyethylene glycols and copolymers, colloidal solids, surfactants (nonionic, ionic and amphoteric), preservatives, buffers Agents, penetration modifiers, propellants, dyes, and fragrances, perfumes,
Cosmetics such as coloring agents, terpenes, ureas, cyclodextrins, silicone copolymers and the like can be mentioned.

[0011] The total amount of pharmaceutical excipients commonly used in the present invention is from about 72 to 99.8% by weight of the composition. The pharmaceutical excipient may be a single substance (eg, a solvent) or may be a mixture (eg, substances used in making creams). If the excipient is more than one substance, the total amount of excipients used in combination is about 72-9.
9.8% by weight. For example, if the pharmaceutically active agent and the silicone gum are provided in the form of a cream, the pharmaceutical excipient will include a mixture of materials commonly used in the manufacture of creams, the total amount of such materials being in the specific range described above. Within the amount. In the present invention, volatile excipients are often preferred. Generally, the volatile excipient should have a volatility that evaporates sufficiently within a time sufficient to leave a substantially thin film (eg, less than 15 minutes). Examples of suitable volatile excipients include hexamethyldisiloxane, octamethyltrisiloxane, decamethyltetrasiloxane and other short-chain linear siloxanes, cyclic siloxanes such as octamethylcyclotetrasiloxane and decamethylcyclopentasiloxane, alkanes Organic substances such as alcohols or ketones, mixtures of such substances, or other substances that do not affect any of the ingredients of the formulation and are capable of diluting the formulation. Preferred in the present invention is hexamethyldisiloxane.

If desired, the formulation may include a filler (eg, a contrast agent for X-rays or other diagnostic radiation), a colorant,
Color indicators, spreading agents such as silicone fluids, silicone resins, other excipients used in dispensing, compounds used as pH buffers to immediately adjust the environment in or around the formulation, cyclic or linear Other components such as polydiorganosiloxanes, bioadhesives, etc. may be included.

The present invention also provides a composition comprising 0.1 to 25% by weight of a pharmaceutically active agent, 0.1 to 3% by weight of a silicone rubber and 72 to 99.8% by weight of a pharmaceutical excipient. Mixing, forming a composition, and then applying the composition to a substrate, preferably a human or animal body, to form a substantially thin film comprising forming a substantially thin film on the substrate About. If volatile excipients are used, an additional step of evaporating the volatile excipients is often used in the deposition step. The compositions of the present invention can be applied in any desired manner. For example, the composition can be applied by hand, immersion, spray, or the like.

When volatile excipients are used, it is often preferred to spray the compositions of the present invention. here,
Spraying is performed by conventional techniques well known in the art. For example, the composition may be sprayed by a mechanical sprayer that mechanically pumps the composition from a container. Similarly, the composition may be a propellant, as is well known in the art.
(propellent) can force spray from the container.
Conventional propellants, such as air or hydrocarbons, will work in the present invention as long as they do not harm the formulation. The composition is generally forcibly sprayed from a nozzle toward the point where application is desired. The nozzle may simply direct the flow of the composition at the desired site, or may make drops of the formulation by techniques known in the art.

The spray mechanism often must be able to deliver the composition in a controlled amount, depending on the type of pharmaceutically active agent, so that an appropriate dose of pharmaceutically active agent is delivered. Mechanisms for adjusting the amount of composition delivered by a spray are known in the art. For example, a mechanical pump can be designed to deliver a regulated amount of the composition using a metering valve.
Similarly, the amount of propellant used with
It can be adjusted to release a discrete amount of the composition.

The present invention has many advantages over the prior art. The method described herein is a method that allows for simple dispensing of a pharmaceutical composition that adheres to the substrate (substantial) for a time sufficient to deliver the drug to the substrate. As such, its application does not require skilled specialists. Similarly, because a small amount of silicone rubber is used,
Costs are kept to a minimum and aesthetics are improved. further,
The amount of silicone rubber is sufficiently small that spraying is possible when volatile excipients are used.

[0017]

EXAMPLES In order to further clarify the present invention, a composition exemplifying the present invention will be described below. Unless indicated otherwise, all parts are parts by weight and all viscosities are at 25 ° C.

Examples 1 to 3 (placebo placebo) 5% by weight of talc, silicone rubber in the amount indicated in Table 1 (average dp = 9500, molecular weight = 700,0) in containers
00, viscosity at 25 ° C. = 0.45 Pa s) and the amount shown in Table 1 of hexamethyldisiloxane (HMDS) (molecular weight = 162, viscosity at 25 ° C. = 0.65 mm ² / s). Spraying was performed using a mechanical nebulizer and a conventional mechanical metering valve to provide these compositions. Table 1 shows the results.

[0019]

[Table 1]

This example shows that compositions containing small amounts of silicone rubber can be sprayed, but large amounts cannot.

Examples 4 to 12 In the same manner as in Example 1, the following compositions were prepared. The silicone rubber and HMDS are the same as in Example 1.

[0022]

Table 2 4 (Control) Silicone rubber 3% HMDS 97% 5 (Control) Ketoprofen 8% Ethyl alcohol 18.4% HMDS 73.6% 6 Ketoprofen 8% Ethyl alcohol 18.4% Silicone rubber 0.7% HMDS 72.9% 7 Ketoprofen 8% Ethyl alcohol 18.4% Silicone rubber 2.2% HMDS 71.4% 8 (Control) Ketoprofen 2.5% Ethyl alcohol 19.5% HMDS 78% 9 Ketoprofen 2.5% Ethyl Alcohol 19.5% Silicone rubber 0.8% HMDS 77.2% 10 Ketoprofen 2.5% Ethyl alcohol 19.5% Silicone rubber 1.6% HMDS 76.4% 11 Ketoprofen 2.5% Ethyl alcohol 19.5 % Silicone rubber 2.3% H DS 75.7% 12 Ketoprofen 19.5% 2.5% ethyl alcohol silicone rubber 2.4% HMDS 75.6%

Examples 13-15 The following compositions were prepared as in Example 1 to demonstrate the compatibility of silicone rubber and volatile excipients with other conventional pharmaceutical volatiles. Silicone rubber and HM
DS is the same as that of the first embodiment.

[0024]

Table 3 13 Ketoprofen 1.2% Menthol 0.03% Ethyl alcohol 7.5% Silicone rubber 2.7% HMDS 88.5% 14 Ketoprofen 1.2% Menthol 0.03% Stearyl alcohol 0.03% Ethyl Alcohol 7.5% Silicone rubber 2.7% HMDS 88.5% 15 Ketoprofen 1.2% Menthol 0.03% Oleic acid 0.07% Ethyl alcohol 7.5% Silicone rubber 2.7% HMDS 88.5% All formulations were clear.

Examples 16 to 17 The following components were mixed in a solid formulation beaker to prepare the following solid compositions. The silicone rubber and HMDS are the same as in Example 1.

[0026]

Table 16 16 (Control) Carbopol 980NF 0.68% NaOH 1N 2.47% Ketoprofen 2.45% Ethyl alcohol 13.8% HMDS 16.3% Deionized distilled water 64.4% 17 Carbopol 980NF 0 0.68% NaOH 1N 2.56% Ethyl alcohol 13.8% Ketoprofen 2.43% Silicone rubber 2.85% HMDS 13.3% Deionized distilled water 64.3%

Examples 18-21 In the evaporation of the formulation
Influence of Silicone Rubber Content In the same manner as in Example 1, the following formulation was prepared. The silicone rubber and HMDS are the same as in Example 1.

[0028]

Table 5 Comparative Example Example Example Example Example Example 18 19 20 21 Silicone 0 wt% 10.7 wt% 5.1 wt% 2.94 wt% 1.07 wt% Rubber HMDS 100 wt% 89.3 wt% 94.9 wt% 97.06 wt% 98.93 wt%

Weighed 130 μl of each of these formulations
In a closed balance at room temperature for 47.2 c.
Sprayed over an m ² metal cup. The distance from the spray nozzle to the cup was 5 cm in each case. The cup was weighed before spraying, 3 seconds after spraying, and every 30 seconds thereafter until all of the HMDS contained in the formulation had evaporated. The time for 90% of the HMDS to evaporate (T90) was recorded for each formulation. The control (0% by weight of silicone rubber) was used to calculate the increase in T90 resulting from the increase in silicone rubber weight.
Table 6 shows the results.

[0030]

[Table 6]

These results show that increasing the silicone rubber content above about 1% by weight sharply reduces the HMDS evaporation rate. A rubber content of about 3% by weight represents the maximum increase in T90 generally accepted in the industry. Above this silicone rubber content, the evaporation of volatile excipients is adversely affected by the loading of the silicone rubber, which limits the practical benefits of topical formulations.

Example 22 Silicone Rubber on Skin
The subject's forearm was washed, and then the formulation of Example 4 was sprayed on several locations. The formulation was allowed to dry for 15 minutes.
The FT-IR / ATR cell was used to analyze the IR spectrum at each spray location. At different points on the sprayed skin, for different times (from 20 minutes to 8
(During time), the IR spectrum was analyzed. The IR of the washed forearm skin was used as a control blank. The percentage of silicone remaining on the skin was calculated relative to the height of the specific silicone peak height (1255 cm ^-1 ) / the specific skin peak height (1538 cm ^-1 ) of the blank test. Table 7 shows the results.

[0033]

[Table 7]

These results clearly show that the substantivity of the silicone rubber decreases with time. However, even after 8 hours, about 25% of the silicone rubber still remains. In contrast, HMDS is not detected on the skin even after 10 seconds of spraying.

Example 23 Ketop with silicone rubber
The forearms of parenchymal subjects with lofen were washed and then sprayed at 10 locations with about 40 mg of the formulations of Examples 8 (control) and 12. The formulation was allowed to dry for 15 minutes. At the selected time (as shown in Table 4), SEBUTAPE (Monaderm Laborat)
ory) The application and peeling of 5 pieces to one place of the treated skin were repeated. The tape was analyzed for spectrum using an FT-IR / ATR cell. The IR of one piece of unused tape was used as a control. The peak height of the drug on each tape was compared to the peak height of unused SEBUTAPE to determine the relative amount of ketoprofen on the tape. The relative amounts for the five tapes were then further added and the results were compared over time. Table 8 shows the results.

[0036]

[Table 8]

These results show the substantivity of the drug on the skin using the formulation of the present invention. Control formulation (8)
In, a significant amount of drug remains on the skin 20 minutes after application, and some is detected even after 3 hours. However, the drug is not detected after 6 hours. In contrast,
40 minutes after application of the formulation (12) of the invention, a significant amount of the drug remains on the skin, some still being detected on the skin after 8 hours.

Example 24 On the skin with silicone rubber
The ketoprofen retention effect of the subject was washed forearms,
About 40 mg of the 10 and 11 formulations were sprayed. 5 minutes after application, the treated skin was treated with SEBUTAPE (M
onaderm Laboratory) was repeated. The IR spectrum of the tape was analyzed using an FT-IR / ATR cell. Unused tape was used as a control. The ratio of the drug peak height to the unused SEBUTAPE peak height (reference) was measured for each tape. The results are as shown in Table 9.

[0039]

[Table 9]

Example 25 On the skin with silicone rubber
The subject's forearm was washed with ketoprofen , and then sprayed with about 40 mg of the formulations of Examples 5 (control), 6 and 7. Example 5,
Approximately 40 mg of Formulations 6 and 7 are referred to as 100%
It was also applied to SEBUTAPE. Approximately 40 mg of placebo formulation (no drug) was also applied to SEBUTAPE as a blank test. Five minutes after application, application and peeling of SEBUTAPE (Monaderm Laboratory) to and from the treated skin were repeated until no drug remained. Each piece of tape was transferred to a 50 ml Erlenmeyer flask containing a magnetic stir bar. 10 ml of ethanol was dispensed into this flask and stoppered. The flask was placed in a 40 ° C. oven for 1 hour at 55 ° C.
Magnetic stirring was performed at 0 rpm. The amount of drug in the extract was then calculated using a 253 nm UV absorbance meter,
% Compared to the reference. The results are as shown in Table 10.

[0041]

[Table 10]

The results show that the control requires 10 tape strips before removing the drug placed on the skin (5), while the formulation containing 2.2% silicone rubber ( In 7), there are 17 tape pieces. In the control, the first piece of tape removes about 50% of the drug (5),
For a formulation containing 0.7% silicone rubber, it is 28% (6), and for a formulation containing 2.2% silicone rubber, it is 8% (7). This clearly shows the peel resistance (substantivity) of the formulation of the present invention.

Example 26 After application in solid formulation
The forearm of the substantive subject of the medicament was washed, and then 40 mg of the formulations of Examples 16 (control) and 17 were applied to two places, respectively.
3 hours and 6 hours after application, SEBUTAPE
(Monaderm Laboratory) The application and peeling of 7 pieces to one place on the skin treated with the control (16) and one place on the skin treated with the formulation (17) of the present invention were repeated. The drug remaining on the skin after exfoliation was collected using a piece of absorbent cotton and alcohol. About 40 mg of each formulation was applied as a 100% control on a piece of Cebutape (SESBUTAPE). Each piece of tape and cotton wool was transferred to a 50 ml Erlenmeyer flask containing a magnetic stir bar. 10 ml of ethanol was dispensed into this flask and stoppered. The flask was placed in an oven at 40 ° C., and magnetic stirring was performed at 550 rpm for 1 hour. The amount of drug in the extract was then calculated at 253 nm using a UV absorptiometer and compared to a 100% control. Table 11 shows the results.

[0044]

[Table 11]

These results indicate that the formulation (17) of the present invention
3 h after application shows no significant difference in parenchyma between the control and control (16). (Amount of drug collected on equivalent tape pieces and total amount of drug collected for both prescriptions) However, 6 hours after application, the prescription of the present invention (1
7) is more substantial than the control formulation (16). It is exemplified by the following facts. That is, while 72% of the drug applied together with the prescription (17) of the present invention remains, it is 61% in the control (16). About 5
1% was removed with 4 strips of tape while the control (1
6) is 94%, and for the formulation (17) of the present invention, after the seventh tape strip, about 13% of the drug remains on the skin, whereas in the control (16), about 13% of the drug remains. 1%.

 ──────────────────────────────────────────────────続 き Continuation of the front page (71) Applicant 591199888 300 ROUTE DES CRETES, 06560 VALBONNED CEDEX, FRANCE (72) Inventor Louis Michel Jacques Aguadische France, 06560 Valbonne, Route de Cannes 925, Clos de Blasset 3

Claims (5)

[Claims] 1. A composition comprising from 0.1 to 25% by weight of a pharmaceutically active agent;
A composition for topically delivering a pharmaceutically active agent to a human or animal body, comprising 0.1 to 3% by weight of silicone rubber and 72 to 99.8% by weight of a pharmaceutical excipient. object. 2. The silicone rubber of claim 1 wherein said silicone rubber has a molecular weight of 200,000 or more and comprises dimethylpolysiloxane end-capped with dimethylhydroxysilyl groups.
A composition according to claim 1. 3. The composition of claim 1, wherein said pharmaceutical excipient comprises hexamethyldisiloxane. 4. The pharmaceutical excipient comprises excipients used to form the composition in a delivery system selected from the group consisting of creams, lotions, ointments, emulsions and gels. A composition according to claim 1. 5. A composition comprising from 0.1 to 25% by weight of a pharmaceutically active agent;
0.1 to 3% by weight of silicone rubber and 72 to 99.8
By weight with a pharmaceutical excipient to form a composition;
A method of forming a substantially thin film, comprising applying the composition to a substrate to form a substantially thin film on the substrate.