MX2007000109A

MX2007000109A - Delivery system.

Info

Publication number: MX2007000109A
Application number: MX2007000109A
Authority: MX
Inventors: Thomas C Riley; R Saul Levinson; Robert C Cuca
Original assignee: Drugtech Corp
Priority date: 2004-07-08
Filing date: 2005-07-08
Publication date: 2007-03-26
Also published as: WO2006016869A1; ES1060042Y; BRPI0513066A; FR2872702B3; CN1771023A; AU2005269844A1; CN102188375A; MXPA04007681A; WO2006014572A1; CA2572919A1; RU2007104782A; RU2379027C2; EP1765452A1; EP1765452A4; NL1026978C1; NZ552406A; CZ15068U1; FR2872702A3; ES1060042U; AU2004100776A4

Abstract

A pharmaceutical delivery system that releases an active agent in a controlledmanner for an extended period in the vaginal cavity to treat or cure ailments associatedwith the vaginal cavity or proximal areas. The delivery system includes an applicatorwhich is composed of a high internal phase emulsion, allowing the delivery systemto adhere to the mueosal surfaces of the body, primarily the lining of vaginalcavity. The delivery system can maintain the high internal phase emulsion ata temperature of 86 F for at least one month, without decomposition or instabilityof the emulsion.

Description

RELEASE SYSTEM FIELD OF THE INVENTION The present invention relates to a pharmaceutical delivery system that includes an applicator demonstrating controlled discharge of active agents, having an elevated internal or external phase ratio value, and which is suitable for use in the vaginal cavity. .

BACKGROUND OF THE INVENTION The medical treatment of the female reproductive system for the prevention, control, diagnosis and cure of diseases usually involves the release of pharmaceutically active agents into the vaginal cavity and nearby organs. In general, the agents are applied in the form of gels, foams, creams, suppositories and dissolving tablets or other forms generally known in the art. However, these release forms have not demonstrated the ability to release active agents into the vaginal cavity in a controlled manner, particularly for periods of three hours or longer, while providing a high level of bioadherence and a high level of stability in environments that either have high or low temperatures. The biological characteristics of the vagina and nearby areas make it difficult to treat and release agents to the vaginal cavity. For example, the vaginal cavity exhibits an aqueous environment, with fluids having a pH in the range of 4.5 to 5.5 and an internal temperature of approximately 37 ° C (98.6 ° F). The environment of the vaginal cavity is also conducive to the growth of microorganisms, such as bacteria and fungi, including yeast, and the retention of foreign particles, such as seminal fluid resulting from sexual contact, and menstrual debris. The vaginal cavity is also characterized by the capacity for considerable physical deformation, such as that which results from sexual contact or the insertion of tampons. Agents, such as fungicides, have been commonly used to treat conditions and afflictions in the vaginal cavity. However, the pharmaceutical and chemical activity of these agents has not achieved an optimum level of effectiveness. This efficiency limitation is due, in part or completely, to the inadequacy of the currently available release systems. In fact, the currently available delivery systems have not shown the ability to release a pharmaceutically active agent in an optimally safe manner for periods of three hours or longer, without encountering problems related to bioadherence or excessive release of the active pharmaceutical ingredient. For example, the delivery systems that are available begin either generally to be solubilized, dispersed or liquefied almost immediately after insertion into the vaginal cavity. In this way, the delivery systems usually have minimal bioadherence to the walls of the vagina. Conventional release systems that have a large proportion of propylene glycol in the formulation have been used to improve the availability of the incorporated drug. The advantage that is taken both from the potential solubilization of the active pharmaceutical compound in a solvent-like molecule such as propylene glycol and the increased penetration potential produced by propylene glycol through the biological membranes. This extrapolation to delivery systems for mucosal membranes can be exaggerated, particularly when used in the vaginal cavity. The aqueous nature of the environment provides optimal conditions for systemic absorption of solubilized active pharmaceutical compounds. The inclusion of high concentrations of compounds which solubilizes active pharmaceutical agents can increase the potential systemic absorption of that agent. Although in some cases this is a desired effect, in the treatment of local mucosal infections removal of the beneficial drug from the immediate area may prolong the treatment regimen, and in some cases may cause systemic absorption of the active pharmaceutical compounds to achieve that are not beneficial. further, there may be physical aspects of the release system that are affected by the inclusion of moderate to excessive amounts of propylene glycol. For conventional emulsions, moderate to excessive amounts of propylene glycol can be added to the solubilization and liquefaction of the delivery system in the hydrophilic environment of the vaginal cavity. For additional single emulsion systems the inclusion of higher levels of propylene glycol can lead to physical instability at both ambient and elevated temperatures. As a result, emulsions from conventional and unique delivery systems can not provide optimal treatment in the vaginal cavity. There is an inadequate need in the art for a controlled discharge release system that provides optimal treatment of vaginal ailments and afflictions. Accordingly, there is an inadequate need for a delivery system that provides a consistent delivery of a pharmaceutically active agent to the vaginal cavity, specifically a system that allows pharmaceutical activity for an extended period of time, such as at least three hours, and provides high levels of bioadherence. In addition, there is an inadequate need in the art for a delivery system that reduces the proportion of propylene glycol in the formulation.

SUMMARY OF THE INVENTION The present invention overcomes the aforementioned problems, as well as others, by providing a delivery system for the vaginal cavity that has increased efficacy over currently available delivery systems. In particular, a first embodiment of the present invention provides a delivery system for the treatment of fungal infections of the vaginal cavity of women comprising an effective amount of an active agent derived from imidazole and one or more pharmaceutically acceptable excipients which allow the active agent discharged in a controlled manner to a site in the vaginal cavity, wherein the delivery system is an emulsion that exhibits an internal or external phase ratio of more than 70%. A second embodiment of the present invention is a method for treating a vaginal fungal infection in a woman, comprising administering to the vaginal cavity a delivery system having an effective amount of an active agent derived from imidazole and one or more pharmaceutically acceptable excipients. which allow the active agent to be discharged in a controlled manner to a site in the vaginal cavity, wherein the delivery system is an emulsion exhibiting an internal to external phase ratio of more than 70%. More specifically, the delivery system comprises a compact, pre-filled applicator ready to be used for dispensing a medicament into a body cavity including an elongate body having a near-dispensing end and a distal fin end. The body is of a sufficient length to distribute medicament to a desired location within a selected body cavity. A close portion of the elongate body forms a reservoir adapted to contain a predetermined amount of the medicament. A distal portion of the elongate body forms a plunger housing. The closing means are disposed at the dispensing end of the reservoir, and the driving means are disposed at their distal end, at the junction of the reservoir and the piston assembly housing. A plunger rod assembly folded like a telescope, which has arresting means associated therewith for limiting the telescopic extension and preventing telescopic collapse of the plunger rod assembly, is connected to the drive means. Assist means is provided to operate the folded plunger rod assembly as a telescope. The applicator is opened by keeping it in the handle end and inserting the closing end first into the desired cavity. The plunger assembly is removed through the grasping means to the limit of the stopping means, and then the plunger assembly is pushed proximally relative to the elongate body, whereby the pressure is created to open the closure member and distribute the medication from the deposit. Other features of the present invention will be apparent together with the accompanying drawings. Additional advantages and novel features of the invention will be more apparent to those skilled in the art about the examination of the following or about learning by practicing the invention.

BRIEF DESCRIPTION OF THE DRAWINGS In the attached drawing sheet: FIGURE 1 is a side elevation view of a medicament applicator illustrating the principles of the present invention, shown in the compact position, ready to be used; FIGURE 2 is an exploded view of the medicament applicator of FIGURE 1, showing a closure portion, a cylindrical body portion, a first plunger member and a second plunger member (together they form a plunger assembly) and a member of the asidor. As illustrated in FIGS. 1 and 2, a medicament applicator 20 has a dispensing end 22 and a feeder end 24. A cylindrical member 26 serves as the main body of the applicator, having a reservoir portion of the medicament, a plunger assembly housing portion, and a portion 32 of the fastener surface. A closure member 34 is slidably received on a portion 36 of reduced outer diameter of the cylindrical member 26. A plunger assembly 38, having a first plunger member 40 with a piston portion 42 and a second plunger member 44, is slidably received within a cylindrical member 26; the piston portion 42 is disposed within the medicament reservoir portion 28 and the rest of the piston assembly 38 is disposed within the piston assembly housing portion 30. A finger 46 is provided for the second plunger member 44.

DESCRIPTION OF THE PREFERRED MODALITIES The present invention provides a delivery system that provides an emulsion exhibiting an elevated internal to external phase ratio between 70% to 90%, preferably wherein the non-lipoidal phases comprise from about 70% to 90% by volume of the system. The formulations of the present invention reduce the amount of propylene glycol of the commercially available bioadhesive systems, preferably from about 20% to about 80%, more preferably about 25%, compared to the prior art formulations, while still maintaining the same ratio of internal emulsion elevated from 70% to 90%. In addition, the present invention can support a temperature of 30 ° C (86 ° F) for at least one month, preferably more than one month, more preferably more than two months, more preferably more than six months, and more preferably more than one year, for example, three to five years. The increased stability allows the present invention to be stored in environments susceptible to climatic changes or extreme temperatures. This improvement is generally known as "improved shelf life". The invention provides a delivery system for the vaginal cavity, wherein the system releases pharmaceutically active agents into the vaginal cavity in a controlled manner for an extended period of time. In a variation of the present invention, the extended period of time is at least three hours, and in most cases, the period of time may last as long as ten days or more. The release system is characterized by a high internal emulsion ratio. The delivery system is preferably an emulsion comprised of at least 70% hydrophilic constituents per system volume. The delivery system provides agents that restore and maintain a healthy vaginal environment, and cure conditions or afflictions that affect the vaginal cavity. The "vaginal cavity" also includes nearby areas, for example, it includes the vagina, the female urinary tract, such as the urethral orifice, organs and tissues at the beginning of the vaginal cavity, as well as reproductive organs accessible through The cavity. The delivery system is also characterized by a capacity to adhere (otherwise known as "bioadhering") to the walls of the vaginal cavity and nearby areas, including epithelial cells, tissue and organs. The delivery system does not discharge only an active agent, but discharges the agent in a controlled manner to obtain optimal absorption. In this way, the active agent is made available for absorption, pharmacology or other effect at an absorption or action site in an amount sufficient to elicit a desired response consistent with the intrinsic properties of the agent and which provides for the preservation of this agent. response at an appropriate level for a desired period of time. The delivery system of the present invention is preferably characterized by controlled release of the active agent to a receptor site, site of action, site of absorption or site of use and achievement of the desired effect at that site. The delivery system is preferably non-miscible in water and is not dangerous for use in the vaginal cavity. The delivery system of the present invention may comprise a combination of active and non-active pharmaceutical ingredients (also generally referred to herein as "excipients"). Non-active ingredients, for example, serve to solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve, protect, color, flavor and mold active ingredients within an applicable and effective preparation that is safe, convenient and otherwise acceptable. for use. The active ingredients, which, for example, can constitute 1.0% to 10% of the total weight percentage of the release system, preferably from about 1.5% to 2.5%, more preferably around 2.0%, provide medical or chemical treatment of the vaginal cavity. These active ingredients are formulated to be discharged in a controlled manner. The active ingredients comprising the active agent can be any of those ingredients that are approved for or used for the treatment, prophylaxis, cure or mitigation or any disease of the vaginal cavity. The primary active ingredients of the delivery system of the present invention are imidazole derivatives, which are antifungal and antibacterial in nature. The imidazole derivatives can be presented in the form of pharmaceutically acceptable salts, such as nitrates. Examples of imidazole derivatives that can be used in this invention include miconazole nitrate, butoconazole nitrate, oxiconazole nitrate, metronidazole nitrate, terconazole nitrate and clotrimazole nitrate, among others known in the art. A preferred imidazole derivative in the delivery system of the present invention is butoconazole nitrate. The delivery system may be comprised of internal phase unit cells. These unitary cells are the basic unit, not divisible, of repetition of the systems. The internal phase may be non-lipoidal, ie, miscible with water, and may comprise water, glycerin or combinations thereof. The internal phase may be multiphasic and may be a solution, suspension, emulsion or combination thereof, and may contain at least a portion of the active agent. The external phase can be a continuous and lipoidal phase, that is, containing organic compounds comprising neutral fats, fatty acids, waxes, phosphatides, petrolatum, fatty acid esters of monoprotic alcohols and mineral oils that are insoluble in water, but soluble in alcohol, ether, chloroform or other fatty solvents. The release system can be conveniently classified, for example, as emulsions, emulsions / dispersions, double emulsions, suspensions within emulsions, suppositories, foams or other classification known in the art. Accordingly, in the embodiments of the invention, the delivery systems may vary in shape. In one embodiment of the present invention, the system is an emulsification of ingredients in a cream form. Other embodiments of the present invention include lotions, gels, foams and various emulsifications. The preferred embodiment has a viscosity range from about 5,000 to 2,000,000 centipoises. In addition, other embodiments of the present invention include liquids, semi-solids and solids having a viscosity range of from about 5,000 to 750,000 centipoise, preferably 350,000 to 650,000 centipoise. Optimizing the viscosity may allow the delivery system to achieve maximum bioadherence in the vaginal cavity. The delivery system is preferably in the form of an emulsion of a medium or elevated internal phase ratio, which is the ratio between the external phase and the internal phase. The relationship value represents how much the internal phase of the system comprises in terms of percentage per volume of the system. In the embodiments of this invention, the ratio can be at least 70% by volume, preferably at least 75%, more preferably at least 80% and even more preferably up to about 90%. The controlled discharge characteristic of the present invention is a product of the high internal phase emulsion exhibited by the present invention. Emulsifiers, auxiliary agents, emulsifying agents or other excipients, such as glycerol monostearate, glycerol monoisostearate, methylparaben, propylparaben and in general oils, glycerides, sucrose esters, sorbitan esters, polysorbates, stearoyl lactylates, lecithin and others similar compounds create emulsified globules comprised of non-active ingredients. The globules contain deposits of the active ingredients. These globules are slowly dispersed in the application, that is, the globules tend to search for the contained surfaces or membranes, and the globules are dispersed locally (ie, in the vaginal cavity), so that a "film" is formed that contains globules that release the active agent, in a form of controlled discharge, over time. This process occurs for a period of time, such as, for example, three hours or up to ten days or more, and is therefore generally known as "controlled discharge".

The bioadherence characteristic of the present invention is an elevated internal phase emulsion product exhibited by the present invention. The emulsified globules, which are comprised of excipients (examples of which are listed above), are small in volume, but have a relatively high surface area. The surface area and the nature of the surfaces allows the globules to interact with human tissue by a number of molecular forces of physical bonds such as Van der Waals or hydrogen bonding forces. These binding forces are intensified due to the high internal phase ratio of the emulsion, a large number of these globules being very small when compared to the small volume of the continuous or external phase comprising the emulsion. The present application incorporates for reference in its entirety the North American patent No. 5,266,329, which was published on November 30, 1999 for Riley, Jr. ("Riley"). At least one change between the delivery system of the present invention and conventional delivery systems, including those described in Riley, is the stability of the delivery system. Propylene glycol can affect the stability and diffusion rate of the delivery system. The propylene glycol can be included in the formulation of the delivery system that serves as a solvent that helps dissolve the active ingredient in the delivery system, for example, imidazole, such as butoconazole nitrate. It has been known in conventional formulations using propylene glycol at 5.00 weight percent. In embodiments of the present invention, the propylene glycol may be present in an amount of from about 1.0 to about 4.0 weight percent, more preferably from about 3.5 to about 3.85 weight percent, and more preferably about 3.75 weight percent, is say, the amount of propylene glycol is reduced by about 25% when compared to the 5.00 weight percent believed to be required in prior release systems. An exemplary embodiment for the delivery system of the present invention is as follows: Butoconazole Nitrate Cream, 2.0% The delivery system of at least one of the embodiments of the present invention improves upon delivery systems known in the art by reducing the amount of propylene glycol in the formulation. The reduction of propylene glycol does not affect the internal phase emulsion ratio, which is greater than 70%, nor does it prevent the formation of an emulsion. In addition, the reduction of propylene glycol used achieves unexpected results that are highly advantageous and beneficial to pharmaceutical and medicinal techniques. The delivery system of the present invention overcomes the limitations of the prior art. For example, reducing the amount of propylene glycol improves the rate of diffusion of the active pharmaceutical agent in the delivery system while maintaining its beneficial pharmaceutical properties and efficacy. In addition, the delivery system of the embodiments of the present invention has demonstrated physical attributes such as bioadhesion and potentially increases physical stability in relation to phase separation and the ability to remain in place by resisting dispersion for extended periods of time. The total increased physical attributes of the delivery system of the present invention provide a more effective product for the consumer and a more optimal treatment in the vaginal cavity, ie, the emulsion is stable and has improved control over the diffusion rates of the ingredient active pharmaceutical in such a way that it is more effective. Finally, the increased stability provides increased shelf life in areas where the temperature can be uncontrolled, also allowing the release system to be used by a larger number of people. Exemplary embodiments of the present invention have now been described in accordance with the above advantages. It will be appreciated that these examples are only illustrative of the invention. Many variations and modifications will be apparent to those skilled in the art.

Claims

CLAIMS 1. A delivery system, characterized in that it comprises: an effective amount of an active agent; and one or more pharmaceutically acceptable excipients which allow the active agent to be released in a controlled manner to a site in the vaginal cavity, wherein the delivery system is an emulsion having an internal to external phase ratio of more than 70% after Store at a temperature of 30 ° C (86 ° F) for at least a month.
2. The delivery system according to claim 1, characterized in that the active agent is an antifungal agent.
3. The delivery system according to claim 2, characterized in that the antifungal active agent constitutes approximately 1.5% to 3% of the total weight percentage of the delivery system.
4. The delivery system according to claim 2, characterized in that the antifungal active agent is an imidazole derivative.
5. The release system according to claim 1, characterized in that the delivery system is comprised of at least 70% hydrophilic constituents in volume of the delivery system.
6. The release system according to claim 4, characterized in that the delivery system is comprised of at least 80% hydrophilic constituents in volume of the delivery system.
The release system according to claim 5, characterized in that the delivery system is comprised of up to about 90% hydrophilic constituents in volume of the delivery system.
8. The delivery system according to claim 1, characterized in that the system exhibits bioadhesion to the walls of the vaginal cavity.
The delivery system according to claim 1, characterized in that the delivery system is in a form selected from the group consisting of an emulsion, emulsion / dispersion, double emulsion and a suspension within an emulsion or mixture.
The delivery system according to claim 4, characterized in that the imidazole derivative is selected from the group consisting of miconazole, butoconazole, oxiconazole, metronidazole and clotrimazole or a pharmaceutically acceptable salt thereof.
11. The delivery system according to claim 10, characterized in that the imidazole derivative is butoconazole or the pharmaceutically acceptable salt thereof.
The release system according to claim 1, characterized in that the delivery system contains about 4.0 weight percent or less of propylene glycol.
The delivery system according to claim 1, characterized in that the delivery system contains about 3.75 weight percent or less of propylene glycol.
The delivery system according to claim 1, characterized in that the delivery system contains propylene glycol in a range of about 1.0 weight percent to about 4.0 weight percent.
The release system according to claim 1, characterized in that the delivery system has an internal phase emulsion ratio of more than 70% after being stored at a temperature of 30CC (86 ° F) for more than one month .
The release system according to claim 1, characterized in that the delivery system has an internal phase emulsion ratio of more than 70% after being stored at a temperature of 30 ° C (86 ° F) for at least two months.
The delivery system according to claim 1, characterized in that the delivery system has an internal phase emulsion ratio of more than 70% after being stored at a temperature of 30 ° C (86CF) for at least six months .
The release system according to claim 1, characterized in that the delivery system has an internal phase emulsion ratio of more than 70% after being stored at a temperature of 30 ° C (86 ° F) for at least one year.
19. The release system according to claim 1, characterized in that the delivery system allows the controlled release of the active agent to the site in the vaginal cavity for at least three hours.
The release system according to claim 1, characterized in that the delivery system is in the form of a liquid or a semi-solid having a viscosity from about 5,000 to about 2,000,000 centipoise.
The release system according to claim 20, characterized in that the delivery system is in the form of a liquid or a semi-solid having a viscosity from about 5,000 to about 750,000 centipoise.
22. The delivery system according to claim 21, characterized in that the delivery system is in the form of a liquid or a semi-solid having a viscosity from about 350,000 to about 650,000 centipoise.
23. The delivery system according to claim 1, characterized in that the active ingredient is presented in a range from about 1% to about 10% of the total weight percentage of the delivery system.
24. The delivery system according to claim 4, characterized in that the active agent derived from imidazole is presented in a range from about 1.5% to about 3% of the total weight percentage of the delivery system, and further comprises: propylene glycol in a range from about 1.0% to about 4.0% of the total weight percentage of the release system.
25. A delivery system suitable for treating fungal infections of a female vaginal cavity, characterized in that it comprises: about 30.0 to about 50.0 weight percent water about 30 to about 50 weight percent sorbitol solution about 3.0 to about 4.0 weight percent propylene glycol; about 0.02 to about 0.08 weight percent disodium edetate; about 1.5 to about 2.5 weight percent butoconazole or the pharmaceutically acceptable salt thereof; about 7.0 to about 9.0 weight percent mineral oil; about 2.0 to about 3.5 weight percent polyglyceryl-3-oleate; about 2.0 to about 3.5 weight percent glyceryl monisostearate about 0.2 to about 0.80 weight percent microcrystalline wax; about 0.5 to 1.5 weight percent of hydrophobic silicon dioxide; about 0.1 to about 0.3 weight percent methylparaben; and about 0.02 to about 0.08 weight percent of propylparaben.
The release system according to claim 24, characterized in that the delivery system comprises: about 37,819 weight percent water about 39,978 weight percent sorbitol about 3,750 weight percent propylene glycol; about 0.050 weight percent disodium edetate about 2000 weight percent butoconazole or the pharmaceutically acceptable salt thereof about 8.032 weight percent mineral oil about 2.713 weight percent polyglyceryl-3-oleate about 2.713 percent by weight weight of glyceryl monosaterate about 0.452 weight percent microcrystalline wax about 1.013 weight percent hydrophobic silicon dioxide about 0.180 weight percent methylparbene; and about 0.050 weight percent propylparaben.
27. A delivery system suitable for treating fungal infections of the female vaginal cavity, characterized in that it consists essentially of: about 35 to 45 weight percent of water; about 35 to about 45 weight percent sorbitol solution; about 3.0 to about 4.0 weight percent propylene glycol; about 0.02 to about 0.08 weight percent disodium edetate; about 1.5 to about 2.5 weight percent butoconazole or the pharmaceutically acceptable salt thereof; about 7.0 to about 9.0 weight percent mineral oil; about 2.0 to about 3.5 weight percent polyglyceryl-3-oleate; about 2.0 to about 3.5 weight percent glyceryl monosaterate; about 0.02 to about 0.08 weight percent microcrystalline wax; about 0.5 to 1.5 weight percent of hydrophobic silicon dioxide; about 0.1 to about 0.3 weight percent methylparaben; and about 0.02 to about 0.08 weight percent of propylparaben.
28. A method to treat a vaginal fungal infection in a woman, characterized in that it comprises: administering to the vaginal cavity a delivery system having an effective amount of an active agent derived from imidazole and one or more pharmaceutically acceptable excipients which allow the active agent to be discharged in a controlled manner to a site in the cavity vaginal, where the release system has an internal phase emulsion ratio of more than 70% after being stored at a temperature of 30 ° C (86 ° F) for at least one month.
29. The method according to claim 28, characterized in that the active agent is released for at least three hours.
30. The method according to claim 28, characterized in that the active agent derived from imidazole is butoconazole or the pharmaceutically acceptable salt thereof.
31. The method according to claim 28, characterized in that the effective amount of the imidazole-derived active agent constitutes about 1.5% to about 3% of the total weight percentage of the delivery system.
32. The method according to claim 28, characterized in that the active agent derived from imidazole is present in an amount ranging from about 1.5% to about 3% of the total weight percentage of the delivery system and the propylene glycol is present in a amount ranging from about 1.0% to about 4.0% of the total weight percentage of the delivery system.
33. A method for making an adequate delivery system for treating fungal infections of the female vaginal cavity, characterized in that it comprises: mixing an effective amount of the antifungal active agent and about 1.0 to about 4.0 weight percent of propylene glycol.
34. A method of preparation according to claim 33, characterized in that the antifungal active agent is an imidazole derivative.
35. A processing method according to claim 34, characterized in that the imidazole derivative is selected from a group consisting of miconazole, butoconazole, oxiconazole, metronidazole and clotrimazole or a pharmaceutically acceptable salt thereof.
36. A method of preparation according to claim 35, characterized in that the imidazole derivative is butoconazole or the pharmaceutically acceptable salt thereof.
37. A processing method according to claim 36, characterized in that the butoconazole or the pharmaceutically acceptable salt thereof is in a range from about 1.5 to about 3 weight percent.
38. A method for reducing the discharge profile of an active pharmaceutical agent from the site discharge system characterized in that it reduces the propylene glycol level of such on-site discharge system.
39. The method according to claim 38, characterized in that the propylene glycol is below four percent by weight.
40. The method according to claim 39, characterized in that the propylene glycol is below 1 weight percent.
41. The method according to claim 38, characterized in that the propylene glycol is completely removed.
42. A delivery system which comprises an applicator, characterized in that it comprises: a compact applicator, pre-filled, ready to be used, for distributing a medicament to the vaginal cavity, the applicator has an elongated body having a close distribution end and a distal finger end; the body is of a sufficient length to distribute medicament to a desired location within the vaginal cavity, a close portion of the elongated body forms a reservoir adapted to contain a predetermined amount of medicament; a distal portion of the elongated body forms a plunger housing; closure means are disposed at the dispensing end of the reservoir, and driving means are disposed at their distal end, at the junction of the reservoir and the piston assembly housing; a plunger rod assembly folded like a telescope having stop means associated therewith for limiting the telescopic extension and preventing telescopic collapse of the plunger rod assembly connected to the drive means, and ripper means for operating the assembly of plunger rod folded like a telescope; the medicament has an effective amount of an active agent and one or more pharmaceutically acceptable excipients which allow the active agent to be released in a controlled manner to a site in the vaginal cavity, where the delivery system has an internal phase emulsion ratio of more than 70% after being stored at a temperature of 30 ° C (86 ° F) for at least one month.
43. The delivery system according to claim 42, characterized in that the active agent is an antifungal.
44. A method for increasing the shelf life of an internal phase, water-based emulsion of a delivery system suitable for treating fungal infections of the vaginal cavity of a woman who is exposed to extreme temperatures, characterized in that it comprises: maintaining propylene glycol less than 4% of the total weight of the system.
45. The use of an internal phase, water-based emulsion of a delivery system having an amount of propylene glycol of less than 4% of the total weight of the system to treat fungal infections of the vaginal cavity of a woman.
46. A delivery system, which comprises an applicator, characterized in that it comprises: an effective amount of an active agent; and one or more pharmaceutically acceptable excipients which allow the active agent to be released in a controlled manner to a site in the vaginal cavity, wherein the delivery system has an internal phase emulsion ratio of more than 70% after being stored at a time. temperature of 30 ° C (86 ° F) for at least a month.