CN2827419Y - Delivery apparatus - Google Patents

Abstract

The utility model relates to a medicine delivery device which releases active reagents in a vaginal cavity in the controlled manner for a long time so as to treat or cure diseases which are associated with a vaginal cavity or areas adjacent to the vaginal cavity. The delivery device comprises an applicator which is composed of high internal phase emulsion so that the delivery device adheres to the surface of a mucous membrane of an organism, mainly to the inner layer of a vaginal cavity. The delivery device maintains the high internal phase emulsion at the temperature of 86 DEG F for at least a month while the degradation or the instability of the emulsion does not exist.

Description

Delivery apparatus

Technical field

This utility model relates to a kind of delivery apparatus that comprises applicator, and this delivery system shows the controlled release of active agent, and this delivery system has high internal phase ratio, and it is applicable in vaginal canal and uses.

Background technology

Be used to prevent, control, the Drug therapy of the female reproductive system of diagnosis and cure diseases generally includes pharmaceutically active agent is delivered to vaginal canal and adjacent organs.Usually, reagent is made gel, foam, emulsifiable paste, suppository, solution tablet or other form well known in the art.Yet these delivery form do not show with active agent in a controlled manner, especially are delivered to vaginal canal in three hours or longer time, and the ability of high-caliber bioadhesion and the high level stability under high temperature and low temperature environment is provided simultaneously.

The biological characteristics of vagina and adjacent domain makes treatment and reagent is delivered to the vaginal canal difficulty.For example, vaginal canal shows aqueous environment, and wherein the pH of liquid is 4.5-5.5, and internal temperature is about 98.6  (37 ℃).The environment of vaginal canal also helps microorganism, as antibacterial and fungus, comprises zymic growth, and foreign particle, and Tathagata is from the seminal fluid of sexual intercourse and retaining of menstruation residue.The characteristics of vaginal canal are significant physical deformation abilities, as sexual intercourse or insert physical deformation due to the tampon.

Be generally used for treating disease in the vaginal canal with uncomfortable such as the reagent of antifungal.Yet the pharmacy of these reagent and chemism all do not reach the optimal level of its effectiveness.The reason of this restriction of effectiveness partly or entirely is because the defective of existing delivery apparatus causes.In fact, existing delivery apparatus be not presented at three hours or in longer time with safest mode releasing pharmaceutically active agent, and do not cause the ability of the problem relevant with bioadhesion or the excessive release of active pharmaceutical ingredient.For example, after inserting vaginal canal, existing delivery apparatus generally almost begins dissolving immediately, disperses or liquefaction.Therefore, these delivery apparatus usually to the bioadhesion of vaginal wall seldom.

Conventional delivery apparatus contains a large amount of propylene glycol in prescription, it is in order to increase the availability of the medicine that is mixed.Active pharmaceutical compounds is at solvent sample molecule, and the biomembranous penetration capacity that penetrates of the increase that provides as the possible dissolving in the propylene glycol and by propylene glycol is favourable.This deduction that is used for the delivery apparatus of mucosa may be by exaggerative, in the time of particularly in being used for vaginal canal.The moisture character of environment provides the optimal conditions for the whole body absorption of dissolved active pharmaceutical compounds.The chemical compound that comprises the lytic activity pharmaceutical agents of high concentration can increase the whole body absorbability of this reagent.Although this is a desired effects in some cases, in the treatment local mucous membrane infects, removes beneficial drug possibility extended treatment state, and in some cases, may cause the whole body of active pharmaceutical compounds to absorb the disadvantageous level that reaches from adjacent domain.

In addition, the delivery apparatus that is subjected to comprising an amount of infringement to excessive propylene glycol may have some physical property.For conventional Emulsion, an amount of extremely excessive propylene glycol can increase dissolving and the liquefaction of this delivery apparatus in the vaginal canal hydrophilic environment.For unique more emulsion systems, the propylene glycol that comprises higher concentration can cause the physical instability under room temperature and the high temperature.

Therefore, the Emulsion of conventional and unique delivery apparatus can not provide optimum vaginal canal internal therapy.In this area the controlled-release delivery need for equipment that vagina and uncomfortable optimum treatment are provided is not met.Therefore, existence is to the demand that is not met of following delivery apparatus, and described delivery apparatus provides the continuous release of pharmaceutically active agents to vaginal canal, particularly this system in long-time, in at least three hours, provide pharmaceutical active, and high bioadhesion level is provided.And then, exist in the art reducing the demand that is not met of the delivery apparatus of propylene glycol ratio in the prescription.

Summary of the invention

The present invention by provide a kind of be used for vaginal canal overcome the problems referred to above and other problem than the more effective delivery apparatus of existing delivery apparatus.Particularly, first embodiment of the present invention provides a kind of delivery apparatus for the treatment of the woman's vaginal cavity fungal infection, it comprises the imdazole derivatives active agent of effective dose and one or more makes the acceptable excipient of pharmacy that the site of this activating agent in vaginal canal discharges in a controlled manner, and wherein the internal phase emulsions of this delivery apparatus is than greater than 70%.Second embodiment of the present invention is a kind of method for the treatment of the vagina fungal infection, described method comprises to giving the delivery apparatus that a kind of imdazole derivatives active agent that contains effective dose of vaginal canal and one or more make the acceptable excipient of pharmacy that the site of activating agent in vaginal canal discharges in a controlled manner, and wherein the internal phase emulsions of this delivery apparatus is than greater than 70%.

More particularly, this delivery apparatus comprises compactness, prefill, the i.e. applicator of usefulness that is used for to body chamber administered medicaments, and described applicator has long and narrow body, and it has near-end to bestow end and far-end prehension end.Body has enough length with the desired site administered medicaments in selected body chamber.The proximal part of long and narrow body forms reservoir, and it is suitable for holding the medicine of scheduled volume.The distal portions of long and narrow body forms piston chamber.Locking device is positioned at the end of bestowing of this reservoir, and propulsion plant is positioned at its far-end, the junction in reservoir and piston accessory chamber.Telescopic piston rod accessory have be attached thereto in order to limit scalable prolongation and to prevent the scalable destructive stopping means of the piston rod of accessory, telescopic piston rod accessory links to each other with propulsion plant.Grasping device is used to operate described telescopic piston rod accessory.The following operation of this applicator: hold its prehension end, and make the closing end pro-and be inserted into the expectation the chamber in.By grip device the piston accessory is withdrawn into the border of stopping means, then piston accessory near-end ground for this long and narrow body is passed, thereby produced pressure, the open closed assembly is also bestowed medicine in reservoir.

With reference to accompanying drawing, other characteristics of the present invention will become clear.Hereinafter or by after realizing that the present invention learns, it is clear that other advantage of the present invention and new feature also will become to those skilled in the art by research.

Description of drawings

Fig. 1 is the side view of applicator of explanation principle of the present invention, even with the position display of compactness;

Fig. 2 is the exploded view of the applicator of Fig. 1, shows enclosure portion, cylinder part, first piston assembly, second piston component (forming the piston accessory together), and gripper.

The specific embodiment

As depicted in figs. 1 and 2, applicator 20 has and bestows end 22 and prehension end 24.Cylindricality assembly 26 has medicament reservoir part, piston accessory chamber part as the main body of this applicator, and grasping surface part 32.Closed component 34 closes at the external diameter that dwindles 36 of cylindricality assembly 26 slidably.Piston accessory 38 has the first piston assembly 40 that has piston portion 42, and second piston component 44, and piston accessory 38 closes in the cylindricality assembly 26 slidably; Piston portion 42 is positioned at medicament reservoir part 28, and the remainder of piston accessory 38 is positioned at piston accessory chamber part 30.Gripper 46 provides for second piston element 44.

The invention provides a kind of delivery apparatus, it has the high internal phase emulsions ratio of 70%-90%, and preferably, non-lipid wherein accounts for about 70 volume %-90 volume % of this device mutually.Compare with the prescription of prior art, prescription of the present invention has reduced about 20% to about 80% with the amount of propylene glycol, and is preferred about 25%, and still keeps the same high internal phase emulsions ratio of 70%-90%.

In addition, the present invention can keep at least one month under the temperature of 86 , be preferably greater than one month, more preferably greater than two months, and more preferably greater than half a year, more preferably greater than 1 year, for example three to five years.Stability increases makes the present invention can be stored in the environment that easily is affected by climate change or in the extreme temperature environment.This improvement is commonly referred to " storage life improvement ".

The invention provides a kind of delivery apparatus that is used for vaginal canal, wherein this delivery apparatus is sent pharmaceutically active agent to vaginal canal in a controlled manner in long-time.In a variant of the present invention, be at least 3 hours for a long time, in most of the cases, the time can continue 10 days or longer.The feature of this delivery apparatus is the High Internal Phase Emulsion ratio.This delivery apparatus is preferably by accounting for the emulsion that this hydrophilic component that installs 70 volume % is formed.

This delivery apparatus provides reparation, safeguards and treats disease or the uncomfortable reagent that influences vaginal canal." vaginal canal " also comprises adjacent domain, and for example, it comprises vagina, female urethra, as the organ and the tissue of urethral orifice, vaginal canal opening part, and by the accessible genitals in this chamber.The feature of this delivery apparatus also is to adhere to (being also referred to as " bioadhesion ") to vaginal canal wall and adjacent domain, comprises the ability of epithelial cell, tissue and organ.

This delivery apparatus not only discharges active agent, and its also in a controlled manner release reagent to obtain optimum absorption.Therefore, this reagent can be absorbed in absorption or action site, performance pharmacology or other effect present in an amount at least sufficient to cause the reaction of the expectation consistent with the intrinsic property of this reagent, and in the time of expectation this reaction are maintained proper level.Delivery apparatus preferable feature of the present invention is that the active agent controlled release is to acceptor site, action site, absorption site or use the site, and realizes the effect of expectation in this site.This delivery apparatus is unmixing in water preferably, and uses harmless in vaginal canal.

Delivery apparatus of the present invention can comprise the combination of active and nonactive ingredient (being also referred to as " excipient " herein).Non-active ingredient for example, is used for dissolving, suspendible, multiviscosisty, dilution, emulsifying, stabilisation, anticorrosion, protection, painted, flavoring and adjustment active component, makes it become safe in utilization, convenient or uses acceptable available and effective preparation.Active component for example, can account for the 1.0%-10% of this delivery apparatus total weight percent, preferably accounts for about 1.5%-2.5%, more preferably accounts for approximately 2.0%, and the medicine or the chemotherapy of vaginal canal are provided.Thereby these active component of filling a prescription discharge in a controlled manner.The active component that comprises active agent can be any approval or the composition that is used for the treatment of, prevents, cures or alleviate any disease of vaginal canal.The main active of delivery apparatus of the present invention is an imdazole derivatives, and they are natural antifungal and antibacterial.Imdazole derivatives can be the form of acceptable salt of pharmacy or nitrate.The example that can be used for imdazole derivatives of the present invention is miconazole nitrate, Nitric acid butoconazole, Oxiconazole Nitrate, Metronidazole mononitrate., nitric acid terconazole (triaconazole) and nitric acid clotrimazole, and other imdazole derivatives as known in the art.Preferred imdazole derivatives in the delivery apparatus of the present invention is a Nitric acid butoconazole.

This delivery apparatus can be made up of unit cell.These unit cell are basic, indivisible repetitives of this system.Unit cell has inner phase and foreign minister, and it represents the inner phase and the foreign minister of this delivery apparatus respectively.Inner phase can be non-lipoid, can be miscible with water, and can comprise water, glycerol or their combination.Inner phase can be heterogenetic, and can be solution, suspension, emulsion or their combination, and can contain at least a portion active agent.The foreign minister can be a continuous phase, and is lipoid, promptly contains organic compound, is included in the water insoluble but be dissolved in neutral fat, fatty acid, wax, phospholipid, vaseline, fatty acid monobasic alcohol ester and the mineral oil of alcohol, ether, chloroform or other fat solvent.

Can carry out general classification to this delivery apparatus, for example, suspension, suppository, foam in Emulsion, Emulsion/dispersion, two Emulsion, the Emulsion, or other classification well known in the art.Therefore, in embodiments of the invention, the form of this delivery apparatus can change.In one embodiment of the invention, this system is that composition is the Emulsion of cream forms.Other embodiment of the present invention comprises lotion, gel, foam and various Emulsion.In addition, other embodiment of the present invention comprises about 5000-750000 centipoise, liquid, semisolid and the solid of preferred 350000-550000 centipoise.Optimizing viscosity can be so that this delivery apparatus be implemented in the maximum bioadhesion on the vaginal canal.

This delivery apparatus is the form of medium emulsion or high internal phase ratio preferably, and is interior to than the ratio that is foreign minister and inner phase.How many contained inner phase of this ratio representative system contains in the percent by volume of system.In embodiments of the invention, this ratio can be 70 volume %, preferred at least 75 volume %, and more preferably at least 80 volume % more preferably reach 90 volume %.

Release characteristics of the present invention is the high inner phase Emulsion product that the present invention shows.Emulsifying agent, adjuvant, emulsifying agent or other excipient, as glyceryl monostearate, a glyceryl isostearate, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, and general oils, glyceride, sucrose ester, sorbitan esters, polysorbate, stearoyl lactate (stearoyllactylates), lecithin and other similar compounds, produce the emulsifying bead of forming by non-active ingredient.This bead contains the reservoir of active agent.These beads slowly disperse when using, that is, this bead is tending towards searching and comprises surface or thin film, and local disperse (that is, in vaginal canal) of this bead, contain " film " that discharges the bead of active agent in a period of time with the controlled release pattern thereby form.This process continues for some time, and for example, therefore is commonly referred to " controlled release " to reaching ten days or longer in three hours.

Bio-adhesive properties of the present invention is the high inner phase Emulsion product that the present invention shows.The emulsifying bead volume of being made up of excipient (example is listed in above) is little, but has high relatively surface area.Surface area and surface nature make this bead by multiple physical bond molecular force, as Van der Waals force or hydrogen bond and with people's tissue interaction.These adhesions are compared with less continuous phase or the outer phase volume of forming emulsion owing to high emulsion internal-phase ratio strengthens, and the number of the bead that these are minimum is very many.

The application is incorporated in and authorized Riley on November 30th, 1999, the United States Patent (USP) 5,266 of Jr. (" Riley "), and 329 is for referencial use.Delivery apparatus of the present invention and conventional delivery apparatus, at least one variation that is included in disclosed delivery apparatus in the patent of Riley is the stability of delivery apparatus.

Propylene glycol can influence the stability and the diffusion velocity of this delivery apparatus.Can comprise propylene glycol in the prescription of this delivery apparatus as solvent, it helps the active component of this delivery apparatus of dissolving, as imidazoles, as Nitric acid butoconazole.The known propylene glycol that in conventional formulation, uses 5.00 weight %.

In embodiments of the invention, the amount of the propylene glycol of existence can be preferably about 3.5 to about 3.85 weight % for about 1.0 to about 4.0 weight %, most preferably be about 3.75 weight %, that is, compare with 5.00 weight % in the delivery apparatus of the prior art of believing, the amount of propylene glycol has reduced about 25%.

The delivery apparatus of some embodiment at least of the present invention improves delivery apparatus well known in the art by the amount that reduces propylene glycol in the prescription.The minimizing of propylene glycol does not influence the internal phase emulsions ratio, and it is greater than 70%, and it does not hinder Emulsion to form yet.In addition, the minimizing of the propylene glycol of use has realized unpredictable result, and it is highly beneficial and favourable for medicine and medical domain.

Delivery apparatus of the present invention has overcome the restriction of prior art.For example, the amount that reduces propylene glycol is improved the diffusion velocity of the active pharmaceutical agent in the delivery apparatus when keeping its favourable pharmaceutical properties and effectiveness.

In addition, the delivery apparatus of embodiment of the present invention shows physical property, as bioadhesive be separated and the suitable relevant physical stability that may increase of anti-dispersibility of maintenance in long-time.The physical property of total increase of delivery apparatus of the present invention provides more effective product to consumer, and the treatment of more optimizing in vaginal canal, that is, the diffusion velocity control of the active pharmaceutical ingredient of improvement is stablized and had to Emulsion, thereby more effective.At last, the stability of increase may provide the storage life of increase in uncontrollable zone in temperature, and then makes that more delivery apparatus can be used by more people.

Exemplary of the present invention has been described according to above-mentioned advantage.Should be understood that these embodiment only are illustrations of the present invention.Many variants and modification are tangible to those skilled in the art.

Claims (4)

1. delivery apparatus that is used for to the vaginal canal administered medicaments, be characterised in that it comprises: compact, the prefill medicine, the i.e. applicator of usefulness (20), described applicator has long and narrow body (26), it has near-end to bestow end (22) and far-end prehension end (24), wherein the proximal part of this long and narrow body (26) forms the medicament reservoir (28) of the medicine that comprises prefill, and the distal portions of this long and narrow body forms piston chamber (30); What locking device (34) was positioned at this medicament reservoir (28) bestows end (22), and piston portion (42) then is positioned at its far-end, is positioned at the joint of medicament reservoir (28) and piston accessory chamber (30); Be connected with the telescopic piston rod accessory (38) of stopping means (43); And grip device (32).

2. the delivery apparatus of claim 1, wherein the medicine of this prefill is the form that is selected from Emulsion, Emulsion/dispersion, two Emulsion and the suspension in Emulsion or mixture.

3. the delivery apparatus of claim 1 should pre-medicine of filling be that viscosity is about 5000 liquid or semisolid forms to about 750000 centipoises wherein.

4. the delivery apparatus of claim 3 should pre-medicine of filling be that viscosity is about 350000 liquid or semisolid forms to about 550000 centipoises wherein.

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