MXPA99002485A - Unit dose chlorhexadine gluconate (chg) applicator having extended chg shelf life - Google Patents

Abstract

A unit dose chlorhexadine gluconate (CHG) applicator is disclosed wherein a unit dose of the CHG is contained in a hermetically sealed manually crushable glass ampule that has an internal volume of the CHG. The CHG in the ampule has an effective shelf life of at least 24 months. The glass ampule of the applicator is preferably protected by a flexible cover to protect the user's hand during manual crushing of the ampule to release the CHG therefrom. In one embodiment of the invention, a cylindrical glass ampule is housed within a tubular, flexible synthetic resin cover which has a porous applicator swab at one end thereof. Upon crushing of the glass ampule, the CHG released therefrom impregnates the swab allowing the user to spread the CHG across an area to be sanitized. In a second embodiment of the invention, a cylindrical glass ampule is received within a semi-cylindrical, open-sided body cover having a flange portion that mounts a sponge-gripping members on the ampule permitting the user to crush the ampule by squeezing themembers toward one another whereupon the CHG is released from the ampule and impregnates the sponge swab. The swab soaked with the CHG antiseptic may be rubbed across an area to be sanitized.

Description

CLORHEXADINE GLUCONATE DOSE UNIT APPLICATOR THAT HAS A LIFE OF AQUA GLUCONATE PROLONGED CHLORHEXADINE BACKGROUND OF THE INVENTION The present invention relates to an antiseptic composition and particularly to an antiseptic of chlorhexadine gluconate (CHG), which is packaged as a dosage unit in a manner that facilitates the application of the antiseptic while at the same time exhibiting a life of shelf longer than previously obtained with the CHG jets prepared in conventional pieces of cloth. DESCRIPTION OF THE PREVIOUS TECHNIQUE CHG has long been used as an antiseptic composition to sterilize selected areas of a patient's skin prior to injecting medicinal agents or in preparation for other medical or surgical procedures. The application of the antiseptic solution to the patient's skin has been facilitated by packing it in a variety of configurations including bulk dose volumes in plastic bottles and single dose volumes in a multi-layer sheet unit enclosing a cloth soaked with amounts of a dose unit of the active solution.

REP. 29456 In order to commercialize any CHG packaging of another drug, it was necessary to demonstrate the stability in the selected closed container during the proposed shelf life period. In view of the fact that a shelf life of two to three years is desirable, the result of the stability studies before marketing may be substantial. Heat accelerated studies are commonly used to reduce the time required to establish shelf lives of two to three years. In heat-accelerated studies, drug packages are exposed to elevated temperatures, often around 40 ° C, for three to six months. The recovery of the drug that is still within specifications at the conclusion of these studies, allows the projection of stability at room temperature for periods beyond those actually measured, under ambient temperature conditions. By using heat accelerated studies, therefore, it is possible to defend a proposed shelf life of two years with studies that had a real duration substantially less than two years. It has been known for some time that CHG is subject to chemical instability under high temperature conditions. Government regulatory agencies have expressed reservations about the acceptance of accelerated shelf life studies for CHG packaging, as support for extended shelf life projections. This reluctance of the government is believed to be based mainly on the concept that the CHG will suffer significant deterioration at high temperatures. Thus, the accelerated test with significant molecular degradation was thought to be not predictive of stability and, therefore, would not be successful in projecting stability at ambient conditions beyond the actual environmental measurement period. The manufacturers of CHG dose unit packages faced requirements to establish the shelf life projected without the assistance of accelerated heat studies. The CHG instability under high temperature conditions also presented a problem with respect to packaging sterilization by conventional ethylene oxide (OET) techniques at elevated temperature. During sterilization with OET, the CHG vessels are typically placed in an enclosed space and the temperature is raised to a level of approximately 120 to 140 ° F (approximately 49 to 60 ° C) in the presence of an OET atmosphere. Then, a vacuum is imposed in the space to remove the OET from inside the packaging, while the temperature of the space is allowed to reach room temperature. This sterilization procedure of the complete package usually requires two to three days. This degree of heat exposure can result in significant CHG degradation in typical fabric dose unit configurations. It has been known for a time that fabrics containing rayon produce reductions in recoverable CHG, wherein said reductions demonstrate an apparent saturability, which could be consistent with physical absorption. Efforts were made to produce stable dose unit packages of CHG using cloth materials for patches that did not contain rayon; however, these efforts were not completely successful. Even with the use of cloth materials without rayon, the instability to heat exposure was significant. The mechanism of the instability of CHG to heat has not been fully defined, although it could be attributable to an unavoidable property of a molecular structure that has a variety of opportunities for rotary or vibrational movements and / or ring opening. Based on all previous knowledge, it is reasonable to conclude that instability under high temperature conditions is an inherent property of the CHG molecule that can not be controlled by packaging techniques.

BRIEF DESCRIPTION OF THE INVENTION During empirical studies related to the effects of temperature on the CHG products, it was unexpectedly discovered that the stability of the CHG under high temperature conditions could be extended over that of the typical dose unit packing configurations, by a packing configuration involving the retention of the CHG solution with a hermetically sealed glass ampule, without contact between the solution and the cloth applicator until the time of use. Therefore, a primary objective of the present invention is to provide a CHG dose unit applicator that exhibits a significantly longer CHG shelf life than previously available for CHG dose unit packages, even after the sterilization with ETO of the applicator under a relatively high temperature. The present invention involves the discovery that, by confining a CHG dose unit in a hand-broken dose unit vial or glass vial that has been hermetically sealed using a flame at the end of the glass vial, the antiseptic composition had a significantly longer shelf life than could be achieved to date with multi-layer fabric package preparations for CHG. In particular, the present invention involves the surprising discovery that when a CHG dose unit is packaged in a glass vial having an internal volume not significantly greater than the volume of the dose unit, the glass vial containing a CHG dose unit can be subjected to an accelerated shelf life test at elevated temperature, without significantly adversely affecting the CHG inside the glass ampoule. Another important object of the present invention is to provide a CHG dose unit applicator having an extended CHG shelf life, which facilitates the application of the antiseptic solution by virtue of the fact that the user can simply break the glass vial containing the CHG to empty the antiseptic into an integral porous fabric, and then rubbing that fabric on the portion of the skin of the patient to be sterilized. A protective cover is provided on the glass vial containing the CHG solution to protect the user's hands from the glass particles created by breaking the dose unit glass container. In one embodiment of the applicator, the vial has a cylindrical shape and the protective cover therein also has a cylindrical configuration and has a porous tip or swab on one end, which is immersed in the antiseptic solution by fracturing the container filled with the liquid. Then, the user can apply the antiseptic agent to the skin of a patient, simply by rubbing the soaked swab tip over the area to be sterilized. In a second embodiment of the present invention, a cylindrical vial containing the antiseptic composition of CHG is housed within a protective cover having a central body section enclosing the vial and two wing-like grasping elements on opposite sides. of the cover body and, therefore, of the ampule. The cover body has an elongated opening that communicates to the inside thereof with a sponge-like element, which is an integral part of the assembly. Thus, by manipulating the wings-like elements toward each other, the cover body is compressed by fracturing the glass ampule and releasing the CHG composition to effect the impregnation of the sponge element with the antiseptic solution. The sponge element soaked with the antiseptic, then, can be rubbed on the part of the skin of the patient to be sterilized. It is thought that the CHG dose unit applicator of the present invention, has a better shelf life over the previously available CHG dispensers, by virtue of the fact that the active ingredient in the dosage unit form is introduced and maintained within a substantially inert environment that does not change significantly during the sterilization of the package or in extended storage periods under varying ambient temperature conditions. Favorable storage conditions are obtained by incorporating a CHG dose unit into a hermetically sealed glass vial having an integral volume that is not significantly greater than the volume of the antiseptic dose. The initially open end of the glass ampoule is subjected to a flame to melt the glass and cause its coalescence for closure. The flame also serves to increase the temperature of the atmosphere immediately above the CHG dose unit of the vial, such that when closing the vial, the volume of the vial above the dose unit has a content of Oxygen very limited due to the expansion of the air over the dose unit at the time of hermetically sealing the glass ampoule. In certain cases, the rarefied atmosphere above the dose unit in the vial may have a negative pressure as the ampoule is cooled after the sealing process. As a consequence, CHG remains completely isolated during storage of conditions or materials such as a piece of cloth, which could otherwise lead to degradation or deterioration of the active material. In addition, the glass vial has a much smaller surface area per total volume of CHG, i.e., total contact area per total volume of active agent, as compared to the folded pieces of cloth enclosed in a cover. In addition, the glass has an atmosphere more devoid of oxygen than the pieces of cloth. The ability to increase the temperature of the atmosphere over the CHG during the sealing of the container using a flame, as described, decreases the amount of oxygen present in the final atmosphere that is in contact with the dose unit of antiseptic solution in the Glass ampoule, compared to the packaging methods available for the preparation of pieces of cloth packed in bent covers, is also believed to have an effect to prevent degradation of the CHG during storage of the antiseptic dose unit. Independently of the complete protection of the CHG from the reduction of the recoverable active ingredient, the ease of application is retained since the user only needs to manually break the glass container and directly over the area to be cleaned. Some tests have shown that the CHG packaged in the manner described here, has a shelf life predicted of at least two years and, under most environmental conditions, must be greater than two years. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a perspective view of a CHG dose unit applicator constructed in accordance with a preferred embodiment of the present invention, wherein the parts have been cut and sectioned for clarity purposes.; and Figure 2 is a perspective view of a CHG dose unit applicator constructed in accordance with a second preferred embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED MODALITIES Initially with reference to Figure 1 of the drawings, a CHG dose unit applicator designated with the numeral 10, in its preferred embodiment, includes a breakable glass vial or ampule 12 with a general cylindrical configuration. The bulb 12 is closed at both ends where the initially open end has been hermetically sealed by applying a flame to the filling end, to melt it and cause the glass at such filling end to coalesce and form a hermetic seal. The internal volume of the vial 12 is not significantly greater than the volume of CHG introduced and stored in the sealed glass container 12. The applicator 10 includes a cover body assembly designated with the numeral 4 for the vial 12, which is constructed and configured in such a way that it can be manufactured for example, by molding the assembly from a synthetic resin material such as a high density polyethylene. The semi-cylindrical wall structure 16 of the assembly 14 is flexible and of a size and shape sufficient to substantially receive and house the elongated cylindrical bulb 12. The flange flange panel 18 is integral with the peripheral edge of the wall structure 16 , it projects outwards and serves to assemble a rectangular porous sponge element 20. In Figure 1 it can be seen that the flange panel 18 has an elongated opening 22 that communicates the interior of the wall structure 16 with the sponge 20. A pair of opposing gripping elements, angularly inclined upwards 24 and 26, also integral with the wall structure 16 along the longer lengths of the elongated aperture 22, have a wing-like configuration and are juxtaposed in such arrangement. so that when the gripping elements 24 and 26 are clamped between the fingers of the user and tightened toward each other, the wall structure 16 it is compressed thereby exerting compressive forces on the side wall of the container 12 and causing fracture of the container 12. When the vial 12 breaks, the CHG solution contained therein is released, so that it can flow into the opening 22 and Soak sponge 20 with the active ingredient. Then, the user can apply the ingredient to the skin area of the patient to be sterilized by holding the wing-like elements 24 and 26 to manipulate the applicator 10. The applicator 10 is preferably packaged in a protective envelope for sanitary purposes, the which can be made of a paper layer on one side of the applicator and a thin sheet of transparent plastic film on the other face thereof. The general packing, then, is subjected to sterilization with OET in the manner previously described. It should be understood in this regard that the applicator 10, if desired, may be constructed and used in accordance with the applicator structure shown and described in US Patent No. 5,538,353 entitled Liquid Applicator, issued July 23, 1996 to the applicant the present and which is incorporated herein by reference specifically. Alternatively, a dose unit applicator of CHG 110 may be constructed in accordance with Figure 2 of the drawings. In the embodiment of the present invention shown in Figure 2, the elongated cylindrical glass vial or container 112 is completely housed within a cylindrical and flexible elongated synthetic resin cover 114 of a size that can completely enclose the container 112. Porous applicator 120 is fitted within one end of applicator cover 114, extends outwardly and desirably rests on an adjacent end of ampoule 112. Applicator 110, also preferably, it is packaged in an envelope having a paper layer and a thin plastic film layer, which are laminated together and subjected to OTS sterilization at elevated temperature. A user who wishes to disinfect an area of the selected skin of a patient simply must break the ampoule 112 by applying adequate forces to the protective cover 114 to break the side wall of the glass container. The antiseptic solution released from the rapidly rotating bulb is absorbed by the porous tip 120, which allows the user to apply the antiseptic solution directly to the skin area of the patient to be disinfected. In the preparation of dose unit applicators 10 and 110, it is first necessary to provide a thin-walled glass vial having a normally open end. The glass vial preferably has a cylindrical configuration and a wall thickness that allows it to be easily broken between the fingers of the user. The internal volume of the glass vial should not be significantly greater than the volume of the antiseptic inside it. After filling each container, the normally open end is sealed to obtain a hermetically sealed container. Preferably an open flame is used to effect the sealing of the initially open end of the glass vial. The flame is applied to the glass container for a sufficient time to melt the glass and cause it to coalesce and seal the container. The flame used to effect the hermetic sealing of the glass vial has the secondary purpose of increasing the temperature of the gaseous atmosphere above the CHG dose unit inside the glass vial, such that the close the vial and then cool the atmosphere above the CHG dose unit, the gaseous atmosphere inside the vial above the CHG agent has a slightly lower pressure than the pressure that existed inside the glass vial before sealing airtight. In view of the decrease in the density of the gaseous atmosphere above the antiseptic agent CHG inside the vial, there is less available oxygen to react with the CHG as time passes, compared to what would be the case if it were retained the atmospheric pressure inside the ampule on the CHG at the time of sealing said ampule. By cooling the hermetically sealed glass body containing the antiseptic agent, the filled glass ampoule can be placed within a respective cover assembly 14 or 114, in which the product is ready to be packaged and distributed. A unit dose of CHG is generally about 1 ml and nominally contains about 2% weight / volume of CHG. If the percent weight / volume ratio of the CHG falls to a level of approximately 1.8% or less during storage over a period of 24 months, the product is not considered to have an acceptable storage life. Thus, in certain cases, CHG providers in dosage unit forms, in the past, provided an excess of CHG solution over that specifically required, for CHG solution over that specifically required, to provide an initial volume of 1. ml of the active ingredient, in order to compensate for the loss of the active ingredient during storage. It has not been discovered, contrary to the recognized procedures of the above test protocols, that the shelf life of a CHG dose unit stored in an applicator can be determined by subjecting the filled glass vial to an elevated temperature for a significant period of time. less than the actual demonstrable shelf life of the product. For example, when you want a product to have a shelf life of at least 24 months, shelf life under normal environmental conditions can be predicted by subjecting the applicator containing one unit of CHG dose at an elevated temperature of about 40 ° C for no more than about six months and normally no more than three months. The accelerated heat test of the pieces of cloth is not equally predictive of the shelf life, because under the high temperature conditions of the test, the CHG undergoes undesirable degradation and deterioration unrelated to the conditions and effects of storage.

EXAMPLE I The shelf life of multilayer sheet packages each containing a piece of cloth and a CHG dose unit was tested using the 40 ° C elevated temperature test described above and was also tested at room temperature. about 72 ° F (22 ° C). In order to provide a more accurate determination of the degree of degradation or deterioration, if any, of the CHG stored in the packs of sheets each having a piece of cloth without rayon, samples containing 1.0 ml, 1.1 ml and 1.2 ml were prepared. of CHG per unit dose of packaging with fabric. In addition, CHG recovery tests were carried out before being introduced to the respective sheets, followed by a sealing of the edges of the packages. Packets of leaves containing the active ingredient and pieces of cloth were placed in a protective envelope of paper and plastic film and then subjected to sterilization with OTS at a temperature of approximately 120 to 140 ° C (49-60 ° C) in accordance with the standard procedure previously described. Stability tests showed that the dosage forms exhibited a significant reduction in the recovery of CHG, at a time as early as one month after starting the test. Not unexpectedly, the - l Dosage forms filled with a larger volume of CHG yielded a greater recovery of CHG. Each of the packages of sheets containing a piece of cloth and which were kept at room temperature, had a slower continuous loss of CHG than the packages of sheets with pieces of cloth subjected to the environmental test of accelerated stability at 40 ° C. However, in all cases the tests showed that the shelf life of the CHG was adversely affected by the presence of the pieces of cloth, even when such pieces of cloth did not contain rayon. Stability of Clorhexadine Gluconate in Cloth Applicators (Cloth Clips)% w / w CHG1 Between day 0 and day 20 of environmental conditions, the samples were subjected to a hot sterilization with OTS.

EXAMPLE II The shelf life of CHG in a glass vial such as the vials designated 12 and 112 of Figures 1 and 2 of the drawings herein were also tested using the 40 ° C high temperature test. previously described and were also tested at an ambient temperature of approximately 72 ° F (22 ° C). These test samples were subjected to an OET sterilization temperature between days 0 and 20 in the same manner as the tests described in Example 1. The results of these accelerated tests were as follows: SEPP - Ampoule of Figure 2 of the drawings of the present > "FREPP - Ampoule of Figure 1 of the drawings of the present It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.

Claims (14)

1. The invention having been described as above, the following is claimed as property: 1. A dose applicator of a bactericidal agent having extended shelf life, characterized in that it comprises: one unit dose of chlorhexadine gluconate; and a manually breakable glass vial containing the dosage unit of chlorhexadine gluconate, wherein the internal volume of the vial is not significantly greater than the volume of the dose unit, wherein the vial has a limb that was closed at time to fill it with chlorhexadine gluconate and an extremity that is sealed with heat after filling the ampule with chlorhexadine gluconate, to obtain a hermetic closure of the vial.
2. 2. A dose applicator of a bactericidal agent according to claim 1, characterized in that the heat-sealed extremity of the ampoule was subjected to a flame sufficient to melt the glass and provide the seal.
3. 3. A dose applicator of a bactericidal agent according to claim 1, characterized in that the glass vial has a general cylindrical shape and the ends are at opposite ends thereof.
4. 4. A dose applicator of a bactericidal agent according to claim 1, characterized in that the ampoule containing the dose unit of chlorhexadine gluconate was subjected to sterilization at elevated temperature after the introduction of the chlorhexadine gluconate into the interior of it and the hermetic sealing of the vial.
5. 5. A bactericidal agent dose applicator according to claim 1, characterized in that a flexible cover is provided on the glass ampoule to protect the hands of the user during the manual breaking of the ampoule to release the chlorhexadine gluconate from the same
6. 6. A bactericidal agent dose applicator according to claim 5, characterized in that elements associated with the flexible cover are provided, to cause the chlorhexadine gluconate to be released directionally from the ampule by manually breaking the latter.
7. 7. A dose applicator of a bactericidal agent according to claim 5, characterized in that the cover has an opening that is in communication with the outer surface of the ampoule and with a porous applicator positioned on the cover and extending through of the opening.
8. 8. A dose applicator of a bactericidal agent according to claim 5, characterized in that the vial is elongated and the cover has an opening therein that extends along the length of the vial and an applicator element of the applicator. sponge in the cover that extends along the length of the opening therein, ready to receive the chlorhexadine gluconate released from the ampule when it breaks.
9. 9. A method for preparing a dose handler of a bactericidal agent having an extended shelf life, characterized in that it comprises: providing a manually breakable glass vial having a closed end and an initially open end; introducing a dosage unit of chlorhexadine gluconate into the ampule, wherein the ampule has an internal volume not significantly greater than the volume of the dosage unit of chlorhexadine gluconate; and subjecting the initially open extremity of the ampoule to heat at a temperature and for a time sufficient to melt the glass, defining the initially opened extremity and forming a closure thereof upon cooling of the heated glass, to obtain a hermetic seal of the gluconate of chlorhexadine inside the vial.
10. A method for preparing a bactericidal agent dose applicator according to claim 9, characterized in that the step of subjecting the glass ampoule containing the dose unit of chlorhexadine gluconate is included., to a high temperature sterilization before sealing the ampoule by heat.
11. A method for preparing a bactericidal agent dose applicator according to claim 10, characterized in that the step of sterilization includes subjecting the glass ampoule containing the dose unit of chlorhexadine gluconate, at a temperature of about 120. at about 140 ° F (from about 49 to about 60 ° C).
12. 12. A method for preparing a dose applicator of a bactericidal agent according to claim 9, characterized in that the heat sealing of the initially open extremity of the ampule is effected by subjecting said extremity to an open flame.
13. A method for preparing a dose applicator of a bactericidal agent according to claim 9, characterized in that the step of placing a flexible cover on the hermetically sealed glass vial is included to protect the hands of the user during manual breaking of the vial to release the chlorhexadine gluconate in it.
14. 14. A method for preparing a dosage unit of chlorhexadine gluconate and for performing an accelerated test to verify that the dose unit has an extended shelf life of at least twenty-four months, characterized in that it comprises the steps of: providing a glass ampoule manually breakable having a closed limb and an initially open limb; introducing a dosage unit of chlorhexadine gluconate into the ampule, wherein the ampule has an internal volume not significantly greater than the volume of the dosage unit of chlorhexadine gluconate; subject the initially open extremity of the vial to heat at a temperature and for a time sufficient to melt the glass, defining the initially open extremity and forming a closure thereof upon cooling of the heated glass, to obtain a hermetic seal of the chlorhexadine gluconate inside the vial; place the hermetically sealed vial in a high temperature environment of approximately 40 ° C for approximately three months; and then breaking the vial, recovering a sample of the chlorhexadine gluconate contained therein and testing such sample to determine the degree of degradation, if any, of the dosage unit of chlorhexadine gluconate. SUMMARY OF THE INVENTION The present invention relates to a dose unit applicator of chlorhexadine gluconate (CHG) (Figure 1), wherein a CHG dose unit is contained in a hermetically sealed, hand-breakable glass ampule, which has an internal volume of CHG. The CHG of the vial has an effective shelf life of at least 24 months. The glass vial of the applicator is preferably protected by a flexible cover to protect the hands of the user during the manual breaking of the vial to release the CHG therein. In one embodiment of the present invention, a cylindrical glass vial is housed within a flexible tubular synthetic resin shell, which has a porous applicator at one end. By breaking the glass vial, the CHG released from it impregnates the porous applicator, allowing the user to apply the CHG in an area to be disinfected. In a second embodiment of the present invention, a cylindrical glass vial is inside a semi-cylindrical body cover with open sides, which has a flange portion containing sponge fasteners in the vial, allowing the user break the bulb by pressing the elements towards each other, whereby the CHG is released from the ampoule and impregnates the sponge. The sponge soaked with the CHG antiseptic can be applied to an area to be disinfected.