PACKAGE FOR A PHARMACEUTICAL PRODUCT AND METHOD OF STERILISING THE PACKAGE

Abstract: A package for a pharmaceutical product, particularly a liqud ophthalmic composition, such as an ophthalmic solution, gel or ointment, for example a tube or a dropper bottle assembly used to dispense said product, wherein said package is made of a specific form of polypropylene and wherein said package shows after an autoclaving processing of at least 121 DEG C and for at least 20 minutes no deformation such as shrinkage or blowing-up and retains a sufficient high squeezability in order to dispense said product. Also claimed is a method for sterilizing a pharmaceutical package comprising the steps: placing closed package into an autoclaving chamber, adjusting the temperature and the pressure in said chamber as a function of time in accordance to the prerequisites of the material of said package, wherein a counter pressure is generated in said chamber and wherein this is regulated electronically via computer, and wherein said counter pressure avoids a deformation such as a blowing-up of said package.

Description: PACKAGE FORAPHARMACEUTICAL PRODUCTAND METHOD OF STERILISING THE PACKAGE The invention relates to a package for a pharmaceutical product, particularly a tube or a dropper bottle assembly used to dispense liquids, aerosols or strings, and a method of sterilizing said package. Particularly dropper bottle assemblies are used to dispense a variety of liquids, typically one drop at a time. For example, the dispensing of a liquid reagent used in laboratories, dispensing eye medication, dispensing ear medication, dispensing nose medication, or in any other environment where dispensing of a liquid in controlled drop increments is desired. A typical prior art bottle assembly comprises a plastic squeeze bottle, a nozzle tip or dropper which is snap fit into the bottle and a cap or closure which is threaded onto the bottle. Liquid is dispensed one drop at a time by squeezing the bottle so as to force liquid out the end of the nozzle tip. The bottle, the nozzle tip and the cap are made of low density polyethylene because this material has a high enough modulus of elasticity for squeezing the cylindrical sidewall of the bottle with one's fingers which causes the liquid therein to pass through a passageway. For filling the bottle with a pharmaceutical product, particularly an ophthalmic liquid which has to fulfill the conditions concerning sterility, it is state of the art to filtrate and to sterilize the solution or liquid which should be filled into the bottles by filtration or autoclaving. Also the bottles, the nozzle tips and the caps are sterilized, e.g. by ethylene oxide treatment, UV, gamma or electron beam irradiation. The filling of the bottles takes place in aseptic room conditions. However, after filling the bottles, inserting the nozzle tip into the neck portion and threading the cap onto the bottle no further sterilization will proceed. The filled and closed bottles are removed from the aseptic area. The aseptic area is normally a room which stands under slight excess air pressure and the entrance and the exit of the room are constructed as sluices. A pharmaceutical product as used hereinbefore or hereinafter is understood to relate in particular to a pharmaceutical composition, which is preferably an aqueous and/or a non- aqueous pharmaceutical composition or a mixture of a non-aqueous and an aqueous pharmaceutical composition, which is preferably a liquid solution, a gel or an ointment, wherein pharmaceutical relates preferably to an ophthalmic, an otic and/or a nasal administration. However, the standard method of filling bottles with pharmaceutical substances, particularly with ophthalmic solutions and gels does not fulfill the European Pharmacopoeia, 3rd. edition (1997) e.g. page 283, and/or the EU regulation (Committee of Proprietory Medicinal Products [CPMP] , Section 5, Manufacturing Process, Note for Guidance). According to this regulation, an ophthalmic pharmaceutical liquid or gel should be terminally sterilized in their final container for achieving the highest level of sterility assurance, if ever possible. But using for sterilization an autoclaving method with a temperature of at least 121 °C for at least 15 minutes for the low density polyethylene bottles known in the prior art deformation, e.g. shrinkage or blowing up occur and the bottles have lost their elasticity so that they are damaged or partly molten and not squeezable anymore. The invention addresses the problem of providing a pharmaceutical package, particularly a bottle assembly or a tube filled with a pharmaceutical product, particularly an ophthalmic solution or gel, meets the requirements of the European Pharmacopoeia regulation and/or EU-regulation without any significant deformation and retaining a sufficient squeezibility for dispensing the liquid after the autoclaving proceedings. The invention solves this problem with the features indicated in both claim 1 and 10. With regard to further substantial design features, reference is made to the dependent claims. The use of a specific form of polypropylene for the material of the package enables to fulfill the European Pharmacopoeia regulation and/or EU regulation. Packages made of a specific form of polypropylene are heat-resistant and retain their formation and their squeezing characteristics after the autoclaving processing. Therefore, the consumer can easily dispense one drop at a time by squeezing the package so as to force the pharmaceutical product out of the package. Particularly the invention provides a tube or a dropper bottle assembly with a high enough squeezibility for dispensing an ophthalmic solution or gel by compressing the tube or bottle. Further details and advantages of the invention are apparent from the following description and drawings. The drawings show: Fig. 2 a front view of a dropper bottle assembly as an example of the invention; Fig. 2 a front view, partially in cross section of a dropper bottle assembly in Fig. 1 ; Fig. 3 a diagram of the temperature and the pressure run in the autoclaving chamber during the autoclaving processing for a 5 ml bottle; Fig. 4 a diagram of the temperature and the pressure run in the autoclaving chamber during the autoclaving processing for a 10 ml bottle; Fig. 5 a test diagram which shows the power as a function of the elasticity for a 5 ml bottle; Fig. 6 a test diagram which shows the power as a function of the elasticity for a 10 ml bottle. Referring to Fig. 1 and Fig. 2, there is illustrated as an example of the invention a dropper bottle assembly 1 which comprises a squeeze bottle 2 having a nozzle tip 3 designed to snap fit within the neck portion 4 of the bottle 2, and a cap 5 designed to fit over the nozzle tip 3 and engage threaded portion 6 of the neck portion 4. The nozzle tip 3 has a passageway 7 for allowing fluid within the bottle 2 to be dispensed through outlet 8. Liquid is dispensed by first removing cap 5 and then squeezing the cylindrical sidewall 9 of bottle 2 with one's fingers which causes the liquid therein to pass through a passageway 7. For safety purposes the bottle assembly is further provided with either a shrink collar or with a temper resistance ring 10. The bottle 2 is made of a specific form of polypropylene, particularly a polypropylene of the type Appryl 3020 SM 3. In comparison with the prior art the bottle 2 has a similar shape with the exception that the bottom 12 has advantageously a concave configuration. This is in particular for avoiding deformation, e.g. shrinkage or blowing-up, of the bottle during the autoclaving processing. Due to the concave configuration the degree of pressure necessary to cause deformation of the bottom is much higher. Naturally, other indentation, grooves, slits or slots can be designed at the bottom 12 or the sidewall 9 to give the bottle 2 a greater stability during the autoclaving processing. The nozzle tip 3 is also particularly formed of a specific form of polypropylene, particularly a polypropylene of the type Appryl 3020 SM 3. There occur no problems during the autoclaving processing which could generate leakage problems. Rather, by using the same material for the bottle 3 and the nozzle tip 3 the two components are sealed a little bit together during the autoclaving processing. Furthermore, as polypropylene is a quite rigid material and it is more difficult to snap fit the nozzle tip 3 into the neck portion 4 of the bottle 2, the nozzle tip 3 has a special configuration to ensure a good seal between the bottle 2 and the nozzle tip 3. The sealing part 13 of the nozzle tip 3 used for sticking the nozzle tip 3 into the neck portion 4 of the bottle 2 is formed in the upper part nearly cylindrical whereas the lower part has the form of a taper shank. As a stopping face the sealing part 13 of the nozzle tip 3 is provided with a collar 14. The cap 5 is threaded on the neck portion 4 of the bottle 2 having external threads 6. The cap 5 as the closure of the bottle assembly is particularly formed of a high density polyethylene, particularly of HDPE GC 7260. The cap 5 can also be made of polypropylene, however in this case during the autoclaving processing a sealing between the nozzle tip 3 and the cap 5 can occur, so that it is quite difficult to open the bottle 2 or the nozzle tip 3 is damaged after opening of the bottle 2. If the cap 5 is made of another material than polypropylene, particularly of high density polyethylene, the risk of a sealing or other damages can be avoided as these two materials have a different modulus of elasticity. The wall thickness of the PP bottle is typically in the range of 0.3 mm to 0.6 mm, preferably 0.45 mm. If the wall thickness is too thin, then the stability of the bottle decreases. However, if the wall thickness is too thick, then the squeezability of the bottle decreases and the bottle becomes too rigid. Indeed, the preferable value of the wall thickness is lower than in comparison with the prior art PE bottles, so that there is much lesser material necessary for molding the bottles, preferably by an injection molding process. When the package of the present invention relates to a tube, the material may also be a so- called laminated PP-foil (polyfoil tube) exhibiting a sandwich-type structure. Typically such a laminated foil contain one or more layers of polypropylene (PP), preferably two (e.g. a top and a bottom layer), and one or more layers of aluminum, preferably one (e.g. the middle layer). Said laminated material provides typically enhanced stability. Further, it is advantageous to adjust the autoclaving processing to the PP-bottles to avoid damages as shrinkage or blowing-up. After filling the bottles with the pharmaceutical liquid or gel, particularly an ophthalmic liquid or gel, the closed bottles are introduced into an autoclaving chamber. In the context of the present application filling of the bottles denotes typically a normal filling, such that for example in the upper part of said bottle some air will remain. As the whole bottles will be sterilized it is not anymore necessary that the filling and closing of the bottles has to take place under aseptic conditions. As it is known in the prior art, such an autoclaving chamber works with steam. The temperature and the pressure run in the chamber as a function of time is demonstrated in Fig. 3 and 4. The chamber contains typically one or more nozzles for the steam entrance and typically several sensors for temperature monitoring. Advantageously the temperature can be adjusted very quickly if some corrections might be necessary. Further, particularly the chamber is provided with a pressure device for generating a counter pressure in the autoclaving chamber. Also the pressure can be adjusted very quickly if some corrections might be necessary. Preferably, the counter pressure is regulated electronically via computer control. Said pressure set-up is advantageously used for avoiding a blowing-up of the bottles. After introducing the bottles into the chamber, the temperature rises typically from room temperature to 121 °C and the pressure rises typically from atmospheric pressure to a maximum value which is characteristic for the sterilization process. Typically, the choice of the pressure value depends on the form of the bottles. Fig. 4 shows in an exemplary fashion the adjusted pressure with a value of 2700 mbar is lower for the 5 ml bottles than for the 10 ml bottles with a value of 3200 mbar. As the 5 ml bottles are more rigid in comparison to the 10 ml bottles a lower pressure value is necessary to avoid blowing up of the bottles. In the beginning of the autoclaving process the increasing of the temperature is quite steep, whereas the gradient of the pressure remains nearly constant up to reaching the maximum value. During the sterilization the values of the temperature and the pressure maintain constant. After the sterilization both the temperature and the pressure decreases continuously. The autoclaving processing takes as a whole nearly one hour. After reaching again room temperature and atmospheric pressure the chamber will be opened for taking out the sterilized bottles. Several test programs have shown that after an autoclaving procedure of a temperature of 121 °C during 20 minutes with an autoclaving procedure according to the above described diagrams no deformation, e.g. shrinkage or blowing-up of the PP bottle assembly could be observed. Two diagrams demonstrating the squeezability of a bottle assembly with a volume of 5 ml and of 10 ml are shown in Fig. 5 and Fig. 6. To achieve typically a compression of 2 mm in comparison to the normal dimension of the bottle, typically a power value of about 9 N is necessary for a 5 ml PP-bottle. For a 10 ml PP bottle, typically a power value of about 14 N is required. For comparative purposes it should be mentioned that prior art PE bottles exhibit typically a similar squeezability, e.g. the 5 ml PE bottle slightly less, the 10 ml PE-bottles a little bit more power. For the consumer these values are virtually equivalent. Further tests concerning the tightness of the bottles before and after the autoclaving procedure show compliance with the regulations for pharmaceuticals. Tests concerning the O 2 -barrier and the H 2 0-barrier properties of the bottles in accordance to the invention (despite of thinner walls) after stress storage during 4 weeks at 80 °C show no difference to the PE-bottles known from the prior art. Furthermore, tests in respect to bacteria toxicity show that no toxicity could be demonstrated for the PP-bottles. PE-bottles known from the prior art are typically twice as thick as the PP-package (PP-bottles) of the present invention. Therefore, the invention provides a package particularly a tube or a dropper bottle assembly for pharmaceutical products, especially for ophthalmic pharmaceutical solutions and gels which can be sterilized as a whole after filling the product into the package by an autoclaving process in accordance to the invention. The package retains after the autoclaving procedure its sqeezability which is important for the consumer for dispensing especially a solution or gel out of the package. Furthermore, no deformation could be observed after having exposed said package to an autoclaving process in accordance to the invention. This means that a package according to the invention, especially a dropper bottle assembly filled with an ophthalmic solution, gel or ointment, fulfills the European Pharmacopoeia, 3rd. edition (1997), and/or the EU regulation mentioned above, which ensure a higher level of safety. In addition, the PP-material used for fabricating the package in accordance to the invention exhibits physical chemical properties which meet the requirements laid down in the supplement of 1998 of the European Pharmacopoeia, 3rd edition (1997). This is in particular applicable to the additives comprised in the PP-material in accordance to the invention.

Claims: Claims 1. A package for a pharmaceutical product, particularly a liquid ophthalmic composition, such as an ophthalmic solution, gel or ointment, for example a tube or a dropper bottle assembly used to dispense said product, wherein said package is made of a specific form of polypropylene and wherein said package shows after an autoclaving processing of at least 121 °C and for at least 20 minutes no deformation such as shrinkage or blowing-up and retains a sufficient high squeezability in order to dispense said product. 2. A package according to claim 1 , wherein said package meets the requirements of the European Pharmacopoeia, 3rd. edition (1997) and the EU-regulation. 3. Package of claim 1 or 2, wherein said package comprises a plastic bottle (2) for holding said product to be dispensed, a plastic nozzle tip (3) for dispensing said product and a cap (5) for closing said bottle. 4. A package according to claim 3, wherein said bottle (2) having a neck portion (4) that includes an externally threaded portion (15) and an outer rim which defines an outlet of the bottle, and said nozzle tip (3) being in fluid contact with said outlet of said bottle and having an dispensing passageway (7) for allowing liquid within said bottle (2) to pass out of an outlet (8) of said nozzle tip (3), and said cap (5) having internal threads for engagement with said externally threaded portion (15) of said neck portion (4). 5. A package according to claim 3 - 4, wherein said bottle (2) is made of a specific form of polypropylene, the nozzle tip (3) is made of a specific form of polypropylene and the cap (5) is made of a specific form of polypropylene and/or of high density polyethylene. 6. A package according to claim 3 - 5, wherein said bottle (2) is made of Appryl 3020 SM 3, the nozzle tip (3) is made of Appryl 3020 SM 3, and the cap (5) is made of HDPE GC 7260 or of polypropylene. 7. A package according to any of claims 3 to 6, wherein the bottom (12) of the bottle (2) has a concave configuration. 8. A package according to any of claims 1 to 7, wherein the wall thickness of the package, particularly the bottle (2) is in the range of 0.3 mm to 0.6 mm. 9. A package according to any of claims 1 to 8, wherein the wall thickness of the package, particularly the bottle (2) is 0.45 mm. 10. Method for sterilizing a pharmaceutical package comprising the steps, placing closed package into an autoclaving chamber, adjusting the temperature and the pressure in said chamber as a function of time in accordance to the prerequisites of the material of said package, wherein a counter pressure is generated in said chamber and wherein this is regulated electronically via computer control, and wherein said counter pressure avoids a deformation such as a blowing-up of said package. 11. Method of claim 10, wherein the pressure value is adjusted to the size of the packages to be sterilized. 12. Method of claim 10, wherein the pressure value is adjusted to the type of polypropylene. 13. Method of claim 10, wherein said package is a bottle, more preferably a PP-bottle. 14. Package of claim 5 - 9, wherein the physical chemical properties of said polypropylene meet the requirements laid down in the supplement of 1998 of the European Pharmacopoeia, 3rd edition (1997).

Inventors: KIS GYOERGY LAJOS, KRAEUTLER ECKHARD, KIS, GYOERGY, LAJOS, KRAEUTLER, ECKHARD
Applicants: KIS GYOERGY LAJOS, KRAEUTLER ECKHARD, NOVARTIS AG, NOVARTIS ERFIND VERWALT GMBH, KIS, GYOERGY, LAJOS, KRAEUTLER, ECKHARD, NOVARTIS-ERFINDUNGEN VERWALTUNGSGESELLSCHAFT MBH
Application year: 2000
Main classification: B65D1
IPC codes: B65B55, B65D1, B65D81