The sealability of a thermoplastic, mono- or multi-layer film having an irradiated sealing layer comprising a polyethylene and/or an ethylene-x-olefin copolymer with a density xe2x89xa70.915 g/cm3 is improved by corona treating said sealing layer. The integrity of the obtained sealed container is maintained under pasteurizing or cook-in conditions.

The present invention relates to a mono- or multi-layer thermoplastic film with improved sealability properties and to bags, pouches, and other containers made therefrom by sealing the film to itself. The invention also relates to the use of such film in packaging food products in which the packaged product is submerged in heated water or autoclaved or retorted for a period of time sufficient for pasteurising and/or cooking the packaged product, the package being essentially non degradable under such conditions.
The term xe2x80x9cpasteurisablexe2x80x9d as used herein is intended to refer to packaging material structurally capable of withstanding exposure to pasteurising conditions while containing a food product. Many food products require pasteurisation after they have been hermetically packaged to destroy harmful microbes which grow in the absence of air. Specific pasteurisation conditions tend to vary from country to country; however limiting conditions are probably submersion of the hermetically closed package in water at 95xc2x0 C. for one hour. Thus, for a bag to be characterised as pasteurisable, structural integrity of the bag must be maintained during pasteurisation, i.e. the bag must have superior high temperature seal strength.
The term xe2x80x9ccook-inxe2x80x9d as used herein is intended to refer to packaging material structurally capable of withstanding exposure to cook-in time-temperature conditions while containing a food product. Cook-in packaged foods are essentially pre-packaged, pre-cooked foods that go directly to the consumer in that configuration which may be consumed with or without warming. Cook-in time-temperature conditions typically refer to a long slow cook, for example submerging the packaged product in water at 75-85xc2x0 C. for four to six hours. Such cook-in time-temperature requirements are representative of institutional cooking requirements. Under such conditions, a packaging material properly characterised as cook-in will maintain seal integrity.
Preferably in both cases the packaging film is a solid-state oriented film, either mono-axially or bi-axially oriented, as solid-state orientation improves the mechanical properties of the end structure.
While said mono- or bi-axially oriented films can then be heat-set, preferably, for use in cook-in applications, these oriented films are not thermofixed and shrink under these cook-in conditions so as to form a tightly fitting package. Heat-shrinkable solid-state oriented films are therefore preferred.
Also, preferably the packaging film is a multilayer film comprising a gas-barrier layer.
Thermoplastic, heat-shrinkable, solid-state oriented films bearing a sealing layer of polyethylene or of an ethylene-xcex1-olefin copolymer, either alone or blended with one or more other resins compatible therewith, are known in the patent literature.
For instance Japanese kokai No. 58-82752 describes a gas-barrier heat-shrinkable film comprising a sealing layer of a copolymer of ethylene and an xcex1-olefin optionally blended with up to less than 80% of ethylene-vinyl acetate.
Japanese kokai No. 58-102762 teaches a heat-shrinkable multi-layer barrier film comprising at least one layer of a blend of three different specific resin and a surface layer of linear low density polyethylene (LLDPE).
U.S. Pat No. 4,424,243 describes a heat-shrinkable barrier film with outer layers of ethylene-xcex1-olefin copolymers and an intermediate ethylene-vinyl acetate copolymer layer interposed between the core barrier layer and at least one outer layer.
U.S. Pat. No. 4,456,646 teaches a heat-shrinkable film comprising a core barrier layer and both outer layers consisting of a blend of an ethylene-xcex1-olefin copolymer with 30 to 80% of ethylene-vinyl acetate copolymer.
These films are generally said to be oil and heat resistant. The tests used to evaluate said properties however provide for submerging a package in water with oil floating on the surface thereof at a temperature of 80-95xc2x0 C. for up to 10 minutes. These conditions therefore are far from those that simulate the heat-treatment used in cook-in applications or for pasteurisation.
In all the above patents the multilayer films are obtained by either coextrusion or extrusion coating of the resins of the different layers to result in a primary thick tube (primary tape) that is quickly cooled to stop or quench the crystallisation of the polymers. The resulting quenched thick tube is thereafter reheated to the so-called orientation temperature and then biaxially stretched at this temperature by a tubular solid-state orientation process using a trapped bubble. In said solid-state orientation step the primary tape is stretched in the transverse direction (TD) by inflation with air pressure to give a bubble, and in the longitudinal or machine direction (MD) by the differential speed between the two sets of nip rolls that contain the bubble. The term xe2x80x9csolid-state orientationxe2x80x9d is used herein to describe the orientation process carried out at a temperature higher than the highest Tg of the resins making up the structure and lower than the highest melting point of at least one polymer, i.e. at a temperature where the resins, or at least some of the resins, are not in the molten state. xe2x80x9cSolid-state orientationxe2x80x9d is contrasted to xe2x80x9cmelt-state orientationxe2x80x9d, i.e. a process, such as the hot blown one, where stretching takes place upon emergence of the molten resins from the die. For the sake of simplicity, in the following xe2x80x9corientationxe2x80x9d and xe2x80x9corientedxe2x80x9d have been used to mean xe2x80x9csolid-state orientationxe2x80x9d and xe2x80x9csolid-state orientedxe2x80x9d respectively.
While mono-layer polyethylene films cannot be oriented by a tubular orientation process unless they are irradiated before orientation, with multi-layer films, depending on the other layers of the structure and on the specific polymer used, irradiation may be not strictly necessary. It is however widely known in the art that with multi-layer films having a sealing layer comprising a polyethylene or an ethylene-xcex1-olefin copolymer, the primary tape comprising said layer is preferably submitted to an irradiation step before orientation to improve bubble stability.
Generally therefore, in the industrial manufacture of heat-shrinkable multi-layer films having a sealing innermost layer comprising a polyethylene or an ethylene-xcex1-olefin copolymer by a tubular process, either all the layers are coextruded, the tape is quenched, irradiated, reheated and oriented, or some of the layers, including the innermost layer that will become the sealing layer of the end packaging material, are extruded, the tape thus obtained is quenched, irradiated and coated by extrusion of the remaining layers thereon, quenched again, reheated and oriented.
Besides increasing bubble stability, irradiation is also known to improve the physical properties (e.g. strength) of the irradiated resins. In some cases therefore, for instance when a non oriented film is desired or when it would be possible to orient the tape even without irradiation, irradiation may be carried out in order to improve the physical properties of the end packaging film.
Irradiation of the sealing layer is however known to decrease heat-sealability of the film, particularly with polyethylene or ethylene-xcex1-olefin copolymers that are easily cross-linkable polymers.
When the film has to be used in the manufacture of pasteurisable containers or containers for cook-in applications that are highly demanding as to the seal strength, this represents a real problem.
It has now been discovered that it is possible to improve the sealability of mono- or multi-layer films having an irradiated sealing layer comprising a polyethylene and/or an ethylene-xcex1-olefin copolymer to such an extent that cook-in pasteurizable bags can be obtained therefrom by using for the sealing layer a polyethylene and/or an ethylene-xcex1-olefin copolymer with a density xe2x89xa70.915 g/cm3 and submitting said sealing layer to a corona discharge treatment.
It has been found in fact that by submitting the irradiated sealing layer of a film, comprising a polyethylene and/or an ethylene-xcex1-olefin copolymer with a density xe2x89xa70.915 g/cm3, to a corona discharge treatment, the integrity of a sealed package made therefrom, unlike that of a sealed package made from the same film not corona treated, is maintained under pasteurising or cook-in conditions.
This finding is surprising as it is widely known (see for instance J. M. Farley and P. Meka, J. Appl. Polym. Sc., 51, 121-131 (1994)) that the heat-sealability of non-irradiated films with a polyethylene or an ethylene-xcex1-olefin copolymer as the sealing layer is impaired and certainly not improved by a corona discharge treatment (CDT).
This effect is particularly remarkable with ethylene-xcex1-olefin copolymers with a density  greater than 0.915 g/cm3, and even more remarkable with ethylene-xcex1-olefin copolymers with a density  greater than 0.917 g/cm3.
A first object of the present invention is therefore a thermoplastic, mono- or multi-layer film having an irradiated sealing layer comprising a polyethylene and/or an ethylene-xcex1-olefin copolymer copolymer with a density xe2x89xa70.915 g/cm3, wherein said sealing layer has been corona treated.
A second object of the present invention is a heat-treatable container obtained by sealing, and in particular by impulse sealing, such a film to itself.
A third object is the use of such a container in cook-in applications or for pasteurisation.
A fourth object is a method of improving the seal strength of impulse seals of a mono- or multi-layer film having an irradiated sealing layer comprising a polyethylene and/or an ethylene-xcex1-olefin copolymer with a density xe2x89xa70.915 g/cm3, said method comprising submitting said sealing layer to a corona discharge treatment before sealing it.
As used herein, the term xe2x80x9cfilmxe2x80x9d includes any flexible plastic web, regardless of whether it is film or sheet. Preferably, films of use in the present invention have a thickness of 250 xcexcm or less, more preferably of 150 xcexcm or less, and even more preferably of 120 xcexcm or less.
As used herein, the term xe2x80x9cheat-shrinkablexe2x80x9d refers to a film which shrinks by at least 10%, preferably at least 15% and even more preferably at least 20%, of its original dimensions, in at least one direction, when heated to 90xc2x0 C. for 5 seconds, in accordance with ASTM method D2732.
As used herein, the term xe2x80x9cirradiatedxe2x80x9d refers to a film that has been irradiated to a dosage level of up to about 180 KGy, typically to a dosage level of from about 50 KGy to about 160 KGy, preferably to a dosage level of from about 60 to about 150 KGy and even more preferably to a dosage level of about 70 to about 140 KGy, such as by passing it through an electron beam irradiation unit.
As used herein, the phrases xe2x80x9cinner layerxe2x80x9d, xe2x80x9cinternal layerxe2x80x9d, or xe2x80x9cintermediate layerxe2x80x9d refer to any film layer having both of its principal surfaces directly adhered to another layer of the film.
As used herein, the term xe2x80x9ccorexe2x80x9d, and the phrase xe2x80x9ccore layerxe2x80x9d refer to any internal film layer which has a primary function other than serving as an adhesive or compatibilizer for adhering two layers to one another.
As used herein, the term xe2x80x9cbarrierxe2x80x9d, and the phrase xe2x80x9cbarrier layerxe2x80x9d, as applied to films and/or film layers, is used with reference to the ability of a film or film layer to serve as a barrier to gasses.
As used herein, the phrase xe2x80x9couter layerxe2x80x9d or xe2x80x9cexterior layerxe2x80x9d refers to any film layer having less than two of its principal surfaces directly adhered to another layer of the film. In multi-layer films, there are two outer layers, each of which has a principal surface adhered to only one other layer of the multilayer film.
As used herein, the phrases xe2x80x9cseal layerxe2x80x9d, xe2x80x9csealing layerxe2x80x9d, xe2x80x9cheat seal layerxe2x80x9d, and xe2x80x9csealant layerxe2x80x9d, refer to the exterior film layer involved in the sealing of the film to itself.
As used herein, the term xe2x80x9csealxe2x80x9d refers to any seal of a first region of a film surface to a second region of a film surface, wherein the seal is formed by heating the regions to at least their respective seal initiation temperatures. The heating can be performed by any one or more of a wide variety of manners, such as by impulse, or using a heated bar, hot air, infrared radiation, etc.
As used herein, the term xe2x80x9couter abuse layerxe2x80x9d refers to the outer layer which is not the sealing layer.
As used herein, the phrase xe2x80x9cdirectly adheredxe2x80x9d, as applied to film layers, is defined as adhesion of the subject film layer to the object film layer, without a tie layer, adhesive, or other layer therebetween. In contrast, as used herein, the word xe2x80x9cbetweenxe2x80x9d, as applied to a film layer expressed as being between two other specified layers, includes both direct adherence of the subject layer between to the two other layers it is between, as well as a lack of direct adherence to either or both of the two other layers the subject layer is between, i.e., one or more additional layers can be imposed between the subject layer and one or both the layers the subject layer is between.
As used herein, the term xe2x80x9cpolymerxe2x80x9d refers to the product of a polymerization reaction, and is inclusive of homopolymers, copolymers, terpolymers, etc.
As used herein, the term xe2x80x9cpolyolefinxe2x80x9d means a thermoplastic homo-, co- or ter-polymer derived from simple olefins, e.g. ethylene, propylene and higher unsaturated aliphatic monomer units, or the halogenated derivatives thereof, as well as the co- or ter-polymers of said simple olefins with co-monomers that are not themselves olefins, e.g. vinyl acetate, acrylic or methacrylic acids, salts, or esters, provided however that the olefin comonomer is present in a major amount. More specifically, included in the term polyolefin are homopolymers of olefins, copolymers of olefins, copolymers of an olefin and a non-olefinic comonomer copolymerizable with the olefin, such as vinyl monomers, and the like. Heterogeneous and homogeneous polymers are included. Specific examples include polyethylene homopolymers, poly-butene, propylene-xcex1-olefin copolymers, ethylene-xcex1-olefin copolymers, butene-xcex1-olefin copolymers, ethylene-vinyl acetate copolymers, ethylene-ethyl acrylate copolymers, ethylene-butyl acrylate copolymers, ethylene-methyl acrylate copolymers, ethylene-acrylic acid copolymers, ethylene-methacrylic acid copolymers, ionomers, chlorinated polyethylene, etc.
As used herein, the phrase xe2x80x9cheterogeneous polymerxe2x80x9d refers to polymerization reaction products of relatively wide variation in molecular weight and relatively wide variation in composition distribution. Such polymers typically contain a relatively wide variety of chain lengths and comonomer percentages.
As used herein, the phrase xe2x80x9chomogeneous polymerxe2x80x9d refers to polymerization reaction products of relatively narrow molecular weight distribution and relatively narrow composition distribution. Homogeneous polymers exhibit a relatively even sequencing of comonomers within a chain, the mirroring of sequence distribution in all chains, and the similarity of length of all chains.
As used herein, the term xe2x80x9cpolyethylenexe2x80x9d refers to homo-polymers derived from the polymerization of ethylene units. Said term is inclusive of LDPE (low density polyethylene with a density of up to 0.935 g/cm3) and of HDPE (high density polyethylene characterised by a density higher than 0.935 g/cm3).
As used herein, the phrase xe2x80x9cethylene-xcex1-olefin copolymerxe2x80x9d refers to co- or ter-polymers of ethylene with one or more (C4-C8)-xcex1-olefins, such as butene-1, hexene-1, 4-methyl-pentene-1, and octene-1. Said term includes such heterogeneous materials as linear low density polyethylene (LLDPE with a density comprised between about 0.915 and 0.925 g/cm3), linear medium density polyethylene (LMDPE with a density higher than 0.925 g/cm3), and very low density polyethylene (VLDPE with a density of less than 0.915 g/cm3); and homogeneous polymers such as Ziegler-Natta-catalyzed homogenous polymers, as well as metallocene-catalyzed homogenous polymers.
As used herein the term xe2x80x9cmodified polyolefinsxe2x80x9d include modified polymers prepared by copolymerizing the homopolymer of the olefin or copolymer thereof with an unsaturated carboxylic acid, e.g., maleic acid, fumaric acid or the like, or a derivative thereof such as the anhydride, ester or metal salt or the like, or by incorporating into the olefin homopolymer or copolymer, an unsaturated carboxylic acid, e.g., maleic acid, fumaric acid or the like, or a derivative thereof such as the anhydride, ester or metal salt or the like.
As used herein, the phrase xe2x80x9ctie layerxe2x80x9d refers to any internal layer having the primary purpose of adhering two layers to one another. Tie layers generally comprise a non-polar or slightly polar polymer having a polar group grafted thereon; preferably, tie layers comprise at least one member selected from the group consisting of polyolefin and modified polyolefin, e.g. ethylene-vinyl acetate copolymer, modified ethylene-vinyl acetate copolymer, heterogeneous and homogeneous ethylene-xcex1-olefin copolymer, and modified heterogeneous and homogeneous ethylene-xcex1-olefin copolymer; more preferably, tie layers comprise at least one member selected from the group consisting of anhydride grafted linear low density polyethylene, anhydride grafted low density polyethylene, homogeneous ethylene-xcex1-olefin copolymer, and anhydride grafted ethylene-vinyl acetate copolymer.
The sealing layer of the film according to the present invention comprises a polymer selected from the group consisting of polyethylene and ethylene-xcex1-olefin copolymers with a density xe2x89xa70.915 g/cm3.
Preferably said sealing layer will comprise at least one ethylene-xcex1-olefin copolymer with a density xe2x89xa70.915 g/cm3. Preferred polymers are those, either heterogeneous or homogeneous, with a density comprised between about 0.915 and about 0.935 g/cm3, and even more preferred those with a density of from about 0.917 to about 0.930 g/cm3.
The melt flow index of said polymers to be used in the construction of the sealing layer in the film according to the present invention generally ranges from between about 0.1 to about 5 g/10xe2x80x2 and preferably between from about 0.5 to about 2.5 g/10xe2x80x2. Melt Flow Index (MFI) is measured according to ASTM D1238 Condition E (2.16 kg loading at 190xc2x0 C.).
In general these polymers may be blended with one or more other polymers compatible therewith, such as polyolefin polymers. These blends will typically comprise 50% or more, preferably 70% or more and even more preferably 80% or more by weight of polyethylene and/or ethylene-xcex1-olefin copolymer with a density xe2x89xa70.915 g/cm3.
In a preferred embodiment of the present invention, said sealing layer will essentially consist of polyethylene and/or ethylene-xcex1-olefin copolymer with a density xe2x89xa70.915 g/cm3.
In another preferred embodiment said sealing layer will essentially consist of a blend of at least 80% by weight of polyethylene and/or ethylene-xcex1-olefin copolymer with a density xe2x89xa70.915 g/cm3 with up to 20% by weight of one or more polymers selected from the group consisting of ethylene-vinyl acetate copolymers, ethylene-alkyl acrylate copolymers, anhydride grafted ethylene-alkyl acrylate copolymers, ethylene-alkyl methacrylate copolymers, anhydride grafted ethylene-alkyl methacrylate copolymers, ethylene-acrylic acid copolymers, ethylene-methacrylic acid copolymers, and ethylene-maleic anhydride-alkyl (meth)acrylate terpolymers.
The sealing layer will typically be at least 4 xcexcm thick, preferably at least 7 xcexcm thick, and even more preferably at least 9 xcexcm thick. Generally the thickness of said sealing layer may range from about 4 to about 25 xcexcm, depending on the overall film thickness and on the number of layers in the structure.
Films according to the present invention are preferably multi-layer films comprising besides the sealing layer as described above at least one core gas-barrier, layer and one outer abuse layer.
The gas of main concern is oxygen and transmission is considered to be sufficiently low, i.e. the gas-barrier material is relatively gas impermeable when the transmission rate is below 100 cm3/day.m2.atm as measured according to the procedures of ASTM D3985 at 23xc2x0 C. and 100% Relative Humidity. To obtain oxygen barrier layers with a transmission rate below that value, PVDC or EVOH, possibly blended with a polyamide or copolyamide, can advantageously be employed. Preferably however the barrier layer will comprise EVOH as this polymer can be irradiated even at high dosage levels without degradation. With an oxygen barrier layer comprising EVOH an irradiated fully coextruded structure is typically employed what reduces any possible risk of delamination that might be present in case of extrusion coated structures when they are subjected to a drastic heat-treatment.
Once the gas-barrier resin has been selected, its thickness will be set to provide for an oxygen transmission rate below 100 cm3/day.m2.atm. Typically the thickness of the barrier layer ranges from about 2 to about 10 xcexcm, preferably from about 3 to about 8 xcexcm, and more preferably from about 4 to about 7 xcexcm.
As the outer abuse layer, particularly when an ethylene-vinyl alcohol copolymer is used as the barrier layer, a moisture-barrier material, such as an ethylene homo- or co-polymer or a propylene homo- or co-polymer is preferably employed. As an example said outer abuse layer may comprise a polyethylene, an ethylene-xcex1-olefin copolymer, an ethylene-vinyl acetate copolymer, an ionomer, a blend thereof with modified polyolefins, a polypropylene, a propylene-ethylene copolymer, etc.. According to a preferred embodiment of the invention said outer abuse layer will comprise an ethylene-vinyl acetate copolymer. In a most preferred embodiment said outer abuse layer will comprise an ethylene-vinyl acetate copolymer with a vinyl acetate content of from about 4 to about 14% by weight and more preferably of from about 5 to about 9% by weight, preferably with a Melt Flow Index lower than 1 g/10xe2x80x2, optionally blended with a heterogeneous or homogeneous ethylene-xcex1-olefin copolymer with a density of from about 0.900 to about 0.935 g/cc.
The thickness of said outer layer is not critical and it is generally comprised between about 2 and about 35 xcexcm, preferably between about 6 and about 30 xcexcm and more preferably between about 10 and about 25 xcexcm.
Additional layers, such as for instance tie layers to improve interlayer adhesion, or bulky structural layers to provide the overall structure with the desired mechanical properties, or shrink layers to improve the shrink properties of the heat-shrinkable films, can be present as known in the art.
If the structure contains tie layers their thickness is generally comprised between about 0.5 and about 7 xcexcm, and preferably between about 2 and about 5 xcexcm.
Non limitative examples of suitable, preferred, structures are for instance 5-, 6- or 7-ply structures of the following type:
Seal/Tie/Gas-barrier/Tie/Outer abuse
Seal/Inner structural/Tie/Gas-barrier/Tie/Outer abuse
Seal/Tie/Inner structural/Tie/Gas-barrier/Tie/Outer abuse
wherein the Inner structural layer, that may be equal or different from the Outer abuse layer, may comprise one or more polymers selected from the groups of polyolefins, polyamides and copolyamides.
Preferably the film according to the present invention is a heat-shrinkable film.
Irradiation may be accomplished by the use of high energy electrons. Preferably electron radiation up to about 200 KGy dosage level is employed. The irradiation source can be any electron beam generator operating in a range of about 150 kV to about 6 MV with a power output capable of supplying the desired dosage. Many apparatuses for irradiating films are known to those skilled in the art. Irradiation is usually carried out at a dosage of from about 50 to about 160 KGy, preferably at a dosage of from about 60 to about 150 KGy, and more preferably at a dosage level of from about 70 to about 140 KGy. Irradiation can be carried out conveniently at room temperature, although higher and lower temperatures, for example 0xc2x0 C. to 60xc2x0 C., may be employed. In case of heat-shrinkable films, as indicated above irradiation is preferably carried out on the primary tape before orientation as irradiation has the main purpose of improving bubble stability. If this is not necessary however, irradiation, to improve the structure strength, can be carried out also after orientation.
The films according to the present invention can be prepared by conventional method of manufacturing, by extrusion, coextrusion or extrusion coating through a round or flat die, followed by irradiation. Preferably however, as indicated above, the film is manufactured by coextrusion. When, according to a highly preferred embodiment of the invention, a heat-shrinkable film is desired, the primary tape thus obtained is quenched and oriented, either by tenterframe, in case of extrusion through a flat die or by a tubular orientation process in case of extrusion through a round die. Irradiation is preferably carried out before orientation, but in some cases it can alternatively be carried out after orientation.
The corona treatment of the sealing layer is carried out just before conversion of the film sheet or tubing into containers by impulse-sealing the film to itself. It is performed in the conventional manner. When the film is in the form of a seamless tubing, corona treatment of the innermost layer is carried out by inflating the tubing with a gas, such as air or other gases such as nitrogen, carbon dioxide, oxygen, ozone, etc., and the mixtures thereof as known in the art, in an amount sufficient to prevent the contact of the internal surfaces of the tube while keeping the tubing in a substantially flat state, and the corona discharge treatment of the innermost sealing layer is conducted from the outside by positioning at least one discharge electrode and at least one counter electrode closed to the upper and lower outer surfaces of the inflated tubing, suitably adjusting the distance between the electrodes to contact the outer surfaces of the inflated tubing, and discharging electricity from the discharge electrode to the counter electrode through the inflated tubing.
The optimum corona treatment level will depend on the kind, thickness and feed rate of the film to be corona treated. It has been found that the improvement in sealability is obtained when the conditions for corona discharge treatment are adjusted so that the treatment provides the surface of the sealing layer with a wet tension strength of at least 30 dyne/cm, preferably at least about 35 dyne/cm, more preferably at least 40 dyne/cm. The corona treatment energy level generally employed with the film according to the present invention is typically from about 150 to about 500 mA. However, lower or higher energy levels might also be suitably employed to provide the film surface with the desired wet tension strength.
The obtained tubing is then converted into bags by cutting lengths of the tubular film and sealing such lengths transversely to obtain end-seal or bottom seal bags. Alternatively the tubing is cut and sealed in such a way to obtain side seal bags.
The bags obtained from the film according to the present invention show outstanding properties in terms of cold and hot seal strength. Thus when such bags are used in food packaging, the food item is inserted in the bag, the package is vacuumized and closed by heat-sealing or by clipping, and the package can then be subjected to various heat treatments such as cooking at a temperature up to about 85xc2x0 C. for several hours or pasteurisation treatment at 95xc2x0 C. for 1 hour. The bags stand these treatments without revealing damages or weakening of the seal.
The examples which follow, only purport to illustrate the invention and not to restrict its field of application.
The following abbreviations have been used in the following Examples to identify the materials:
PE1 Heterogeneous ethylene-xcex1-olefin copolymer with d=0.920 g/cm3 and MI=0.8-1.2 g/10xe2x80x2 (DOWLEX(trademark) 2044E by Dow Chemical Co.)
PE2 Homogeneous ethylene-xcex1-olefin copolymer with d=0.923 g/cm3 and MI=0.85 g/10xe2x80x2 (AFFINITY(trademark) XU59900.00 by Dow Chemical Co)
PE3 Heterogeneous ethylene-xcex1-olefin copolymer with d=0.920 g/cm3 and MI=4.4 g/10xe2x80x2 (STAMYLEX(trademark) 1046F by DSM)
PE4 Homogenous ethylene-xcex1-olefin copolymer with d=0.918 g/cm3 and MI=3 g/10xe2x80x2 (AFFINITY(trademark) DSL 1515.00 by Dow Chemical Co.)
PEC Heterogeneous ethylene-xcex1-olefin copolymer with d=0.911 g/cm3 and MI=5.7-7.5 g/10xe2x80x2 (STAMYLEX(trademark) 08-076 F by DSM)
LG1 anhydride modified EVA-based adhesive with MI=0.9-1.3 g/10xe2x80x2xe2x80x94(BYNEL(trademark) 3062 by DuPont).
EVA1 EVA (6% VA) with MI=2.5 g/10xe2x80x2xe2x80x94(ESCORENE(trademark) FL 00206 by Exxon).
EVA2 EVA (13% VA) with MI=2.5 g/10xe2x80x2xe2x80x94(ESCORENE(trademark) FL 00212 by Exxon)
EVA3 EVA (13% VA) with MI=0.4 g/10xe2x80x2xe2x80x94(EVATANE(trademark) 1003 VN 4 by Elf Atochem)
EBA Ethylene-butyl acrylate copolymer (7% BA) with MI=1.1 g/10xe2x80x2 (NCPE-6472 by Borealis)
EMAA Ethylene-methacrylic acid copolymer (12% MAA) with MI=1.4-2.0 g/10xe2x80x2 (NUCREL(trademark) 1202 by DuPont)
BL1Blend of PE1 (80% by weight) and EVA3 (20% by weight)
BL2Blend of PE1 (80% by weight) and EMAA (20% by weight)
BL3Blend of PE1 (80% by weight) and EBA (20% by weight)
EVOH Ethylene-vinyl alcohol copolymer with 44% by mole of ethylene content and MI=4.9-6.1 g/10xe2x80x2xe2x80x94(EVAL(trademark) EP-E105A by Marubeni)

Packaging film and containers made therefrom


Processes for preparing linear polyesters by reacting a dicarboxylic acid having from 2 to 10 carbon atoms, a polyol having from 2 to 15 carbon atoms, a low-boiling primary alcohol and a catalytic-effective amount of a lipase, wherein the reaction mixture is free of additional solvents; are described. The use of such linear polyesters in cosmetics is also described.

Chemically, the esterification of dicarboxylic acids with polyhydric alcohols is very difficult to control and gives highly crosslinked polyesters at very high temperatures, i.e. beyond the melting points of the dicarboxylic acids. By contrast, the lipase-catalyzed transesterification of dicarboxylic acid esters leads to the formation of linear polyesters under mild reaction conditions. By contrast, the esterification of the free dicarboxylic acids depends on the use of a solvent because the optimal reaction temperatures of the lipase are below the melting temperatures of the dicarboxylic acids.
Since the free dicarboxylic acids are more readily accessible on an industrial scale than their esters, the problem addressed by the present invention was to provide a new process which would enable linear polyesters to be obtained in quantitative yields and favorable reaction times from dicarboxylic acids and polyols under mild conditions without the use of solvents.
The present invention relates, in general, to processes for the production of linear polyesters from aliphatic, substituted aliphatic, aromatic and/or substituted aromatic dicarvoxylic acids and polyols in the presence of small quantities of a low-boiling primary alcohol and lipase as catalyst but without the addition of solvent. The linear polyesters can be used as thickeners and softeners in cosmetic preparations.
The present invention also relates to the use of linear polyesters obtained by reaction of aliphatic, substituted aliphatic, aromatic and/or substituted aromatic dicarboxylic acids containing 2 to 10 carbon atoms and polyols containing 2 to 15 carbon atoms and at least two primary hydroxyl groups in the presence of small quantities of a low-boiling primary alcohol and lipase as catalyst without the addition of solvents as thickeners and softeners in cosmetic preparations.
It has surprisingly been found that linear polyesters can be obtained from dicarboxylic acids and polyols for the first time without the addition of solvents providing the reaction is carried out in the presence of a low-boiling primary alcohol and lipase as catalyst. The esterification is distinguished by mild reaction conditions, favorable reaction times and quantitative yields. The invention includes the observation that advantageously water-soluble linear polyesters are also obtained where dicarboxylic acid mixtures containing hydroxydicarboxylic acids are used.
Aliphatic, substituted aliphatic, aromatic and/or substituted aromatic dicarboxylic acids containing 2 to 10, preferably 3 to 9 and more preferably 4 to 6 carbon atoms are used for the production of polyesters. The aliphatic dicarboxylic acids used include, for example, oxalic acid, malonic acid, succinic acid and adipic acid, azelaic acid, dodecanedioic acid and brassylic acid while the aromatic dicarboxylic acids used include phthalic acid, isopththalic acid and terephthalic acid. The substituted dicarboxylic acids used include the aminodiacids, preferably glutamic acid, and hydroxydicarboxylic acids containing at least two primary hydroxyl groups, preferably maleic acid, citric acid, glutaconic acid and glutaric acid and, more particularly, tartaric acid. Aliphatic unbranched dicarboxylic acids and hydroxydicarboxylic acids are preferably used.
In addition, mixtures of dicarboxylic acids may be used, in which case at least one dicarboxylic acid is a hydroxydicarboxylic acid containing at least two primary hydroxyl groups, preferably malic acid, citric acid, glutaconic acid and glutaric acid and, more particularly, tartaric acid. The molar ratio of dicarboxylic acid to hydroxydicarboxylic acid is 1:10 to 10:1, preferably 1:5 to 5:1 and more preferably 1:2 to 1:1.
Polyols suitable for the purposes of the invention preferably contain 2 to 15, more preferably 3 to 7 and more particularly 4 to 6 carbon atoms and at least 2, preferably at most 6 and more particularly 3 hydroxyl groups. The polyols may contain other functional groups, more particularly amino groups, or may be modified with nitrogen. Typical examples are
glycerol;
alkylene glycols such as, for example, ethylene glycol, diethylene glycol, propylene glycol, butylene glycol, hexylene glycol and polyethylene glycols with an average molecular weight of 100 to 1000 dalton;
technical oligoglycerol mixtures with a degree of self-condensation of 1.5 to 10 such as, for example, technical diglycerol mixtures with a diglycerol content of 40 to 50% by weight;
methylol compounds such as, in particular, trimethylol ethane, trimethylol propane, trimethylol butane, pentaerythritol and dipentaerythritol;
lower alkyl glucosides, particularly those containing 1 to 8 carbon atoms in the alkyl group, for example methyl and butyl glucoside;
sugar alcohols containing 5 to 12 carbon atoms, for example sorbitol or mannitol,
sugars containing 5 to 12 carbon atoms, for example glucose or sucrose;
amino sugars, for example glucamine;
dialcoholamines, such as diethanolamine or 2-aminopropane-1,3-diol.
Preferred alkylene glycols are propylene glycol, butylene glycol, hexylene glycol and polyethylene glycols with an average molecular weight of 100 to 1,000 dalton. Particularly suitable polyols are glycerol, sorbitol, sorbitan, trimethylol propane, pentaerythritol and 2-aminopropane-1,3-diol. Oligomers thereof, for example dimers, trimers, tetramers, pentamers and/or hexamers, may also be used.
Low-boiling primary alcohols suitable for the purposes of the invention are alcohols with a boiling point below 100xc2x0 C. Methanol, isopropanol and propanol and particularly ethanol are preferably used.
Lipases derived from Candida cylindracea, Candida lipolytica, Candida rugosa, Candida antarctica B, Candida utilis, Chromobacterium viscosum, Geotrichum viscosum, Geotrichum candidum, Mucor javanicus, Mucor miehei, porcine pancreas, Pseudomonas species, Pseudomonas fluorescens, Pseudomonas sepacia, Rhizomucor meihei, Rhizopus arrhizus, Rhizopus delemar, Rhizopus delemar, Rhizopus niveus, Rhizopus oryzae, Aspergillus niger, Penicillium roquefortii, Penicillum cambertii, Pseudomonas fluorescens or from an esterase of Bacillus sp., Bacillus thermoglucosidasius, Mucor miehei, horse liver, Saccharomyces cerevisiae, pig liver are used as catalyst for the production of the linear polyols according to the invention. The lipases may be used individually or in combination with one another. The lipases are used in quantities which effect adequate catalysis of the polyesterification according to the invention and lead to a desired molecular weight of the linear polyesters. Lipases derived from Mucor miehei and Aspergillus niger are preferably used. In particular, Novozym(copyright) 388 L (Rhizomucor miehei lipase, free), Lipozym(copyright) IM (Rhizomucor miehei lipase, immobilized), Novozym(copyright) 735 L (Candida antarctica B lipase, free), Novozym(copyright) 525 L (Candida antarctica B lipase, free) and/or Novozym(copyright) 435 (Candida antarctica B lipase, immobilized), which are all products of Nono Nordisk, Denmark, are used. The lipases are preferably used in quantities of 0.01 to 15% by weight and more particularly in quantities of 1 to 10% by weight, based on the dicarboxylic acid.
According to the invention, the linear polyols are obtained by reaction of mixtures of dicarboxylic acids containing a hydroxydicarboxylic acid with polyols in the presence of small quantities of a low-boiling primary alcohol and lipase as catalyst without the addition of solvents. The low-boiling alcohol released is preferably removed from the reaction mixture. The reaction is carried out at temperatures of preferably 50 to 90xc2x0 C. and more particularly 70xc2x0 C. and under pressures of generally 0 to 1013, preferably 0.01 to 500 and more preferably 10 to 250 mbar. The reaction time is 8 hours to 4 days and preferably 24 to 48 hours. To produce the polyesters according to the invention, the dicarboxylic acids and polyols are used in a molar ratio of 2:1 to 0.5:1 and preferably 1.2:1 to 0.8:1. The low-boiling primary alcohols are used in a 0.1 to 5 molar, preferably 0.2 to 2 molar and more preferably 0.3 to 1 molar excess, based on the dicarboxylic acid. Polyesters with a molecular weight of 483 to 10,000 (as determined from GPC data and calibration with polyethylene glycol) or 22,000 (as determined from GPC data and calibration with polystyrene) may be obtained by this process.
The linear polyesters according to the invention may be used for the production of cosmetic preparations such as, for example, hair shampoos, hair lotions, foam baths, shower baths, creams, gels, lotions, alcoholic and aqueous/alcoholic solutions, emulsions, oils, wax/fat compositions, stick preparations, powders or emollients. These preparations may contain mild surfactants, oil components, emulsifiers, superfatting agents, pearlizing waxes, consistency factors, thickeners, polymers, silicone compounds, fats, waxes, stabilizers, biogenic agents, deodorizing agents, anti-dandruff agents, film-formers, swelling agents, UV protection fractors, antioxidants, hydrotropes, preservatives, insect repellents, self-tanning agents, solubilizers, perfume oils, dyes, germ inhibitors and the like as further auxiliaries and additives.
Typical examples of suitable mild, i.e. dermatologically compatible, surfactants are fatty alcohol polyglycol ether sulfates, monoglyceride sulfates, mono- and/or dialkylsulfosuccinates, fatty acid isethionates, fatty acid sarcosinates, fatty acid taurides, fatty acid glutamates, ether carboxylic acids, alkyl oligoglucosides, fatty acid glucamides, alkyl amidobetaines and/or protein fatty acid condensates (preferably based on wheat proteins).
Suitable oil components are, for example, Guerbet alcohols based on fatty alcohols containing 6 to 18 and preferably 8 to 10 carbon atoms, esters of linear C6-22 fatty acids with linear C6-22 fatty alcohols, esters of branched C6-13 carboxylic acids with linear C6-22 fatty alcohols, esters of linear C6-22 fatty acids with branched alcohols, more particularly 2-ethyl hexanol, esters of hydroxycarboxylic acids with linear or branched C6-22 fatty alcohols, more particularly dioctyl malate, esters of linear and/or branched fatty acids with polyhydric alcohols (for example propylene glycol, dimer diol or trimer triol) and/or Guerbet alcohols, triglycerides based on C6-10 fatty acids, liquid mono-/di-/triglyceride mixtures based on C6-18 fatty acids, esters of C6-22 fatty alcohols and/or Guerbet alcohols with aromatic carboxylic acids, more particularly benzoic acid, esters of C2-12 dicarboxylic acids with linear or branched alcohols containing 1 to 22 carbon atoms or polyols containing 2 to 10 carbon atoms and 2 to 6 hydroxyl groups, vegetable oils, branched primary alcohols, substituted cyclohexanes, linear and branched C6-22 fatty alcohol carbonates, Guerbet carbonates, esters of benzoic acid with linear and/or branched C6-22 alcohols (for example Finsolv(copyright) TN), linear or branched, symmetrical or nonsymmetrical dialkyl ethers containing 6 to 22 carbon atoms per alkyl group, ring opening products of epoxidized fatty acid esters with polyols, silicone oils and/or aliphatic or naphthenic hydrocarbons.
Suitable emulsifiers are, for example, nonionic surfactants from at least one of the following groups:
(1) products of the addition of 2 to 30 moles of ethylene oxide and/or 0 to 5 moles of propylene oxide onto linear fatty alcohols containing 8 to 22 carbon atoms, onto fatty acids containing 12 to 22 carbon atoms and onto alkylphenols containing 8 to 15 carbon atoms in the alkyl group;
(2) C12/18 fatty acid monoesters and diesters of addition products of 1 to 30 moles of ethylene oxide onto glycerol;
(3) glycerol monoesters and diesters and sorbitan monoesters and diesters of saturated and unsaturated fatty acids containing 6 to 22 carbon atoms and ethylene oxide adducts thereof;
(4) alkyl mono- and oligoglycosides containing 8 to 22 carbon atoms in the alkyl group and ethoxylated analogs thereof;
(5) products of the addition of 15 to 60 moles of ethylene oxide onto castor oil and/or hydrogenated castor oil;
(6) polyol esters and, in particular, polyglycerol esters such as, for example, polyglycerol polyricinoleate, polyglycerol poly-12-hydroxysterate or polyglyerol dimerate isostearate. Mixtures of compounds from several of these classes are also suitable;
(7) products of the addition of 2 to 15 moles of ethylene oxide onto castor oil and/or hydrogenated castor oil;
(8) partial esters based on linear, branched, unsaturated or saturated C6/22 fatty acids, ricinoleic acid and 12-hydroxystearic acid and glycerol, polyglycerol, pentaerythritol, dipentaerythritol, sugar alcohols (for example sorbitol), alkyl glucosides (for example methyl glucoside, butyl glucoside, lauryl glucoside) and polyglucosides (for example cellulose);
(9) mono-, di- and trialkyl phosphates and mono-, di- and/or tri-PEG-alkyl phosphates and salts thereof;
(10) wool wax alcohols;
(11) polysiloxane/polyalkyl polyether copolymers and corresponding derivatives;
(12) mixed esters of pentaerythritol, fatty acids, citric acid and fatty alcohol according to DE 11 65 574 PS and/or mixed esters of fatty acids containing 6 to 22 carbon atoms, methyl glucose and polyols, preferably glycerol or polyglycerol;
(13) polyalkylene glycols and
(14) glycerol carbonate.
Products of the addition of ethylene oxide and/or propylene oxide onto fatty alcohols, fatty acids, alkylphenols, glycerol monoesters and diesters and sorbitan monoesters and diesters of fatty acids or onto castor oil are known commercially available products. They are homolog mixtures of which the average degree of alkoxylation corresponds to the ratio between the quantities of ethylene oxide and/or propylene oxide and substrate with which the addition reaction is carried out. C12/18 fatty acid monoesters and diesters of addition products of ethylene oxide onto glycerol are known as refatting agents for cosmetic compositions from DE 20 24 051 PS.
C8/18 alkyl mono- and oligoglycosides, their production and their use are known from the prior art. They are produced in particular by reacting glucose or oligosaccharides with primary alcohols containing 8 to 18 carbon atoms. So far as the glycoside component is concerned, both monoglycosides where a cyclic sugar unit is attached to the fatty alcohol by a glycoside bond and oligomeric glycosides with a degree of oligomerization of preferably up to about 8 are suitable. The degree of oligomerization is a statistical mean value on which a homolog distribution typical of such technical products is based.
In addition, zwitterionic surfactants may be used as emulsifiers. Zwitterionic surfactants are surface-active compounds which contain at least one quaternary ammonium group and at least one carboxylate and one sulfonate group in the molecule. Particularly suitable zwitterionic surfactants are the so-called betaines, such as the N-alkyl-N,N-dimethyl ammonium glycinates, for example cocoalkyl dimethyl ammonium glycinate, N-acylaminopropyl-N,N-dimethyl ammonium glycinates, for example cocoacylaminopropyl dimethyl ammonium glycinate, and 2-alkyl3-carboxymethyl-3-hydroxyethyl imidazolines containing 8 to 18 carbon atoms in the alkyl or acyl group and cocoacylaminoethyl hydroxyethyl carboxymethyl glycinate. The fatty acid amide derivative known under the CTFA name of Cocoamidopropyl Betaine is particularly preferred. Ampholytic surfactants are also suitable emulsifiers. Ampholytic surfactants are surface-active compounds which, in addition to a C8/18 alkyl or acyl group, contain at least one free amino group and at least one xe2x80x94COOHxe2x80x94or xe2x80x94SO3Hxe2x80x94 group in the molecule and which are capable of forming inner salts. Examples of suitable ampholytic surfactants are N-alkyl glycines, N-alkyl propionic acids, N-alkylaminobutyric acids, N-alkyliminodipropionic acids, N-hydroxyethyl-N-alkylamidopropyl glycines, N-alkyl taurines, N-alkyl sarcosines, 2-alkylaminopropionic acids and alkylaminoacetic acids containing around 8 to 18 carbon atoms in the alkyl group. Particularly preferred ampholytic surfactants are N-cocoalkylaminopropionate, cocoacylaminoethyl aminopropionate and C12/18 acyl sarcosine. Besides ampholytic emulsifiers, quaternary emulsifiers may also be used, those of the esterquat type, preferably methyl-quaternized difatty acid triethanolamine ester salts, being particularly preferred.
Superfatting agents may be selected from such substances as, for example, lanolin and lecithin and also polyethoxylated or acylated lanolin and lecithin derivatives, polyol fatty acid esters, monoglycerides and fatty acid alkanolamides, the fatty acid alkanolamides also serving as foam stabilizers.
Suitable pearlizing waxes are, for example, alkylene glycol esters, especially ethylene glycol distearate; fatty acid alkanolamides, especially cocofatty acid diethanolamide; partial glycerides, especially stearic acid monoglyceride; esters of polybasic, optionally hydroxysubstituted carboxylic acids with fatty alcohols containing 6 to 22 carbon atoms, especially long-chain esters of tartaric acid; fatty compounds, such as for example fatty alcohols, fatty ketones, fatty aldehydes, fatty ethers and fatty carbonates which contain in all at least 24 carbon atoms, especially laurone and distearylether; fatty acids, such as stearic acid, hydroxystearic acid or behenic acid, ring opening products of olefin epoxides containing 12 to 22 carbon atoms with fatty alcohols containing 12 to 22 carbon atoms and/or polyols containing 2 to 15 carbon atoms and 2 to 10 hydroxyl groups and mixtures thereof.
The consistency factors mainly used are fatty alcohols or hydroxyfatty alcohols containing 12 to 22 and preferably 16 to 18 carbon atoms and also partial glycerides, fatty acids or hydroxyfatty acids. A combination of these substances with alkyl oligoglucosides and/or fatty acid N-methyl glucamides of the same chain length and/or polyglycerol poly-12-hydroxystearates is preferably used. Suitable thickeners are, for example, polysaccharides, more especially xanthan gum, guar-guar, agar-agar, alginates and tyloses, carboxymethyl cellulose and hydroxyethyl cellulose, also relatively high molecular weight polyethylene glycol monoesters and diesters of fatty acids, polyacrylates (for example Carbopols(copyright) [Goodrich] or Synthalens(copyright) [Sigma]), polyacrylamides, polyvinyl alcohol and polyvinyl pyrrolidone, surfactants such as, for example, ethoxylated fatty acid glycerides, esters of fatty acids with polyols, for example pentaerythritol or trimethylol propane, narrow-range fatty alcohol ethoxylates or alkyl oligoglucosides and electrolytes, such as sodium chloride and ammonium chloride.
Suitable cationic polymers are, for example, cationic cellulose derivatives such as, for example, the quaternized hydroxyethyl cellulose obtainable from Amerchol under the name of Polymer JR 400xc2x0 , cationic starch, copolymers of diallyl ammonium salts and acrylamides, quaternized vinyl pyrrolidone/vinyl imidazole polymers such as, for example, Luviquat(copyright) (BASF), condensation products of polyglycols and amines, quaternized collagen polypeptides such as, for example, Lauryidimonium Hydroxypropyl Hydrolyzed Collagen (Lamequat(copyright) L, Grxc3xcnau GmbH), quaternized wheat polypeptides, polyethyleneimine, cationic silicone polymers such as, for example, amodimethicone, copolymers of adipic acid and dimethylaminohydroxypropyl diethylenetriamine (Cartaretine(copyright), Sandoz AG), copolymers of acrylic acid with dimethyl diallyl ammonium chloride (Merquat(copyright) 550, Chemviron), polyaminopolyamides as described, for example, in FR 2 252 840 A and crosslinked water-soluble polymers thereof, cationic chitin derivatives such as, for example, quatemized chitosan, optionally in microcrystalline distribution, condensation products of dihaloalkyls, for example dibromobutane, with bis-dialkylamines, for example bis-dimethylamino-1,3-propane, cationic guar gum such as, for example, Jaguar(copyright) CBS, Jaguar(copyright)C-17, Jaguar(copyright)C-16 of Celanese, USA, quaternized ammonium salt polymers such as, for example, Mirapol(copyright) A-15, Mirapol(copyright) AD-1, Mirapol(copyright) AZ-1 of Miranol, USA.
Suitable anionic, zwitterionic, amphoteric and nonionic polymers are, for example, vinyl acetate/crotonic acid copolymers, vinyl pyrrolidone/vinyl acrylate copolymers, vinyl acetate/butyl maleate/isobornyl acrylate copolymers, methyl vinylether/maleic anhydride copolymers and esters thereof, uncrosslinked and polyol-crosslinked polyacrylic acids, acrylamidopropyl trimethylammonium chloride/acrylate copolymers, octylacrylamide/methyl methacrylate/tert.-butylaminoethyl methacrylate/2-hydroxypropyl methacrylate copolymers, polyvinyl pyrrolidone, vinyl pyrrolidone/vinyl acetate copolymers, vinyl pyrrolidone/dimethylaminoethyl methacrylate/vinyl caprolactam terpolymers and optionally derivatized cellulose ethers and silicones.
Suitable silicone compounds are, for example, dimethyl polysiloxanes, methylphenyl polysiloxanes, cyclic silicones and amino-, fatty acid-, alcohol-, polyether-, epoxy-, fluorine-, glycoside- and/or alkyl-modified silicone compounds which may be both liquid and resin-like at room temperature. In addition, a detailed review of suitable liquid silicones was published by Todd et al. in Cosm. Toil. 91, 27 (1976).
Typical examples of fats are glycerides while suitable waxes are inter alia beeswax, carnauba wax, candelilla wax, montan wax, paraffin wax, hydrogenated castor oils, fatty acid esters solid at room temperature or microwaxes, optionally in combination with hydrophilic waxes, for example cetyl stearyl alcohol or partial glycerides. Metal salts of fatty acids such as, for example, magnesium, aluminum and/or zinc stearate or ricinoleate, may be used as stabilizers.
In the context of the invention, biogenic agents are, for example, tocopherol, tocopherol acetate, tocopherol palmitate, ascorbic acid, deoxyribonucleic acid, retinol, bisabolol, allantoin, phytantriol, panthenol, AHA acids, amino acids, ceramides, pseudoceramides, essential oils, plant extracts and vitamin complexes.
Suitable deodorizers are, for example, antiperspirants, such as aluminum chlorhydrates. These antiperspirants are colorless hygroscopic crystals which readily deliquesce in air and which accumulate when aqueous aluminum chloride solutions are concentrated by evaporation. Aluminum chlorhydrate is used for the production of perspiration-inhibiting and deodorizing compositions and probably acts by partially blocking the sweat glands through the precipitation of proteins and/or polysaccharides [cf. J. Soc. Cosm. Chem. 24, 281 (1973)]. For example, an aluminum chlorhydrate which corresponds to the formula [Al2(OH)5Cl].2.5H2O and which is particularly preferred for the purposes of the invention is commercially available under the name of Locron(copyright) from Hoechst AG of Frankfurt, FRG [cf. J. Pharm. Pharmcol. 26, 531 (1975)]. Besides the chlorhydrates, aluminum hydroxylactates and acidic aluminum/zirconium salts may also be used. Other suitable deodorizers are esterase inhibitors, preferably trialkyl citrates, such as trimethyl citrate, tripropyl citrate, triisopropyl citrate, tributyl citrate and, in particular, triethyl citrate (Hydagen(copyright) CAT, Henkel KGaA, Dxc3xcsseldorf, FRG). Esterase inhibitors inhibit enzyme activity and thus reduce odor formation. The free acid is probably released through the cleavage of the citric acid ester, reducing the pH value of the skin to such an extent that the enzymes are inhibited. Other esterase inhibitors are sterol sulfates or phosphates such as, for example, lanosterol, cholesterol, campesterol, stigmasterol and sitosterol sulfate or phosphate, dicarboxylic acids and esters thereof, for example glutaric acid, glutaric acid monoethyl ester, glutaric acid diethyl ester, adipic acid, adipic acid monoethyl ester, adipic acid diethyl ester, malonic acid and malonic acid diethyl ester, hydroxycarboxylic acids and esters thereof, for example citric acid, malic acid, tartaric acid or tartaric acid diethyl ester. Antibacterial agents which influence the germ flora and destroy or inhibit the growth of perspiration-decomposing bacteria, may also be present in stick products. Examples of such antibacterial agents are chitosan, phenoxyethanol and chlorhexidine gluconate. 5-Chloro-2-(2,4-dichloro-phenoxy)-phenol, which is marketed under the name of Irgasan(copyright) by CibaGeigy of Basel, Switzerland, has also proved to be particularly effective.
Suitable antidandruff agents are climbazol, octopirox and zinc pyrithione. Standard film formers are, for example, chitosan, microcrystalline chitosan, quaternized chitosan, polyvinyl pyrrolidone, vinyl pyrrolidone/vinyl acetate copolymers, polymers of the acrylic acid series, quaternary cellulose derivatives, collagen, hyaluronic acid and salts thereof and similar compounds. Suitable swelling agents for aqueous phases are montmorillonites, clay minerals, Pemulen and alkyl-modified Carbopol types (Goodrich). Other suitable polymers and swelling agents can be found in R. Lochhead""s review in Cosm. Toil. 108, 95 (1993).
Examples of UV protection factors include organic substances (light filters) which are liquid or crystalline at room temperature and which are capable of absorbing ultraviolet radiation and of releasing the energy absorbed in the form of longer-wave radiation, for example heat. UV-B filters can be oil-soluble or water-soluble. The following are examples of oil-soluble substances:
3-benzylidene camphor or 3-benzylidene norcamphor and derivatives thereof, for example 3-(4-methylbenzylidene)-camphor, as described in EP 0693471 B1;
4-aminobenzoic acid derivatives, preferably 4-(dimethylamino)-benzoic acid-2-ethylhexyl ester, 4-(dimethylamino)-benzoic acid-2-octyl ester and 4-(dimethylamino)-benzoic acid amyl ester;
esters of cinnamic acid, preferably 4-methoxycinnamic acid-2-ethylhexyl ester, 4-methoxycinnamic acid propyl ester, 4-methoxycinnamic acid isoamyl ester, 2-cyano-3,3-phenylcinnamic acid-2-ethylhexyl ester (Octocrylene);
esters of salicylic acid, preferably salicylic acid-2-ethylhexyl ester, salicylic acid-4-isopropylbenzyl ester, salicylic acid homomenthyl ester;
derivatives of benzophenone, preferably 2-hydroxy-4-methoxy-benzophenone, 2-hydroxy-4-methoxy-4xe2x80x2-methylbenzophenone, 2,2xe2x80x2 -dihydroxy-4-methoxybenzophenone;
esters of benzalmalonic acid, preferably 4-methoxybenzalmalonic acid di-2-ethylhexyl ester;
triazine derivatives such as, for example, 2,4,6-trianilino-(p-carbo-2xe2x80x2-ethyl-1xe2x80x2-hexyloxy)-1,3,5-triazine and Octyl Triazone, as described in EP0 818 450 A1;
propane-1,3-diones such as, for example, 1-(4-tert.butylphenyl)-3-(4xe2x80x2-methoxyphenyl)-propane-1,3-dione;
ketotricyclo(5.2.1)decane derivatives, as described in EP 0 694 521 B1.
Suitable water-soluble substances are
2-phenylbenzimidazole-5-sulfonic acid and alkali metal, alkaline earth metal, ammonium, alkylammonium, alkanolammonium and glucam-monium salts thereof;
sulfonic acid derivatives of benzophenones, preferably 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid and salts thereof;
sulfonic acid derivatives of 3-benzylidene camphor such as, for example, 4-(2-oxo-3-bornylidenemethyl)-benzene sulfonic acid and 2-methyl-5-(2-oxo-3-bornylidene)-sulfonic acid and salts thereof.
Typical UV-A filters are, in particular, derivatives of benzoyl methane such as, for example I-(4xe2x80x2-tert.butylphenyl)-3-(4xe2x80x2-methoxyphenyl)-propane-1,3-dione, 4-tert-butyl4xe2x80x2-methoxydibenzoylmethane (Parsol 1789) or 1-phenyl-3-(4xe2x80x2-isopropylphenyl)-propane-1,3-dione. The UV-A and UV-B filters may of course also be used in the form of mixtures. Besides the soluble substances mentioned, insoluble pigments, i.e. finely dispersed metal oxides or salts, may also be used for this purpose. Examples of suitable metal oxides are, in particular, zinc oxide and titanium dioxide and also oxides of iron, zirconium, silicon, manganese, aluminum and cerium and mixtures thereof. Silicates (talcum), barium sulfate and zinc stearate may be used as salts. The oxides and salts are used in the form of the pigments for skin-care and skin-protecting emulsions and decorative cosmetics. The particles should have an average diameter of less than 100 nm, preferably from 5 to 50 nm and more preferably from 15 to 30 nm. They may be spherical in shape although ellipsoidal particles or other non-spherical particles may also be used. So-called micro- or nanopigments are preferably used in sun protection products. Micronized zinc oxide is preferably used.
Other suitable UV filters can be found in P. Finkel""s review in Sxc3x96FW-Journal 122, 543 (1996).
Besides the two above-mentioned groups of primary protection factors, secondary protection factors of the antioxidant type may also be used. Secondary sun protection factors of the antioxidant type interrupt the photochemical reaction chain which is initiated when UV rays penetrate into the skin. Typical examples of suitable antioxidants are amino acids (for example glycine, histidine, tyrosine, tryptophane) and derivatives thereof, imidazoles (for example urocanic acid) and derivatives thereof, peptides, such as D,L-carnosine, D-carnosine, L-camosine and derivatives thereof (for example anserine), carotinoids, carotenes (for example xcex1-carotene, xcex2-carotene, lycopene) and derivatives thereof, chlorogenic acid and derivatives thereof, liponic acid and derivatives thereof (for example dihydroliponic acid), aurothioglucose, propylthiouracil and other thiols (for example thioredoxine, glutathione, cysteine, cystine, cystamine and glycosyl, N-acetyl, methyl, ethyl, propyl, amyl, butyl and lauryl, palmitoyl, oleyl, xcex-linoleyl, cholesteryl and glyceryl esters thereof) and their salts, dilaurylthiodipropionate, distearylthiodipropionate, thiodipropionic acid and derivatives thereof (esters, ethers, peptides, lipids, nucleotides, nucleosides and salts) and sulfoximine compounds (for example butionine sulfoximines, homocysteine sulfoximine, butionine sulfones, penta-, hexa- and hepta-thionine sulfoximine) in very small compatible dosages (for example pmole to xcexcmole/kg), also (metal) chelators (for example xcex1-hydroxyfatty acids, palmitic acid, phytic acid, lactoferrine), xcex1-hydroxy acids (for example citric acid, lactic acid, malic acid), humic acid, bile acid, bile extracts, bilirubin, biliverdin, EDTA, EGTA and derivatives thereof, unsaturated fatty acids and derivatives thereof (for example xcex3-linolenic acid, linoleic acid, oleic acid), folic acid and derivatives thereof, ubiquinone and ubiquinol and derivatives thereof, vitamin C and derivatives thereof (for example ascorbyl palmitate, Mg ascorbyl phosphate, ascorbyl acetate), tocopherols and derivatives (for example vitamin E acetate), vitamin A and derivatives (vitamin A palmitate) and coniferyl benzoate of benzoin resin, rutinic acid and derivatives thereof, xcex1-glycosyl rutin, ferulic acid, furfurylidene glucitol, carnosine, butyl hydroxytoluene, butyl hydroxyanisole, nordihydroguaiac resin acid, nordihydroguaiaretic acid, trihydroxybutyrophenone, uric acid and derivatives thereof, mannose and derivatives thereof, Superoxid-Dismutase, zinc and derivatives thereof (for example ZnO, ZnSO4), selenium and derivatives thereof (for example selenium methionine), stilbenes and derivatives thereof (for example stilbene oxide, trans-stilbene oxide) and derivatives of these active substances suitable for the purposes of the invention (salts, esters, ethers, sugars, nucleotides, nucleosides, peptides and lipids).
Suitable preservatives are, for example, phenoxyethanol, formaldehyde solution, parabens, pentanediol or sorbic acid and the other classes of compounds listed in Appendix 6, Parts A and B of the Kosmetikverordnung (xe2x80x9cCosmetics Directivexe2x80x9d). Suitable insect repellents are N,N-diethyl-m-toluamide, pentane-1,2-diol or Insect Repellent 3535. A suitable self-tanning agent is dihydroxyacetone.
Suitable perfume oils are mixtures of natural and synthetic fragrances. Natural fragrances include the extracts of blossoms (lily, lavender, rose, jasmine, neroli, ylang-ylang), stems and leaves (geranium, patchouli, petitgrain), fruits (anise, coriander, caraway, juniper), fruit peel (bergamot, lemon, orange), roots (nutmeg, angelica, celery, cardamon, costus, iris, calmus), woods (pinewood, sandalwood, guaiac wood, cedarwood, rosewood), herbs and grasses (tarragon, lemon grass, sage, thyme), needles and branches (spruce, fir, pine, dwarf pine), resins and balsams (galbanum, elemi, benzoin, myrrh, olibanum, opoponax). Animal raw materials, for example civet and beaver, may also be used. Typical synthetic perfume compounds are products of the ester, ether, aldehyde, ketone, alcohol and hydrocarbon type. Examples of perfume compounds of the ester type are benzyl acetate, phenoxyethyl isobutyrate, p-tert.butyl cyclohexylacetate, linalyl acetate, dimethyl benzyl carbinyl acetate, phenyl ethyl acetate, linalyl benzoate, benzyl formate, ethylmethyl phenyl glycinate, allyl cyclohexyl propionate, styrallyl propionate and benzyl salicylate. Ethers include, for example, benzyl ethyl ether while aldehydes include, for example, the linear alkanals containing 8 to 18 carbon atoms, citral, citronellal, citronellyloxyacetaldehyde, cyclamen aldehyde, hydroxycitronellal, lilial and bourgeonal. Examples of suitable ketones are the ionones, xcex1-isomethylionone and methyl cedryl ketone. Suitable alcohols are anethol, citronellol, eugenol, isoeugenol, geraniol, linalool, phenylethyl alcohol and terpineol. The hydrocarbons mainly include the terpenes and balsams. However, it is preferred to use mixtures of different perfume compounds which, together, produce an agreeable fragrance. Other suitable perfume oils are essential oils of relatively low volatility which are mostly used as aroma components. Examples are sage oil, camomile oil, clove oil, melissa oil, mint oil, cinnamon leaf oil, lime-blossom oil, juniper berry oil, vetiver oil, olibanum oil, galbanum oil, labolanum oil and lavendin oil. The following are preferably used either individually or in the form of mixtures: bergamot oil, dihydromyrcenol, lilial, lyral, citronellol, phenylethyl alcohol, xcex1-hexylcinnamaldehyde, geraniol, benzyl acetone, cyclamen aldehyde, linalool, Boisambrene Forte, Ambroxan, indole, hedione, sandelice, citrus oil, mandarin oil, orange oil, allylamyl glycolate, cyclovertal, lavendin oil, clary oil, xcex2-damascone, geranium oil bourbon, cyclohexyl salicylate, Vertofix Coeur, Iso-E-Super, Fixolide NP, evernyl, iraldein gamma, phenylacetic acid, geranyl acetate, benzyl acetate, rose oxide, romillat, irotyl and floramat.
Suitable dyes are any of the substances suitable and approved for cosmetic purposes as listed, for example, in the publication xe2x80x9cKosmetische Fxc3xa4rbemittelxe2x80x9d of the Farbstoffkommission der Deutschen Forschungs-gemeinschaft, Verlag Chemie, Weinheim, 1984, pages 81 to 106. These dyes are normally used in concentrations of 0.001 to 0.1% by weight, based on the mixture as a whole.
Typical examples of germ inhibitors are preservatives which act specifically against gram-positive bacteria such as, for example, 2,4,4xe2x80x2-trichloro-2xe2x80x2-hydroxydiphenyl ether, chlorhexidine (1,6-di-(4-chlorophenyl-biguanido)-hexane) or TCC (3,4,4xe2x80x2-trichlorocarbanilide). Numerous perfumes and essential oils also have antimicrobial properties. Typical examples are the active substances eugenol, menthol and thymol in clove, mint and thyme oil. An interesting natural deodorant is the terpene alcohol farnesol (3,7,11-trimethyl-2,6,10-dodecatrien-1-ol) which is present in linden blossom oil and which smells of lily-of-the-valley. Glycerol monolaurate has also been successfully used as a bacteriostatic agent. The percentage content of the additional germ-inhibiting agents is normally about 0.1 to 2% by weight, based on the solids component of the preparations.
The total percentage content of auxiliaries and additives may be from 1 to 50% by weight and is preferably from 5 to 40% by weight, based on the particular composition. The compositions may be produced by standard hot or cold processes and are preferably produced by the phase inversion temperature method.


The invention is based on the discovery that angiogenic vessels have heterogeneous surface charge and that cationic liposomes actually target human tumor blood vessels only in irregularly shaped patches. The invention thus features methods for delivering therapeutic compounds to angiogenic vascular endothelial surfaces using a mixture, or xe2x80x9ccocktailxe2x80x9d, of positively charged and neutral liposomes. The new methods can be used to target multiple regions on the same tumor vessel and/or clusters of vessels within the same tumor. Liposomes with different chemical and/or physical properties (e.g., charge, stability, solubility, diameter) can be delivered simultaneously, and can target tumor vessels and other angiogenic vessels with greater efficiency compared to cationic liposomes alone.

The invention relates to drug delivery.
The efficiency of drug transport to solid tumors can vary as a function of host microenvironment, tumor type, and growth. Several barriers have been shown to impede delivery of therapeutics to solid tumors in clinically relevant concentrations (Jain, Scientific American, 271(1):58-65, 1994). These barriers include a heterogeneous blood supply, elevated tumor interstitial pressure (Jain, Nature Medicine, 6:655-657, 1998), and a dynamic range of tumor blood vessel pore sizes (Hobbs et al., Proc. Natl. Acad. Sci. USA, 95:4607-4612, 1998). Delivery of drugs to solid tumors can thus present a formidable challenge.
Studies have shown anatomical and morphological differences between normal and tumor blood vessels (Baldwin et al., Microvascular Research, 42:160-178, 1991). Most tumors are angiogenesis-dependent (Folkman, Journal of the National Cancer Institute, 82(1):4-6, 1989), requiring the development of new blood vessels. The glycoprotein layer of the vascular endothelium of angiogenic blood vessels is composed primarily of negatively charged functional groups (Baldwin et al., Microvascular Research, 42:160-178, 1991). These functional groups can facilitate molecular interactions with positively charged macromolecules (Dellian et al., British Journal of Cancer, 82:1513-1518, 2000). Accordingly, it was hypothesized that cationic liposomes could be used to target tumor vessels where established glycoprotein layers had formed. Indeed, it was found that cationic liposomes are taken up by tumor vessels to a greater extent than by the normal vascular endothelia. Cationic liposomes have thus been used to target anionic endothelial cells in tumors and chronic inflammation in mice, with some success (Thurston et al., Journal of Clinical Investigation 101:1401-1413, 1998; Roberts et al., Cancer Research 57:765-772, 1997).
In addition to tumor growth, numerous other disease states are associated with abnormal angiogenesis. Increased angiogenesis in the bones, joints, skin, liver, kidney, lung, ear, nerves, heart, skeletal muscles, adipose tissue, peritoneum pleura, endocrine organs, hematopoiesis, lymph, and other organs and systems, for example, is associated with tumors and chronic inflammation in those organs, as well as obesity, warts, uterine bleeding, and respiratory disease. On the other hand, vascular insufficiency is associated with diseases such as aseptic necrosis, impaired healing of fractures, decubitus or stasis ulcers, gastrointestinal ulcers, pulmonary and systemic hypertension, placental insufficiency, stroke, vascular dementia, Alzheimer""s disease, CADASIL, ischemic heart and limb disease, and thyroid pseudocysts. Other vascular abnormalities have been implicated in psoriasis, diabetes, and hypertension.
The invention is based on the discovery that angiogenic vessels have heterogeneous surface charge and that cationic liposomes actually target human tumor blood vessels only in irregularly shaped patches. The invention thus features methods for delivering therapeutic compounds to angiogenic vascular endothelial surfaces using a mixture, or xe2x80x9ccocktailxe2x80x9d, of positively charged and neutral liposomes. The new methods can be used to target multiple regions on the same tumor vessel and/or clusters of vessels within the same tumor. Liposomes with different chemical and/or physical properties (e.g., charge, stability, solubility, diameter) can be delivered simultaneously, and can target tumor vessels and other angiogenic vessels with greater efficiency compared to cationic liposomes alone.
In general, the invention features a formulation that includes cationic liposomes, containing a first therapeutic agent, and electrostatically neutral liposomes, containing a second therapeutic agent, where the first and second therapeutic agents can be the same or different. Each therapeutic agent can include, for example, one or more compound that have, or are suspected to have, some biological activity, as well as other additives and excipients. Preferably, such additives or excipients are substantially non-toxic at the concentration and quantity employed. The cationic and neutral liposomes can be present in various ratios (e.g., between about 1:9 and 9:1, between about 1:3 and 3:1, or between about 2:3 and 3:2, such as about 1:1. Either or both of the first and second therapeutic agents can be, for example, an anti-tumor drug (e.g., a chemotherapeutic agent such as paclitaxel, doxorubicin, or other plant alkaloids, antibiotics, alkylating agents, antimetabolites, or miscellaneous agents), a nucleic acid, or another natural or synthetic therapeutic agent. The cationic lipids can include, for example, dioleoyltrimethyl-ammonium propane (DOTAP), N-[1-(2,3-dioleoyloxy)-propyl]-N,N,N-trimethylammonium chloride (DOTMA), dimethyldioctadecylammonium bromide (DDAB), 1,2-dimyristyloxypropyl-3-dimethylhydroxyethyl (DMRIE), dioleoyl-3-dimethylammonium propane (DODAP), N,N-dioleyl-N,N-dimethylammonium chloride (DODAC), or N-(1-(2,3-dioleyloxy)propyl)-N-(2-(sperminecarboxamido)ethyl)-N,N-dimethyl ammonium trifluoroacetate (DOSPA), or any other natural or synthetic cationic lipids. The neutral liposomes can include, for example, dioleoylphosphatidyl-choline (DOPC), dipalmitoylphosphatidylcholine (DPPC), disteroylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), or 1,2-sn-dioleoylphosphatidylcholine (DOPE), or any other natural or synthetic electrostatically neutral lipids.
The invention also features several methods of administering a drug to a patient. One method includes the steps of providing a formulation as described above (i.e., where at least one of the first and second therapeutic agents includes the drug to be administered), and administering the formulation to the patient (e.g., intravenously or intraarterially or by any other suitable route). The patient can be, for example, a patient suspected of having a tumor. The patient can be, for example, a mammal such as a human, a mouse, a rat, a sheep, a goat, a dog, a cat, a pig, a cow, or other animal used for research, human companionship, agriculture, or consumption. Another method includes administering to the patient a formulation that includes a heterogeneously charged drug delivery system that can include liposomes or other drug carriers. A third method includes administering to the patient two differently charged therapeutic formulations, either or both of which can include the drug.
The invention provides several advantages. Liposome formulations can function as vascular targeting systems. Several reasons currently exist for applying vascular targeting strategies. First, damage to even a single vessel can leaves hundreds or thousands of neoplastic cells starving for nutrients, resulting in the death of a significant number of malignant cells. The blood vessels carry nutrients to the cells; without the nutrients, the cells cannot survive. Second, the physical barriers that impede delivery of drugs to solid tumors do not provide an obstacle to drug delivery to the vascular endothelium. The new methods are also not limited to delivery of therapeutics to tumor interstitial space where the majority of tumor cells reside. Additionally, the vascular targeting agent can target both the tumor vascular endothelium and a percentage of tumor cells in the tumor interstitium, resulting in additional gains in therapy. Third, endothelial cells are generally non-malignant, although they can in some cases mutate as a tumor progresses. As a result, mutant phenotypes are rare, and drug resistance is unlikely to arise.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
The new formulations and methods provide improved vascular targeting of drugs to solid tumors. Liposomes that include PEG lipids conjugated to phospholipid surfaces can enhance systemic circulation, reduce side effects (e.g., nausea, vomiting, headache, leukopenia), and to improve the general therapeutic dose.
We have discovered that the charge lining the vascular endothelium of tumor vessels is heterogeneous, and that overall vascular targeting efficiency can be improved by intravenously injecting a mixture of cationic and neutral liposomes simultaneously. We have found that this method enhances uptake of liposomes. Tumor charge heterogeneity can thus be exploited to optimally deliver therapeutics to blood vessels of solid tumors. The new formulations and methods thus improve delivery of drugs, for example, to the vasculature of solid tumors and angiogenic tissue, and increase the probability of tumor cell death. Moreover, while cationic liposomes target the vascular surface, electrostatically neutral liposomes can associate with the vascular wall. Due to large tumor vascular pore sizes, they also have the ability to extravasate into tumoral tissues over time. Hence, although the normal vasculature may take up some of the drug carried by the neutral liposomes, the total accumulation in tumors is still greater.
Liposome Formulations
The new formulations generally include both cationic liposomes and electrostatically neutral liposomes.
The ratio of cationic liposomes to neutral liposomes will depend on the desired overall percent charge. The optimal percent charge for a particular tumor type can be determined by preparing a series of formulations with different percent charges (e.g., from 0% to about 50%), then determining which formulation best targets the tumor vasculature. Targeting can be quantified by intravital microscopy of cationic liposomes at the tumor vascular surface in vivo, according to the methods used in Fan Yuan et al. (Cancer Research, 54:3352-3356, 1994) to study microvascular permeability and interstitial penetration of sterically stabilized (xe2x80x9cstealthxe2x80x9d) liposomes in a human tumor xenograft.
The half-life of the new liposome formulations in blood varies as a function of percent charge. Plasma clearance curves associated with the new formulations indicate that high percent charge liposomal formulations clear faster than lower percent charged formulations do. Optionally, circulation times be extended by temporarily blocking the reticuloendothelial system (RES), which can function to eliminate liposomes from systemic circulation.
In general, the liposomes are prepared as follows: A desired phospholipid composition is selected for use in making the liposomes. The selected lipids can be freeze-dried or lyophilized (e.g., to enhance lipid packing and/or eliminate trace amounts of organic solvents). An optimal number of phosopholipid head groups are exposed for efficient hydration in a desired buffer (e.g., 50:50 saline/distilled water, 308 mM NaCl, or 40 mM Hepes; pH 7.4) to form liposomes of acceptable grade. The liposomes can be fixed to a specific size by using an extruder that contains special membranes containing fixed pore sizes (e.g., 100 nm). The cationic and neutral liposomes are then combined to yield a desired ratio (e.g., from about 1:9 to about 9:1, e.g., about 3:2 to about 2:3).
The neutral liposomes can be prepared, for example, from dioleoylphosphatidyl-choline (DOPC), cholesterol (CHOL), and polyethylene glycol (PEG) in various ratios (e.g., 50:45:5). Other electrostatically neutral phospholipids (e.g., dipalmitoylphosphatidylcholine (DPPC), disteroylphosphatidylcholine (DSPC), dimyristoylphosphatidylcholine (DMPC), or 1,2-sn-dioleoylphosphatidylcholine (DOPE), or other synthetic or naturally occurring electrostatically neutral lipids) can be substituted for DOPC. These and other components can be purchased, for example, from Avanti Polar Lipids, Inc. (Alabaster, Ala.).
The cationic liposomes can be prepared from DOPC, CHOL, dioleoyltrimethyl-ammonium propane (DOTAP), and PEG in various ratios (e.g., 35:10:50:5 or 45:10:40:5), to yield a desired net positive charge (defined as mole fraction of cationic lipids divided by mole fraction of all lipids in the cationic liposome) at physiological pH (e.g., pH 7.4). DOTAP has low toxicity in vivo, but other cationic lipids (e.g., N-[1-(2,3-dioleoyloxy)-propyl]-N,N,N-trimethylammonium chloride (DOTMA), dimethyldioctadecylammonium bromide (DDAB), 1,2-dimyristyloxypropyl-3-dimethylhydroxyethyl (DMRIE), dioleoyl-3-dimethylammonium propane (DODAP), N,N-dioleyl-N,N-dimethylammonium chloride, (DODAC), N-(1-(2,3-dioleyloxy)propyl)-N-(2-(sperminecarboxamido)ethyl)-N,N-dimethyl ammonium trifluoroacetate (DOSPA), or other synthetic or naturally occurring cationic lipids) can be used in its place.
The size of the liposomes can also affect selectivity. Prolonged circulation time of liposomes enhances target binding and retention of liposomes. Relatively small liposomes (e.g., 200 nm or smaller) circulate longer than large liposomes (e.g., 500 nm or larger). Moreover, incorporation of polyethylene glycol derivatized with phosphatidyl ethanolamine (PEG-PE) into the formulations of the individual liposomes can prolong circulation time, possibly by providing a steric barrier that prevents close contact with other liposomes or cells. Cationic liposomes without PEG are taken up by the reticuloendothelial system (RES) at a much higher rate than PEGylated cationic liposomes are.
Both hydrophobic and water-soluble drugs can be incorporated or encapsulated in the new formulations. Paclitaxel, a chemotherapeutic drug used to treat solid malignancies such as breast, ovarian, head, and neck cancer, for example, can be stably incorporated into a liposome cocktail. Similarly, doxorubicin can be incorporated into the new liposome cocktails to achieve better vascular targeting than that observed with standard doxorubicin/liposome preparations such as DOXIL(copyright). Other chemotherapeutic agents such as alkylating agents (e.g., mechlorethamine hydrochloride, cyclophosphamide, ifosfamide, chlorambucil, melphalan, busulfan, thiotepa, carmustine, lomustine, streptozocin), plant alkaloids (e.g., vincristine, vinblastine, vinorelbine, docetaxel), antimetabolites (e.g., methotrexate, mercaptopurine, thioguanine, fluorouracil, cytarabine, azacitidine, fludarabine, cladribine, pentostatin), antibiotics (e.g., dactinomycin, daunorubicin, idarubicin, mitoxantrone, bleomycin, plicamycin, mitomycin), or miscellaneous agents (e.g., hydroxyurea, procarbazine, dacarbazine, cisplatin, carboplatin, asparaginase, etoposide, amsacrine, mitotane, topotecan, tretinoin) can also be incorporated into the cocktails, either alone or in combination, as can other natural or synthetic therapeutic agents such as those listed in the Merck Manual and/or the Merck Index, both of which are incorporated by reference.
Nucleic acids such as DNA can also be incorporated into the new liposome cocktails (e.g., for gene therapy applications and for delivery of immunostimulatory agents such as poly I:C). The positively charged lipids of the cationic liposomes can form an electrostatic complex with the phosphate backbone of the DNA. This interaction can facilitate delivery and uptake of DNA by cells.
The binding of cationic liposomes to tumor vascular endothelium is heterogeneous. The liposome formulations of the invention accordingly provide a new approach to the delivery of clinically relevant concentrations of drugs to tumors. Liposome formulations containing only cationic liposomes lack the ability to target the heterogeneous tissue as thoroughly as the new formulations do. The new formulations can also include liposomes varying in pharmacokinetic profiles. For example, charge appears to regulate liposome plasma clearance rates.
PEGylated cationic liposomes (including 5 mol % PEG) having 10% or 20% net positive charge clear the blood at a rate much slower than that of PEGylated cationic liposomes containing 40% or 50% net positive charges. Liposomes having such different plasma clearance rates can be used together to enhance therapy. In addition, electrostatically neutral liposomes have a plasma clearance kinetic profile completely different from that of charged liposomes, and thus further regulate the clearance profile of a given liposome cocktail of the invention. The combination of liposomes having different surface charges and plasma clearance rates can be advantageous for cancer therapy, since one type of liposome may work immediately, while another remains in circulation, available to target the tumor at a later point in time.

Drug delivery formulations and targeting


An antibiotic film comprises at least one organic polymeric film containing antibiotic zeolite, in which the content of the antibiotic zeolite is 10 to 100 mg per 1 m.sup.2 of the organic polymeric film and the thickness of the organic polymeric film is not more than 15 microns and an antibiotic laminated film comprises a substrate, at least one side of which is laminated with the aforementioned antibiotic film. These films exhibit excellent antibiotic action although they contain rather small amount of antibiotic zeolite and the films also exhibit high transparency. These films can be used as materials for packaging foods, medical equipments and accessories and the like.

1. Field of the Invention
The present invention relates to an antibiotic zeolite-containing film and more particularly to an antibiotic zeolite-containing film exhibiting satisfactory antibiotic action although it contains a relatively small amount of antibiotic zeolite and having a high transparency as well as an antibiotic laminated film comprised of a substrate, at least one side of which is laminated with such antibiotic zeolite-containing film(s).
2. Description of the Prior Art
There have been known so-called antibiotic zeolites comprised of zeolites carrying antibiotic metals such as silver, copper and zinc (see, for instance, Japanese Patent Publication for Opposition Purpose (hereinafter referred to as "J. P. KOKOKU") No. 61-22977 and Japanese Patent Unexamined Publication (hereinafter referred to as "J. P. KOKAI") No. 60-181002). Moreover, it is also known that such a zeolite can be incorporated into materials such as resins to impart antibiotic action to such materials (see, for instance, J. P. KOKAI No. 59-133235).
However, the antibiotic zeolites are rather expensive. Therefore, it is necessary, from a practical point of view, to impart sufficient antibiotic action to resins while using the antibiotic zeolite as small amounts as possible. However, in the method disclosed in J. P. KOKAI No. 59-133235, the antibiotic zeolite is dispersed in whole the molded resin products, which leads to the formation of very expensive antibiotic resin products.
There is another problem, concerning the use of the antibiotic zeolite in materials such as resins, that the resins or the like tends to cause the reduction in their transparency if the antibiotic zeolite is used in an amount greater than a certain limit. Therefore, a relatively thick film obtained by simply forming a resin admixed with such antibiotic zeolite into a film exhibits low transparency and the commercial value thereof as a transparent film also becomes low.

by Yuriko Niira, Kiyotaka Niira, Hideaki Niira, legal heirs


The invention provides a rotor nozzle, comprising a casing and a rotor body arranged therein. The rotor body has a flow-through channel and a spherical bearing part in a step bearing surrounding an exit opening of the casing. An end part closes the casing and has several selectively closable passages arranged therein which open from an inlet side into the interior of the casing or into flow channels in the casing leading to additional outlets. The end part widens in steps from the interior to the inlet side, and is inserted into a stepped receiving opening. A seal is provided between the end part and the inner wall of the receiving opening. An outlet for a passage of the end part is arranged in the area of at least one step and a flow channel begins in the casing in the area of this step.

The invention relates to a rotor nozzle, in particular, for a high-pressure cleaning device, comprising a casing and a rotor body which is arranged therein, has a flow-through channel and is accommodated with a spherical bearing part in a step bearing which surrounds an exit opening of the casing, an end part which closes the casing on the side located opposite the step bearing and in which several, selectively closable passages are arranged which open from an inlet side into the interior of the casing accommodating the rotor body or into flow channels in the casing which lead to additional outlets of the casing.
A rotor nozzle of this type is known, for example, from DE 43 19 743 A1. In this respect, two passages are provided in the end part which can be selectively closed or released via a spherical closure member so that liquid can be introduced either centrally into the interior closed by the casing or tangentially into it.
For reasons of space, it is extremely difficult to accommodate more than these two passages in the end part. In addition, it is hardly possible to provide additional possibilities for discharging the liquid, for example, via stationary compact nozzles or flat spray nozzles without increasing the diameter of the rotor nozzle.
The object of the invention is to design a generic rotor nozzle such that the possibility is created for additional passages and discharge points for the liquid whilst retaining a small constructional size for such a rotor nozzle.
This object is accomplished in accordance with the invention, for a rotor nozzle of the type described at the outset, in that the end part widens in steps in its longitudinal direction leading from the interior of the casing to its inlet side, that the end part is inserted into a stepped receiving opening in the casing which widens correspondingly, that a seal is provided between end part and the inner wall of the receiving opening above and below a respective step of the end part, that an outlet for a passage of the end part is arranged in the area of at least one step and that a flow channel begins in the casing in the area of this step.
This design makes it possible to accommodate additional passages in the end part in addition to the known, central passages and to connect these in a space-saving manner to flow channels which are incorporated in the wall of the casing and extend next to the interior of the casing in the casing itself, i.e., in the casing wall and lead to additional discharge points for the liquid. As a result, the constructional size of the rotor nozzle is not, altogether, increased; the space available is, on the contrary, utilized in an optimum manner as a result of the stepped design of the end part and the connection of the passages to the flow channels in the area of the steps.
It may be provided, in particular, for the outlets of the passages arranged in the area of the steps to exit from the end part transversely to the longitudinal direction at the level of the step.
The flow channels may extend in longitudinal direction in the casing in the area of the steps, i.e., abut on the interior on their outer side. As a result of the arrangement of the flow channels parallel to the longitudinal direction of the casing, a minimal space requirement is generated in a radial direction; since the flow channels are arranged in the area of the step, they do not project in a radial direction beyond the widest part of the end part but rather are located within the contour of the end part.
It is favorable when the steps of the end part and the steps of the casing are offset slightly relative to one another in longitudinal direction so that a gap results between them which provides a flow connection between the outlet of a passage and the beginning of a flow channel.
A particularly preferred development results when steps following one another in longitudinal direction are arranged on oppositely located sides of the end part. The space above the steps can then be used on both sides of the end part for accommodating the flow channel and so an optimum utilization of space results.
In a particularly preferred embodiment, it is provided for the sections of the end part separated from one another by the steps to each be of a circular-cylindrical design. This end part is then inserted in a sealed manner into sections of the receiving opening which are of a correspondingly circular-cylindrical shape.
The longitudinal axes of the circular-cylindrical sections, which adjoin a section located therebetween on both sides, are preferably arranged so as to be concentric to one another whereas the longitudinal axis of the section located therebetween is, in comparison, offset to the side. As a result, steps automatically result in the area of transition and these are arranged essentially on oppositely located sides of the end part.
In this respect, it is advantageous when the diameter of the section located therebetween is selected such that this merges into the adjoining, broader section without any steps on its side located opposite the step.
It is also favorable when the diameter of the narrower section is selected such that this merges into the section located therebetween without any steps on its side located opposite the step. In this way, the steps extend only over part of the circumference of the end part and become ever narrower towards the side located opposite.
In order to seal the end part in relation to the inner wall of the receiving bore, O-ring seals can be provided which are preferably inserted into circumferential grooves of the end part.
In a modified embodiment, it is provided for welding seams connecting the end part to the casing to be provided for sealing the end part in relation to the inner wall of the receiving bore. For example, this may be a weld connection, which is produced by way of a very localized application of ultrasonic energy, when a thermoplastic material is used for the end part and for the casing.
The flow channels in the casing preferably lead to nozzle members which form an outlet for the flow channels, for example, flat spray nozzles or atomizing nozzles for discharging a cleaning chemical.
These nozzle members may preferably be inserted into receiving recesses of the casing in a sealed manner.
It is particularly advantageous when two such flow channels are provided in the casing and they are located diametrically opposite one another.
A passage which enters the interior centrally parallel to the longitudinal direction may be provided in the end part.
In addition, an additional passage may be connected to channels which enter the interior with a tangential component remote from the central axis of the interior in such a manner that the liquid in the interior is caused to rotate about the central axis of the interior. As a result of this rotation, the rotor body mounted in the interior is also taken along and moves on a conical path.
These channels may be incorporated directly in the end part but in another preferred embodiment it is provided for the channels to be arranged in a cap which is placed in a sealed manner on the end part and covers a hollow space therein which communicates with a passage and with the channels.
In a preferred embodiment it is provided for the passages to enter the inlet side of the end part parallel to the longitudinal direction.
A receiving chamber for closure members, which close all the respective passages except for one, may be positioned in front of the inlet side of the end part.
These closure members are preferably spheres which can be mounted in the receiving chamber so as to be freely movable and are moved in front of the inlets to the corresponding passages, which they then close, with a corresponding orientation of the rotor nozzle and due to the action of the liquid, wherein the number of passages is always greater by one than the number of closure members.
It is favorable when the closure members are tensioned by springs against oppositely located entry openings of the passages.
A liquid connection can open into the receiving chamber, the end part and the casing being mounted on this liquid connection in a sealed manner and so as to be rotatable about the longitudinal axis of the end part. The user can, therefore, decide, when the supply of liquid is switched off, which of the passages are closed by a closure member and which passage remains open simply by turning the rotor nozzle in relation to the end part.
In a preferred embodiment, the casing and the end part inserted into it are covered by a hood.
This hood can secure the end part and the casing to a liquid connection so as to be axially non-displaceable and rotatable about the longitudinal axis of the end part.
The following description of preferred embodiments of the invention serves to explain the invention in greater detail in conjunction with the drawings.

Rotor nozzle, in particular, for a high-pressure cleaning device