A process for producing microparticles containing biologically active substance, in which process an aqueous solution of the said substance is prepared, this solution is mixed with an aqueous solution of PEG such that the substance is concentrated and/or solidified, the substance is optionally washed, the substance is mixed with an organic polymer solution, the composition obtained is mixed, after the admixture of said polymer solution, with an aqueous polymer solution, thereby forming an emulsion of droplets of first mentioned polymer as the internal phase, said droplets are solidified into microparticles, the microparticles are dried and a release-controlling shell is optionally applied to these.

The present invention lies within the field of galenic formulations for the administration of biologically active substances, more specifically microparticles for controlled release primarily intended for parenteral administration of biologically active substances, especially drugs. More specifically, it relates to a novel production process for such particles containing a biologically active substance and to a novel process for converting a water-soluble protein into a concentrated and/or solidified form thereof.
Many drugs have to be administered by injection, since they are either subjected to degradation or are insufficiently absorbed when they are given, for example, orally or nasally or by the rectal route. A drug preparation intended for parenteral use has to meet a number of requirements in order to be approved by the regulatory authorities for use on humans. It must therefore be biocompatible and biodegradable and all used substances and their degradation products must be non-toxic. In addition, particulate drugs intended for injection have to be small enough to pass through the injection needle, which preferably means that they should be smaller than 200 xcexcm. The drug should not be degraded in the preparation to any great extent during production or storage thereof or after administration and should be released in a biologically active form with reproducible kinetics.
One class of polymers which meets the requirements of biocompatibility and biodegradation into harmless end products is the linear polyesters based on lactic acid, glycolic acid and mixtures thereof. These polymers will also hereinafter be referred to as PLGA. PLGA is degraded by ester hydrolysis into lactic acid and glycolic acid and has been shown to possess excellent biocompatibility. The innocuous nature of PLGA can be exemplified, moreover, by the approval by the regulatory authorities, including the U.S. Food and Drug Administration, of several parenteral delayed release preparations based on these polymers.
Parenterally administrable delayed release products currently on the market and based on PLGA include Decapeptyl(trademark) (Ibsen Biotech), Prostap SR(trademark) (Lederle), Decapeptyl(copyright) Depot (Ferring) and Zoladex(copyright) (Zeneca). The drugs in these preparations are all peptides. In other words, they consist of amino acids condensed into a polymer having a relatively low degree of polymerization and they do not have any well-defined three-dimensional structure. This, in turn, usually allows the use of relatively stringent conditions during the production of these products. For example, extrusion and subsequent size-reduction can be utilized, which techniques would probably not be allowed in connection with proteins, since these do not, generally speaking, withstand such stringent conditions.
Consequently, there is also a need for controlled release preparations for proteins. Proteins are similar to peptides in that they also consist of amino acids, but the molecules are larger and the majority of proteins are dependent on a well-defined three-dimensional structure as regards many of their properties, including biological activity and immunogenicity. Their three-dimensional structure can be destroyed relatively easily, for example by high temperatures, surface-induced denaturation and, in many cases, exposure to organic solvents. A very serious drawback connected with the use of PLGA, which is an excellent material per se, for delayed release of proteins is therefore the need to use organic solvents to dissolve said PLGA, with the attendant risk that the stability of the protein will be compromised and that conformation changes in the protein will lead to an immunological reaction in the patient, which can produce both a loss of therapeutic effect, through the formation of inhibitory antibodies, and toxic side effects. Since it is extremely difficult to determine with certainty whether a complex protein has retained its three-dimensional structure in every respect, it is very important to avoid exposing the protein to conditions which might induce conformation changes.
Despite intense efforts aimed at modifying the PLGA technology in order to avoid this inherent problem of protein instability during the production process, progress within this field has been very slow, the main reason probably being that the three-dimensional structures for the majority of proteins are far too sensitive to withstand the manufacturing conditions used and the chemically acidic environment formed with the degradation of PLGA matrices. The scientific literature contains a large number of descriptions of stability problems in the manufacture of microspheres of PLGA owing to exposure to organic solvents. As an example of the acidic environment which is formed upon the degradation of PLGA matrices, it has recently been shown that the pH value in a PLGA microsphere having a diameter of about 40 xcexcm has been shown to fall to 1.5, which is fully sufficient to denature, or otherwise damage, many therapeutically usable proteins (Fu et al, Visual Evidence of Acidic Environment Within Degrading Poly(lactic-co-glycolic acid) (PLGA) Microspheres, Pharmaceutical Research, Vol. 17, No. 1, 2000, 100-106). Should the microspheres have a greater diameter, the pH value can be expected to fall further owing to the fact that the acidic degradation products then get more difficult to diffuse away and the autocatalytic reaction is intensified.
The technique which is currently most commonly used to encapsulate water-soluble substances, such as proteins and peptides, is the use of multiple emulsion systems. The drug substance is dissolved in an aqueous or buffer solution and subsequently mixed with an organic solvent, immiscible with water, containing the dissolved polymer. An emulsion is formed which has the aqueous phase as the inner phase. Different types of emulsifiers and vigorous mixing are often used to create this first emulsion. This emulsion is then transferred, under agitation, to another liquid, usually water, containing another polymer, for example polyvinyl alcohol, which produces a water/oil/water triple emulsion. The microspheres are then hardened in some way. The most common way is to utilize an organic solvent having a low boiling point, typically dichloromethane, and to distil off the solvent. If the organic solvent is not fully immiscible with water, a continuous extraction procedure can be used by adding more water to the triple emulsion. A number of variations of this general procedure are also described in the literature. In certain cases, the primary emulsion is mixed with a non-aqueous phase, for example silicone oil. Solid drug materials can also be used instead of dissolved ones.
PLGA microspheres containing proteins are described in WO-A1-9013780, in which the main feature is the use of very low temperatures during the production of the microspheres for the purpose of preserving high biological activity in the proteins. The activity for encapsulated superoxide dismutation is measured, but only on the part which has been released from the particles.
This method has been used to produce PLGA microspheres containing human growth hormone in WO-A1-9412158, wherein human growth hormone is dispersed in methylene chloride containing PLGA, the obtained dispersion is sprayed into a container of frozen ethanol beneath a layer of liquid nitrogen in order to freeze the fine droplets and said droplets are allowed to settle in the nitrogen on the ethanol. The ethanol is subsequently thawed and the microspheres start to sink in the ethanol, where the methylene chloride is extracted in the ethanol and the microspheres are hardened. Using this methodology, the protein stability can be better retained than in the majority of other processes for enclosing proteins in PLGA microspheres, and a product has also recently been approved by the registration authorities in the USA. However, this still remains to be clearly demonstrated for other proteins and the problem remains of exposing the enclosed biologically active substance to a very low pH during the degradation of the PLGA matrix.
In the aforementioned methods based on encapsulation with PLGA, the active substances are still exposed to an organic solvent and this, generally speaking, is harmful to the stability of a protein. Moreover, the discussed emulsion processes are complicated and probably problematical in any attempt to scale up to an industrial scale. Furthermore, many of the organic solvents which are utilized in many of these processes are associated with environmental problems and their high affinity for the PLGA polymer makes their removal difficult.
A number of attempts to solve the above-described problems caused by exposure of the biologically active substance to a chemically acidic environment during the biodegradation of the microsphere matrix and organic solvents in the manufacturing process have been described. In order to avoid an acidic environment during the degradation, attempts have been made to replace PLGA as the matrix for the microsphere by a polymer which produces chemically neutral degradation products, and in order to avoid exposing the biologically active substance to organic solvents, either it has been attempted to manufacture the microspheres in advance and, only once they have been processed and dried, to load them with the biologically active substance, or attempts have been made to exclude or limit the organic solvent during manufacture of the microspheres. A process for limiting the quantity of solvent used where polymers are used which can only be dissolved in organic solvents is described in WO 99/20253, in which the limitation is obtained by the use of an aqueous PEG solution to form an emulsion. In this publication, there is no discussion of any technique for concentrating or solidifying the biologically active substance to be incorporated in the microparticles.
WO 97/14408 describes the use of air-suspension technology for producing microparticles for sustained release after parenteral administration, without the biologically active substance being exposed to organic solvents. However, the publication provides no guidance towards the process according to the invention or towards the novel microparticles which can thereby be obtained.
In U.S. Pat. No. 5,470,582, a microsphere consisting of PLGA and containing a macromolecule is produced by a two-stage process, in which the microsphere as such is first manufactured using organic solvents and then loaded with the macromolecule at a later stage in which the organic solvent has already been removed. This procedure leads to far too low a content of the biologically active substance, generally 1-2%, and to a very large proportion being released immediately after injection, which very often is entirely unsuitable. This far too rapid initial release is already very high given a 1% load and becomes even more pronounced when the active substance content in the microspheres is higher. Upon the degradation of the PLGA matrix, the pH falls to levels which are generally not acceptable for sensitive macromolecules.
It is in many cases necessary or desirable to modify a biologically active substance, for example a drug, from soluble to solid form, for example in order to improve its stability and/or enable effective production of a formulation of the substance in question. For example, in an encapsulation procedure which utilizes an emulsifying operation, it can be necessary to use a solid form of the biologically active substance to obtain higher efficacy through the avoidance of transport to the outer phase, or the interface between the outer and inner phase, and in order to retain the biological activity of the substance. In connection with e.g. use of PLGA as a microparticle matrix there is thus a requirement for stabilizing the biologically active substance, both during the incorporation thereof into the microparticles and during the release stage after parenteral administration, and therefore, processes for the stabilization of e.g. macromolecules are extremely valuable. For substances which tolerate harsh manufacturing conditions, extrusion and grinding can be used, but for sensitive biologically active substances, such as proteins, it is a question in the vast majority of cases of acquiring the solid form through chemical complexing. A well known example of one such drug preparation on the market is crystalline insulin complex-bonded with zinc.
Thus it is well known that, for proteins and peptides, complex-bonding with divalent metal ions, preferably zinc, has long been utilized to convert the biologically active substance into solid form. Basically, it is not possible to form chemical complexes, e.g. with zinc, with all biologically active substances, and not all complex-forming agents are acceptable for parenteral administration. There are however a large number of drawbacks with such procedures. One drawback is the often complicated chemistry which, even in apparently simple cases, can require a significant amount of effort in order to be controlled and well-characterized. Another drawback is that the registration authorities in certain countries consider that even well known and marketed substances, after such complexing, are to be regarded as new chemical substances, which lead to demands for extensive and very expensive characterizations from the chemical, safety and clinical aspects. Further drawbacks are introduced when the active substance is to be converted into solid and dry form, since this often involves spraying and drying procedures which are equipment-intensive and in many cases can be complex. Many sensitive substances do not tolerate exposure to an air/water or air/organic-liquid interface or to those shear forces which are required in order to form the spray droplets. Neither is it unusual for problems in dispersing or resuspending the substance converted into solid form, after it has been dried, not to yield a usable result, for example owing to the fact that these particles attach to one another in such a way that they cannot be driven apart by the use of acceptable conditions. In many of these procedures, organic solvents are used which risk being harmful to sensitive biologically active substances and to staff coming into contact with the substances and have an adverse effect upon the environment.
U.S. Pat. No. 5,654,010 and U.S. Pat. No. 5,667,808 describe the production of a solid form of recombinant human growth hormone, hGH, through complexing with zinc in order to create an amorphous complex, which is then micronized through an ultrasound nozzle and sprayed down in liquid nitrogen in order to freeze the droplets. The liquid nitrogen is then allowed to evaporate at a temperature of xe2x88x9280xc2x0 C. and the resultant material is freeze-dried. Apart from the fact that the procedure is complex and generally difficult to apply, it comprises a spraying procedure in which the biologically active substance is exposed to a water/air surface and in which the amorphous form of the protein which is formed is suspended in methylene chloride. Methylene chloride is an entirely undesirable organic solvent from a toxicological viewpoint, both for the patients and for the working staff.
A process for the production of parenterally administrable microparticles and having the following features would therefore be extremely desirable:
a process which makes it possible to concentrate or solidify the biologically active substance to be incorporated without the use of chemical complexing and with retention of the biological activity of the substance;
a process which makes it possible to concentrate or solidify the biologically active substance to be incorporated in a parenterally administrable preparation without exposure of the substance to air/water or air/organic solvent interfaces;
a process which makes it possible to concentrate or solidify the biologically active substance to be incorporated in a parenterally administrable preparation, without the use of a spraying process or drying process;
a process which makes it possible to avoid a reconstitution stage and/or resuspension stage of the biologically active substance from dry state without prior stabilization through incorporation in microparticles;
a process which makes it possible to entrap sensitive, biologically active substances in microparticles with retention of their biological activity;
a process by means of which a substantially fully biodegradable and biocompatible preparation can be produced, which is suitable for injecting parenterally;
a process by means of which a parenterally injectable preparation having a size exceeding 20 xcexcm and, preferably exceeding 30 xcexcm, is produced for the purpose of avoiding phagocytosis of tissue macrophages and which simplifies processing of the same during manufacture;
a process for the production of microparticles containing a biologically active substance, which microparticles can be used as intermediate product in the production of a preparation for controlled, sustained or delayed release;
a substantially fully biodegradable and biocompatible microparticulate preparation which is suitable for injecting parenterally;
a microparticulate preparation containing a biologically active substance and having a particle size distribution which is suitable for coating by means of air suspension technology and having sufficient mechanical strength for this purpose;
a coated microparticulate preparation containing a biologically active substance, which preparation gives a controlled release after parenteral administration,
According to a first aspect of the present invention, there is provided a process for the production of microparticles. More specifically, it relates to the production of microparticles containing a biologically active substance and primarily intended for parenteral administration of said substance to a mammal, especially humans. Primarily, it is a question of the production of microparticles intended for injection. Since the microparticles are primarily intended for injection, it is preferably a question of the production of particles having a mean diameter within the range of 10-200 xcexcm, usually 20-100 xcexcm and especially 20-80 xcexcm.
The expression xe2x80x9cmicroparticlesxe2x80x9d is used in connection with the invention as a general term for particles of a certain size according to the art which is known per se. One type of microparticles is therefore constituted by microspheres, which have a substantially spherical form, whilst the term microparticle can in general include deviation from such a perfect spherical form. The term microcapsule, which is known per se, also falls within the expression microparticle according to the prior art.
More specifically the process according to the present invention comprises:
a) preparing an aqueous solution of the biologically active substance to be incorporated in the microparticles,
b) mixing the solution obtained in step a) with an aqueous solution of polyethylene glycol (PEG) under such conditions that the biologically active substance is concentrated and/or solidified,
c) optionally washing the concentrated and/or solidified biologically active substance obtained in step b),
d) mixing the concentrated and/or solidified biologically active substance obtained in step b) or c) with a solution of a biodegradable polymer in an organic solvent,
e) mixing the composition obtained in step d) with an aqueous solution of a polymer having the ability of forming an emulsion, so as to form an emulsion of droplets of said biodegradable polymer, which contain the biologically active substance as the inner phase in an outer phase of said polymer solution,
f) causing or allowing the droplets obtained in step e) to solidify into microparticles,
g) drying the microparticles from step f), and
h) optionally applying a release-controlling shell of a biocompatible and biodegradable polymer to the dried microparticles from step f).
Even though it is generally possible to incorporate biologically active substances in microparticles in a highly effective manner, since the biologically active substance is present in soluble form during the entrapment stage, it is in certain cases preferable for the biologically active substance to be converted into solid form. For example, it can be a matter of further stabilizing the biologically active substance during the entrapment stage, which is especially valuable for sensitive macromolecules exposed to organic solvents, of further increasing the yield or the load by converting the substance into a form which, after mixing with the inner phase (the polymer solution), cannot be distributed out in the outer phase or to the interface between the inner and outer phases, or of converting the substance into a form which is as inert as possible during the manufacture of the microparticles, this so that improved properties shall be acquired, for example, in terms of the size distribution of the microparticles.
It has thus very surprisingly been found that PEG, which is often used as the polymer to create the outer phase in a two-phase aqueous system, can also be used to concentrate and/or solidify the biologically active substance which is to be entrapped, and that this can be realized under mild conditions which can preserve, for example, the three-dimensional conformation and biological activity of a protein.
This process has a number of advantages compared with the prior art. In the first place, it is not necessary to complex-bond the biologically active substance, preferably a protein or a peptide, in order to obtain the concentration/solidification. In the second place, the use of this process often also produces better stability during the incorporation in the microparticles, compared with soluble protein. The fact that the process does not comprise a spraying or drying process before the biologically active substance is incorporated in the microparticles also means that exposure of the biologically active substance to high shearing forces and to interfaces (air/water or air/organic solvent) is avoided. Aggregation owing to electrostatic charges, something which is very common for small, dry particles, is also avoided. Any problems with wetting and resuspension of a dry powder of the biologically active substance can also be avoided. In purely general terms, spraying processes are also complex and poorly controlled. Neither is it necessary to utilize process steps such as freezing and slow thawing in order to convert the biologically active substance into dry form. It is also a distinct advantage that no organic solvents are used to convert the biologically active substance to the concentrated/solidified form.
For step a) of the process according to the invention, the aqueous solution of the biologically active substance is prepared by means of methods which are well known within the field and which do not need here to be described in further detail. However, fundamental to this is that the solution is prepared under such mild conditions, primarily in terms of temperature and agitation, that the bioactivity of the biologically active substance is preserved. Within the field, moreover, well-known buffer substances which are acceptable for parenteral use are often used to control or regulate the pH value of the solution. Where required, substances which are well known within the field and are acceptable for parenteral use can also be used, for example to adjust ionic strength and osmolarity. When so desired, the obtained solution can be sterilized by means of, for example, sterile filtration.
Through the use of the aqueous solution of polyethylene glycol in step b), a concentration of the biologically active substance, for example a protein, can be obtained. This concentration often results in the biologically active substance precipitating out, i.e. forming a precipitation, solid particles thereby being formed. This can be detected, for example, by examination with a light microscope. Since the process is often carried out quickly, the structure of the particles is generally amorphous. Other forms of particles, for example crystals and supercooled glass, are also covered by the invention, however, depending on how the process is carried out.
The term xe2x80x9cis concentratedxe2x80x9d also however covers the case in which the biologically active substance does not precipitate, but merely forms a more or less highly viscous solution. The term xe2x80x9cis solidifiedxe2x80x9d thus also covers the case in which a highly viscous solution of this kind forms such stable droplets that, in practice, it can be handled and incorporated in microparticles in substantially the same way as if it were a precipitation. The concentrated/solidified biologically active substance can be found in the microparticle matrix in the form of islands or discrete particles.
One embodiment of the process according to the invention is thus represented by the case in which step b) is performed such that the solidification of the biologically active substance leads to a precipitation of the same.
In another embodiment, step b) is performed such that the solidification of the biologically active substance results in a highly viscous solution, which has the ability of forming droplets which can be handled at room temperature.
In a further embodiment of the process, step b) is performed to form a reversibly solidified active substance.
In yet another embodiment of the process, the solidified biologically active substance forms a pellet or a highly viscous or solid bottom phase in centrifugation or ultracentrifugation.
By xe2x80x9creversibly solidifiedxe2x80x9d is meant, in general terms, that the biologically active substance in question, when dissolved in a medium suitable for each unique biologically active substance and under suitable conditions, and/or when released from the microparticles in vitro and/or in vivo, is restored to essentially the same form, both chemically and biologically, as it had prior to the concentration/solidification with polyethylene glycol.
That the solidified biologically active substance forms a pellet or a highly viscous or solid bottom phase in centrifugation or ultracentrifugation provides a means of detecting the desired concentration/solidification. This means, moreover, that the substance in question is present in another physical form than the soluble form which is present in step a) after the preparation of the aqueous solution.
That the biologically active substance is present in concentrated form means, in general terms, that it is present in a concentration which exceeds the concentration obtainable when the substance in question is dissolved in an aqueous medium, with or without stabilizers and solubility-promoting substances, and with the retention of biological activity and chemical stability.
A combination of molecular weight and concentration of the PEG such that the desired concentration and/or precipitation of the biologically active substance is obtained should be chosen. Such conditions can simply be tried out for each specific biologically active substance as they will be dependent on the properties of the biologically active substance, for example molecular weight and solubility. The molecular weight of the PEG can be in the range of 400-100,000 Daltons, more preferably 4000-35000 Daltons, even more preferably 6000-20,000 Daltons, and most preferably 20,000 Daltones. The concentration of the PEG can be in the range of 1-50%, preferably 2-45%, more preferably 10-40% and most preferably 20-35%. That a concentration and/or precipation has been obtained can be investigated as above. That the biologically active substance has retained its bioactivity is most easily measured at this stage by dilution, for example in a suitable buffer solution, and chemical analysis of the biologically active substance, or alternatively by suitable immunological and/or animal assays. If unsatisfactory results are obtained in the initial trials adjustment of pH, the buffer substance, or buffer substances used, and their concentration, temperature and/or inclusion of stabilizers known in the art should be investigated, as well as a change in the concentration and mean molecular weight of the PEG used, such adjustments being readily available to anyone skilled in the art. This step may obviously also be performed under an inert atmosphere to avoid oxidation reactions, the simplest way being to purge the oxygen in the solution by an inert gas, like nitrogen or helium. For extremely sensitive substances it may be necessary to use a very pure PEG to avoid, for example, oxidation reactions.
The extent to which step c) of the process according to the invention needs to be executed or not, i.e. whether the obtained concentrated and/or solidified active substance should be washed and, if so, to what extent, has to be determined in each individual case and depends, inter alia, on the proportion of the biologically active substance which is present in dissolved form in the PEG solution, on whether the dissolved substance is sufficiently stable in this form to be able to be incorporated in the microparticles without far too large a quantity of undesirable degradation products being formed, on the effect which this dissolved substance has on the manufacture of the microparticles, on whether other conditions are required to be used, for example in terms of the concentration and average molecular weight of ERG, as well as pH and ionic strength, than those employed in step b), on whether PEG constitutes a stabilizer for the biologically active substance per se or by retaining the substance in undissolved form or preventing adsorption to surfaces.
The actual washing of the concentrated and/or solidified active substance can be effected by means of suitable techniques established within this technical field. In the simplest form of all, centrifugation washes can be Used and in many cases filtration can also be used. In the latter case, conditions are preferably employed under which the concentrated and/or solidified active substance is not allowed to dry, since this can lead, for example, to aggregation, and the process time is shortened by the application of pressure. Fundamental to this, of course, is that the liquid which is used must not dissolve the concentrated and/or solidified active substance and that the conditions which are suitable should be determined for each individual biologically active substance. In many cases, conditions can be chosen, in terms of buffer composition, additives and temperatures, such that this requirement is met, and necessary information can be obtained from the literature or via simple experiments. Naturally, polymers can be added to avoid dissolution of the concentrated and/or solidified active substance and, in the simplest case of all, the same composition of the PEG solution is used as when the concentration/solidification was carried out. This step can also be performed under an inert atmosphere and at a low temperature.
As to the mixing step d) there are many suitable methods in the art for carrying out such an encapsulation step, for example those described in EP 0 330 180, U.S. Pat. No. 3,737,337, U.S. Pat. No. 3,691,090, WO 99/20253, U.S. Pat. No. 4,389,330, U.S. Pat. No. 5,407,609 and U.S. Pat. No. 5,622,657. Of these WO 99/20253 and U.S. Pat. No. 5,622,657 are preferred.
The biodegradable polymer used in step d) can be selected in accordance with previously known art per se, i.e. among polymeric materials which are previously known as matrix materials for microparticles, provided that the polymer in question is soluble in an organic solvent (hereby for instance starch is excluded) and biocompatible, i.e. biologically acceptable.
Especially, however, a homo or copolymer containing L-hydroxy acid units is preferred, preferably lactic acid and/or glycolic acid, e.g. PLGA.
Preferably the polymer has an average molecular weight in the range of 2-200 kDA, more preferably 2-110 kDA.
For the mixing operation in step d), a weight ratio of biodegradable polymer:biologically active substance within the range of 3:1 to 10,000:1 is expediently used.
As has been discussed above, it is also the case for the mixing operation that the active substance is concentrated/solidified with the use of a PEG solution before being mixed with the polymer solution. It is possible to add the polymer solution to the biologically active substance or vice versa. After this, a homogeneous distribution of the concentrated/solidified active substance in the polymer solution is created by means of a suitable technique. Such a technique is well known within the field, examples which might be quoted being magnetic agitation, propeller agitation or the use of one or more static mixers.
Regarding the polymer used in step e) for the purpose of forming an emulsion, information is published, within precisely this technical field, on a large number of polymers with the capacity to form such emulsions. All such polymers must be considered to lie within the scope of the present invention. An especially suitable polymer in this context, however, is polyethylene glycol. The molecular weight of said polyethylene glycol generally is within the range of about 1 to 40 kDa, preferably 5 to 35 kDa. Dependent on said molecular weight and the properties of the active substance to be encapsulated, the concentration of the polyethylene glycol is adjusted so as to be in the range of 20-80% (w/w), preferably 20-60% (w/w), such as 30-55% (w/w) or 30-50% (w/w). In other words, a relatively high PEG concentration is used in the outer phase such that a stable emulsion is obtained and diffusion of active ingredient from the droplets/particles is prevented. An evaluation of the optimum concentration can be made by experiments which are relatively simple to perform for a person skilled in the art.
The mixing operation in step e) can be performed in many different ways, for example through the use of propeller agitation or at least one static mixer. The mixing is normally carried out within the temperature range of 4-50xc2x0 C., preferably 20-40xc2x0 C., often about 37xc2x0 C. In a batch process, the solution of the first polymer can be added to the second polymer solution or vice versa. Where static mixers or blenders are utilized, the operation is expediently executed by the two solutions being pumped in two separate pipelines into a common pipeline containing the blenders.
The emulsion can be formed using low shearing forces. In most cases, magnetic or propeller agitation is sufficient. On a larger scale, for example when the quantity of microparticles to be produced exceeds 50 g, it is expedient to use so-called baffles to obtain even more effective agitation in the container which is used. An alternative way of forming the emulsion is to use at least one static mixer, the organic polymer solution expediently being pumped at regulated speed in a pipe in which the static mixers have been placed. The pumping can be effected with any type of suitable pump, provided that it gives an even flow rate under these conditions, does not expose the mixture to unnecessarily high shearing forces and is acceptable for the manufacture of parenteral preparations in terms of purity and non-leakage of unwanted substances. In those cases, too, in which static mixers are used to create the emulsion, it is generally advantageous to have the solidification into microparticles take place in a vessel with suitable agitation.
A preferred embodiment of the process according to the invention means that in step e) the polymer solution is added to the composition in at least two stages, in which an addition is effected after the emulsion has been created or has begun to be created.
It is also within the scope of the present invention, of course, to add the polymer solutions in many stages and to change, for example, the average molecular weight and/or concentration of the polymer used.
The mixing operation in step e) is expediently performed, moreover, under such conditions that the formed droplets acquire the size required for the microparticles, i.e. preferably a mean diameter, in the dry state, within the range of 10-200 xcexcm, more preferably 20-100 xcexcm and most preferably 20-80 xcexcm. However, also other previously known methods for the solidification of the microparticles are within the scope of the invention.
In connection with the solidification of the microparticles, it is important that this should take place under conditions which are mild for the incorporated biologically active substance(s). In other words, it is primarily a question of using a temperature which is not harmful to the current substance.
Confirmation that the chosen conditions are correct or appropriate can be obtained by establishing that the microparticles have a desired size distribution, are stable during the subsequent washing and drying operations and are dissolved substantially completely in vitro and/or that the incorporated substance has been encapsulated effectively and has retained bioactivity. The last-mentioned is usually examined using chromatographic methods or using other methods established within the art, in vitro or in vivo, after the microparticles have been dissolved.
The formed microparticles are preferably washed in a suitable manner in order to remove the outer phase and any surplus of active substance. Such washing is expediently effected by filtration, which is made possible by the good mechanical stability and suitable size distribution of the microparticles. Washing by means of centrifugation, removal of the supernatant and resuspension in the washing medium may often also be appropriate. In each washing process, one or more suitable washing media are used, which generally are buffer-containing aqueous solutions. In this connection, sifting can also be used, if required, in order to adjust the size distribution of the microparticles, for example to eliminate the content of too small microparticles and to ensure that no microparticles above a certain size are present in the finished product.
The microparticles can be dried in any way appropriate, for example by spray-drying, freeze-drying or vacuum-drying. Which drying method is chosen in the individual case often depends on what is most appropriate for the retention of the biological activity for the enclosed biologically active substance. Process considerations also enter into the picture, such as capacity and purity aspects. Freeze-drying is often the preferred drying method, since, correctly designed, it is especially mild with respect to the enclosed biologically active substance. That the incorporated biologically active substance has retained its bioactivity can be established by means of analysis appropriate to the substance after the substance has been dissolved under mild conditions.
In order to modify the release properties of the microparticles, a release-controlling shell made from a biocompatible and biodegradable polymer might also be applied, moreover. Examples of suitable polymers in this context are found in the prior art, and polymers of lactic acid and glycolic acid (PLGA) can especially be mentioned. The shell in question is preferably applied using air suspension technology. An especially suitable technique of this kind is described in WO97/14408 and details in this regard can thus be obtained from this publication, the content of which is included in the text by reference. The microparticles which are obtained by means of the process according to the present invention are extremely well suited to be coated by means of the said air suspension technology, and the coated microparticles obtained are especially well suited to parenteral administration.
When the produced microparticles are used, either they are coated with a release-controlling outer shell or not, the dry microparticles are suspended in a suitable medium, specifically to permit injection. Such media and processes in these regards are well known within the art and will not need here to be described in further detail. The actual injection can be given through a suitable needle or with a needle-free injector. It is also possible to inject the microparticles using a dry powder injector, without prior resuspension in an injection medium.
Apart from the advantages which have been discussed above, the process according to the invention has the advantage that the yield of the biologically active substance is generally high, that it is possible to obtain a very high active substance content in the microparticles whilst retaining the bioactivity of the substance, that the obtained microparticles have the correct size distribution for use for parenteral, controlled (for example delayed or sustained) release, since they are too large to be phagocytized by macrophages and small enough to be injectable through small needles, for example 23 G-25 G.
The process according to the invention is especially interesting in connection with proteins, peptides, polypeptides, polynucleotides and polysaccharides or, in general, other drugs or biologically active substances which are sensitive to or unstable in, for example, organic solvents. Recombinantly produced proteins are a very interesting group of biologically active substances. Generally speaking, however, the invention is not limited to the presence of such substances, since the inventive concept is applicable to any biologically active substance which can be used for parenteral administration. Apart from in connection with sensitivity or instability problems, the invention can thus also be of special interest in such cases where it would otherwise be difficult to remove solvent or where toxicological or other environmental problems might arise.
Examples of biologically active substances of the above-specified type are growth hormone, erythropoietin, interferon (xcex1, xcex2, xcex3-type), vaccine, epidermal growth hormone, Factors IV, V, VI, VII, VIII and IX, LHRH-analogue, insulin, macrophage-colony-stimulating factor, granulocyte-colony-stimulating factor and interleukin.
Usable biologically active substances of the non-protein drug type can be chosen from the following groups:
Antitumour agents, antibiotics, anti-inflammatory agents, antihistamines, sedatives, muscle-relaxants, antiepileptic agents, antidepressants, antiallergic agents, bronchodilators, cardiotonic agents, antiarrhythmic agents, vasodilators, antidiabetics, anticoagulants, haemostatic agents, narcotics and steroids.
In connection with the invention the term biodegradable means that the microparticles, after parenteral administration, are dissolved in the body to form endogenic substances, ultimately for example lactic acid. The biodegradability can be determined or examined through incubation with any suitable medium in vitro. The biodegradability can also be examined through parenteral injection of the microparticles, for example subcutaneously or intramuscularly, and histological examination of the tissue as a function of times
Normally, biodegradable microparticles from for instance PLGA dissapear from the tissue within a few weeks or months.
The biocompatibility can also be examined through parenteral administration of the microparticles, for instance subcutaneously or intramuscularly, and histological evaluation of the tissue, it being important to bear in mind that the biologically active substance, which often is a protein, has in itself the capacity to induce for instance an immunodefense if administered to another genus. For example, a large number of recombinantly produced human proteins can give rise to an immun response in test animals.
Those microparticles which are obtained when using the process according to the invention are suitable for parenteral administration, preferably via injection, to a mammal, especially a human being.
The microparticles obtained essentially consist of a parenterally administrable, biodegradable polymer as the matrix, which in turn contains the biologically active substance in essentially non-chemically complex-bonded form and in the form of solid particles having a mean size within the range of 0.05-30 xcexcm.
By mean size is usually meant, in this context, mean diameter, at least in the case of spherical or substantially spherical particles. In another configuration, reference is generally to the mean value for the largest extent of the particle in any direction.
According to one alternative, the particles of the biologically active substance are obtained by precipitation, i.e. are present in precipitated form.
The solid particles preferably have a mean size within the range of 0.2-10 xcexcm, more preferrably 0.5-5 xcexcm, and most preferably 1-4 xcexcm.
Preferably, the biodegradable polymer is a homo or copolymer containing xcex1-hydroxy acid units. Said xcex1-hydroxy acid is preferably lactic acid and/or glycolic acid,
Preferably, the microparticles also have a release-controlling shell of the type discussed in connection with the process. Reference is also made to the process regarding preferred variants of the said shell.
However, an interesting alternative is represented by the case where the release-controlling shell has another polymer composition than the matrix.
Other microparticles obtainable by the process are those in which the bioactivity of the biologically active substance is at least 80%, preferably at least 90% and most preferably essentially maintained compared with the bioactivity exhibited by the substance prior to its incorporation in the polymer,
Others still are those which are biodegradable and are eliminated from tissue after subcutaneous or intramuscular administration. The biologically active substance is preferably a protein and more preferably a recombinantly produced protein.
The protein is preferably chosen from amongst growth hormones, colony-stimulating factors, erythropoietines, interferons and vaccines.
More preferably the protein is a growth hormone, especially a human growth hormone (hGH).
That the biologically active substance in the polymer matrix is present in essentially non-chemically complex-bonded form means in general that the molecular ratio of total metal cations:biologically active substance is less than 0.2:1.
According to prior technique, it is primarily zinc which has been utilized for complex-bonding in similar context. Thus, the microparticles obtained have the advantage that they are essentially or wholly lacking in such zinc.
More preferably, the abovementioned molecular ratio of metal cations:biologically active substance is less than 0.1:1, especially less than 0.01:1, and most peferably, of course, as close to 0 as possible.
Where a human growth hormone constitutes the biologically active substance, this is preferably of the type whose dimers content is less than 2% by weight, and more preferably less than 1% by weight, and whose polymers content is less than 0.2% by weight, preferably less than 0.1% by weight.
Microparticles which form a parenterally administrable, biodegradable microparticle preparation containing a biologically active substance which, during the first 24 hours after injection, has an active substance release which is less than 30% of the total release, determined from a concentration-time graph in the form of the ratio between area under the curve during the first 24 hours and total area under the curve in question.
Preferably, the release during the first 24 hours after the injection is less than 20%, more preferably less than 15%, even more preferably less than 10% and most preferably less than 5%, of the total release.
Microparticles which produce a microparticle preparation of the abovementioned type, which, during the first 48 hours after injection, has an active substance release in which the maximum concentration in plasma or serum is less than 300% of the maximum concentration of the biologically active substance during any point in time in excess of 48 hours after injection.
The said maximum concentration is preferably less than 200% and more preferably less than 100% of the maximum concentration in question.
Another example is a microparticle preparation of the abovementioned type, which has a biologically active substance release in which the bioavailability of the said substance is at least 35% of the bioavailability obtained when the substance in question is injected intravenously in soluble form.
The said bioavailability is preferably at least 45%, more preferably at least 50%, of the bioavailability obtained when the biologically active substance is injected intravenously.
A further example is a microparticle preparation of the said type which has an active substance release characterized in that, in the release occurring during any continuous seven-day period, the quotient of the highest concentration of the biologically active substance in serum or plasma divided by the mean concentration during the said seven-day period is less than 5, provided that the chosen seven-day period does not include the first 24 hours after injection.
The said release is preferably less than 4 times, more preferably less than 3 times, and most preferably less than 2 times,
Another microparticle preparation which can be obtained by means of the process according to the invention has a biologically active substance release in which the mean residence time for the substance in question is at least 4 days.
Preferably, the said mean residence time is at least 7 days, more preferably at least 9 days, for example at least 11 days, or especially at least 13 days.
The features which have been specified for the above-presented microparticle preparations can be combined in any suitable combinations whatsoever.
The different characteristics specified for the microparticle preparation above primarily relate to the terms MRT, burst and bioavailability.
These can be defined as follows:
An object of preparations for controlled release is to obtain a sustained release of the active material. One measure which can be used to quantify the release time is mean residence time (MRT), which is the recognized term within pharmacokinetic.
MRT is the average time for which the molecules introduced into the body reside within the body. (Clinical Pharmacokinetics. Concepts and Applications. Malcolm Rowland and Thomas N. Tozer, 2nd ed., Lea and Febiger, Philadelphia London).
The MRT value can be calculated from plasma concentration data, using the following formula.   MRT  =                    ∫        0        ∞                          tC                          xe2x80x83                                  ⅆ          t                                    ∫        0        ∞                          C                          xe2x80x83                                  ⅆ          t
where C is the plasma concentration and t is the time.
A common problem with controlled release preparations for parenteral use is that a large part of the drug is released during the early phase immediately following administration in the body. Within the specialist literature, this is termed the xe2x80x9cburst effectxe2x80x9d. This is generally due to the fact that the drug is located on the surface of the formulation or that the formulation (which can consist of microparticles) bursts. A low burst effect is very desirable, since a high concentration of drug can be toxic and the part which disappears rapidly in the initial period, moreover, is poorly utilized, which means that more drug is required to maintain a therapeutic level of the drug during the intended treatment period.
Burst is defined as that fraction of the drug which is absorbed during the first 24 hours of the total fraction which is absorbed.
In mathematical terms, it can be defined using xe2x80x9carea under curvexe2x80x9d calculations from plasma concentration graphs.   Burst  =                                          ∫            0                          24                            h                                                      C                                      xe2x80x83                                                  ⅆ              t                                                            ∫            0            ∞                                          C                                      xe2x80x83                                                  ⅆ              t                                          ·      100            %
Bioavailability is a measure of how large a part of the supplied drug is absorbed in active form from the site of administration to the blood. Bioavailability is often compared with data from intravenous supply of the drug, in which there are therefore no absorption barriers, and is then referred to as absolute bioavailability.
Absolute bioavailability is defined according to the following formula:   F  =                    AUC        x            ·              D        iv                            D        x            ·              AUC        iv
where AUCx is the area-under-the-curve value for the examined formulation, AUCxi is the area-under-the-curve value for an intravenous supply of the drug, Dx is the dose of the drug in the formulation and Div is the intravenous dose.
The determination of the release profile and the pharmacokinetic parameters is preferably realized through animal trials. The most relevant species, owing to its similarity to humans, is the pig. Where the biologically active substance can induce, during the test, an immune response which threatens to affect the determination of the pharmacokinetic parameters for the biologically active substance, inhibition of the immune response should be used, for example by drug treatment. This is known within the technical field, and details can be obtained from the scientific literature, for example Agersxc3x6 et al, (J. Pharmacol Toxicol 41 (1999) 1-8).
Other interesting microparticles are those which are biodegradable in vitro in the presence of alpha-amylase and/or amyloglucosidase,
Further preferred microparticles are those which are biodegradable and are eliminated from tissue after subcutaneous or intramuscular administration,
As regards the determination of the biological activity of the microparticles containing active substance, this must be carried out in a manner appropriate to each individual biological substance. Where the determination is effected in the form of animal trials, a certain quantity of the biologically active substance incorporated in the microparticles is injected, possibly after these microparticles have been previously dissolved under mild conditions, and the biological response is compared with the response obtained after injection of a corresponding quantity of the same biologically active substance in a suitable solution. Where the evaluation is made in vitro, for example in test tubes or in cell culture, the biologically active substance is preferably made fully available before the evaluation by the microparticles being dissolved under mild conditions, after which the activity is determined and compared with the activity for a control solution having the same concentration of the biologically active substance in question. In any event, the evaluation shall include any non-specific effects of the degradation products of the microparticles.
Finally, as can be gathered from the above-mentioned, another interesting aspect of the invention is represented by a process for converting a protein, or in general any other biologically active substance that is sensitive to or unstable in organic solvents, into a concentrated and/or solidified form thereof, which process comprises mixing an aqueous solution of said substance with an aqueous solution of polyethylene glycol (PEG) under such conditions that the protein is concentrated and/or solidified.
As to details and preferable embodiments of such conditions reference is made to the corresponding passages in connection with the process for producing microparticles. Thus, especially such details can be found in connection with the disclosure of step b) of last-mentioned process. Therefore, they need not be repeated here.
From the above-mentioned disclosure of the inventive idea it can, however, also be gathered that the process for converting a water-soluble protein into a concentrated and/or solidified form therof is also preferably performed in the absence of any freezing or lyophilization operation and/or in the absence of any organic solvent and/or in the absence of any spraying operation.


A method and composition for treating hypertrophic scars so as to reduce the size and approve the appearance of scars comprises applying to the scar a composition comprising a film-forming carrier such as a Collodion which contains one or more active ingredients such as a topical steroid, silicone gel and vitamin E. Novel compositions using the Collodion film-forming carrier are also useful to treat a variety of adverse skin disorders.

This invention relates to a method for the treatment of scars and, in particular, to a method for improving the size and appearance of scar tissue. The invention also relates to a novel topical composition for treatment of scars and other skin conditions and diseases.
When skin or dermis has been traumatized by cutting or burning, scar tissue is formed. In most cases, a small cut or burn area will result in a correspondingly small amount of scar tissue which is not readily discernable to a casual observer. In other cases, where the traumatized area is large and/or lengthy, scarring and scar tissue are quite apparent to a casual observer. This cannot only be embarrassing for the person who is scarred, but can be a distraction for the casual observer. The problem is compounded when, over time, scar tissue tends to darken, become thick and project outwardly from the skin surface, thus becoming more apparent.
In normal wound-healing or sore-healing processes, the abundant vascular network is regenerated in the wound or the sore during the maturing phase and the collagen fibers collect in large bundles. Changing patterns of the connective tissue matrix during growth, development, and repair during the healing if a wound and sore require a delicate balance between the synthesis and degradation of collagen. Under normal circumstances, the balance between the synthesis and degradation of collagen is maintained. However, sometimes this maturing process fails to occur, so that scar tissue remains beneath the covering epithelium for a relatively long period of time and may even develop and become enlarged. This is the clinical nature of a hypertrophic scar.
Although balanced scar formation and remodeling are essential processes in skin wound healing, disorders of excess scar formation remain a common and therapeutically refractory clinical problem. A hypertrophic scar is an excessive scar which by definition has grown in size beyond that required for normal wound healing. Hypertrophic scars can emerge from many wound types, such as from a burn or a sharp incision. A hypertrophic scar is a raised, red and itching enlargement. The scar may be tender to the touch and to other external pressure and can form on every afflicted part of the body.
Hypertrophic scars often remain for a very long time, sometimes through the entire life of the person so afflicted. In the case of adults, the hypertrophic scar will normally transform to a typical soft and pale scar after a year or so. In addition to itching and being relatively unsightly, if the hypertrophic scar happens to overlay a skeletal joint, movement of the joint is often painful and restricted. In the past, such complications were overcome by covering the scar tissue with clothing, makeup, or avoiding contact with other people. This strategy is often not possible nor desirable. Scar tissue and the tissue adjacent thereto can often become hyper-sensitive to contact with clothing, and often, a person will not cover the scar tissue to the detriment of socialization. In some instances, a person might not be able to tolerate the application of makeup over scar tissue, again to the detriment of socialization. In other instances, a person may be required to wear a certain type or style of clothing which does not cover scar tissue locations.
Many medical care givers have recognized the problems associated with scar tissue and now include scar tissue management as part of the overall treatment of patients.
A number of techniques have been proposed for the improvement of scars. These include the application of pressure and treatments such as with hydrocortisone, collagen, vitamins such as vitamins E and A, and extracts from vegetable and animal sources. While some of these treatments have had modest success, all of the treatments can be cumbersome, inconvenient or even painful.
The use of pressure dressings is believed to be the first truly effective scar treatment. Application of pressure apparently increases the activity of collagenase, which is an enzyme capable of degrading and modeling the scar tissue and is employed by the body in the equilibrium of the formation and degradation of collagen during the healing process. However, pressure dressings are bulky rendering them uncomfortable to the user and often inconvenient to keep in place on the affected scar tissue.
The application of a steroid such as cortisone also increases the collagen degradation activity of collagenase. With a large amount of extra scar tissue such as a hypertrophic scar or keloid, depending on the severity, a physician often recommends cortisone injections. In less severe cases, cortisone creams or cortisone tapes do show modest benefit. However, creams are often inconvenient to use as they are messy and can stick to and discolor clothing. The use of tapes are also disadvantageous as such tapes often hold moisture and fall off the affected area. Further, the cortisone creams are required to be rubbed or massaged onto the scar. For some persons, this can be painful. Cortisone injections can also be very painful to the patient.
Vitamin treatment such as vitamin E is believed to decrease the collagen bonding during the wound healing process and has been used to soften scars. Cutting vitamin E gelatin capsules in half and squeezing out the oil has been the most common way to apply vitamin E to wounds. Obviously, a vitamin E oil is messy and cutting the capsules in half is a tedious process. The addition of vitamins A and E in creams and lotions is also known, but such creams and lotions are often oily to the touch and do not dry so as to remain in an oily condition or take a long period of time to rub completely into the skin. Again, rubbing or massaging a cream or oil onto and/or into certain scar tissue can be painful to some persons.
It has been discovered in recent years that the shrinkage of hypertrophic scars can be increased by applying silicone-gel plates or sheets to the scars. The exact mechanism by which the silicone-gel interacts with such scars has not been established, however. A number of products are available commercially for this purpose, for instance such products as Dow Corning Silastic Sheeting, Cica-Care (Smith and Nephew), Epi-Derm (Biodermis), Nagosil (Nagor), among others. These products have the form of molded silicone-gel sheets having a thickness of 2-4 millimeters. In treating hypertrophic scars, these sheets are placed over the scars and are worn for a relatively long period of time, often from 3-12 months, until the scars either have decreased or have regenerated. Examples of recent patents which disclose such silicone-gel sheets include U.S. Pat. Nos. 5,759,560; 5,891,076; 5,895,656 and 5,919,476.
The known silicone sheets are relatively rigid and after having been placed over the scar have insufficient adhesion to remain securely in position without some form of assistance. Consequently, it is necessary to secure the sheets against the skin with the aid of securing, stocking, bandage, self-adhesive tape or some like means. The sheets can often trap too much moisture causing irritation on the affected area. Additionally, gel sheets of the type that utilize silicone are tacky to the touch, both on the inner body, body contacting surface and the exterior surface. Having a body contacting surface which is tacky to the touch is advantageous and desirable. However, having an exterior which is tacky to the touch is not. A disadvantage of having a tacky exterior is that articles of clothing tend to adhere to the gel sheet. This presents several problems. One problem is that often the gel sheet adheres to an article of clothing with greater force than it adheres to the skin. Thus, when the article of clothing is removed, the gel sheet is removed from the body. Another problem is that the articles of clothing would adhere to the gel sheet and prevent normal range of motion. An additional problem encountered with gel sheets which are tacky to the touch is that they tend to become soiled more quickly.
Other physical treatments are available, including surgery, x-ray therapy and cryotherapy. Such treatments are expensive or potentially dangerous and not normally recommended.
Accordingly, while there have been physical treatments, compositions and/or articles which contain medicaments which have had modest success in reducing, softening and lightening hypertrophic scars, these prior attempts are expensive, inconvenient to use, difficult to apply or simply have not been very effective in achieving the desired purpose.
As expressed above, existing therapy for hypertrophic scars and keloids has included surgery, mechanical pressure, X-ray irradiation, cryotherapy, and the application of various medicaments such as steroids, vitamins, as well as vegetable and animal extracts. Again, there are many disadvantages associated with each of these methods. Thus, surgical removal of the scar tissue is often incomplete and can result in the development of hypertrophic scars and keloids at the incision and suture points. X-ray therapy is the only predictably effective treatment to date, however, because of its potential for causing cancer, X-ray therapy is not generally recommended or accepted. The most common approach to control hypertrophic scar and keloid formation is to apply pressure, which appears to be effective in many instances. However, this treatment has limited application, generally based on the size and location of the scar tissue on the body. Steroid injections are unpredictable and often result in depigmentation of the skin. Application of silicon-based gels such as in sheets has resulted in general improvement in the appearance and size of treated scars, but the mechanism of such healing is not known and the inconvenience of such silicone gel sheets has been discussed previously.
Accordingly, a primary objective of the present invention is to provide an effective and, yet convenient to use composition which can improve the size and appearance of scars, in particular, hypertrophic scars.
In its broadest aspect, the present invention is directed to a method for the treatment of hypertrophic scars with a medicament capable of reducing the size or improving the appearance of scars and which is carried within a film-forming carrier which can be accurately and directly applied to the affected scar tissue, and dries to a substantially clear film to hold the medicament in place. The film-forming carrier of the present invention is Collodion which comprises a solution of pyroxilin (nitrocellulose) in a 25/75 mixture of alcohol and ether, or Flexible Collodion which comprises a mixture of Collodion with camphor and castor oil. This film-forming carrier is not oily or greasy as has characterized carriers used with the application of vitamins or other vegetable or animal extracts or with steroids. The film-forming carrier of the present invention can be applied directly onto the scar to be treated without the need for rubbing or the application of pressure such as with oily or greasy carriers which application can often be painful to the person whose scar is being treated.
In another aspect of the present invention, a composition is provided which is effective for reducing the size and appearance of hypertrophic scars and can be readily and accurately applied directly to the scar without the problems associated with oils and greases, or wraps and sheets, which have been used to merely apply pressure or provide contact with silicon gels. In this aspect of the invention, a composition is provided comprising a Collodion or Flexible Collodion film-forming carrier which includes a dermatologically effective steroid such as a corticosteroid which can be applied directly onto the scar tissue and which dries to a clear film which contains the steroid medicament.
In an alternative to the invention described immediately above, a corticosteroid, silicone gel or vitamin E, or mixtures thereof is provided in a Collodion or Flexible Collodion film-forming carrier and used to treat not only scars but a variety of skin conditions and disorders.
In still another aspect of the present invention, a composition for the treatment of hypertrophic scars so as to reduce the size of the scar and improve the appearance thereof is provided by combining a dermatologically effective steroid such as hydrocortisone, a silicone gel and, optionally, vitamin E in a single carrier which can be applied directly to the scar tissue and presents for the first time a multicomponent medicament composition combining the effective properties of components which have been used singly. It has been found that the steroid, silicone gel and vitamin E can be effectively mixed within a film-forming carrier such as Collodion or Flexible Collodion and be applied directly to the scar tissue in a convenient manner without the need for massaging the composition into the scar. The composition dries to a clear film, remaining on the affected area without the need for wraps, tapes, and without the disadvantages of oils or greases which disadvantageously can discolor clothing and need to be rubbed or massaged onto and into the scar.
The method of the present invention is directed to the application of a film-forming carrier to the affected scar tissue. The film-forming carrier contains one or more medicaments (active ingredients) which applied onto the scar tissue and held in place by the carrier film can reduce the size of a hypertrophic scar and/or improve the appearance thereof. Thus, the method of the present invention is the application of a film-former and one or more effective scar-treating medicaments to a hypertrophic scar. When the film-former dries, it forms a protective film over the site of application to maintain contact of the active ingredients on the scar and prevent removal of the active ingredients from the site. The film-former which is preferably used in the method of the present invention is Collodion or Flexible Collodion. Collodion is a solution of 4 g. of pyroxylin (chiefly nitrocellulose) in 100 ml of a mixture of 25 milliliters alcohol and 75 milliliters ether. Collodion is a colorless or slightly yellow, clear or slightly opalescent syrupy liquid. The flexible Collodion comprises simple Collodion with the addition of camphor and 3% castor oil (by weight). Flexible Collodion is slightly yellow and is a syrupy liquid which contains 67% ether and about 22% absolute alcohol by volume. When the Collodion or Flexible Collodion evaporates it leaves a tough and colorless film. The topical compositions of the invention may also contain a solvent added to the carrier which serves to dissolve the active ingredient. An example of a solvent which may be used is acetone.
In the method of this invention, an active ingredient which is effective to treat hypertrophic scars is included in the Collodion or Flexible Collodion film-forming carrier. Any active ingredient which is so effective, known or unknown at the present time, is useful in the method of this invention. Such active ingredients include dermatologically active steroids, e.g. corticosteroids, vitamins and other vegetable and animal extracts known to treat scars, as well as silicones, including silicone gels which have been used in silicone gel sheets and plates.
In preparing topical compositions for use in the method of this invention, there can be added conventional adjuvants such as propionic acid, propylene glycol, acetone and lactic acid, conventional penetration enhancers such as erucic acid, oleic acid and bahemic acid; conventional buffers, preservatives, hydrophilic emulsifiers, lipophilic emulsifiers, sun-screening agents, perfumes, emollients, deodorants, humectants, and the like. Colorants may also optionally be added in the useful compositions of the invention. obviously, adjuvants which would be harmful to scar tissue or the surrounding skin should be avoided, as well as those adjuvants which may react with and/or adversely reduce the effectiveness of the active ingredient which is incorporated within the film-forming carrier. Current Collodion-based FDA monograph approved formulas may be employed in such topical liquid compositions.
Preferably, in the method of this invention, the Collodion-based composition is applied to the scar tissue to be treated by any common applicator such as a brush, roll or eye dropping apparatus conveniently used to apply compositions to the skin. The compositions may also be applied by impregnating a porous base with the composition and wiping the composition onto the scar or where the porous base includes an adhesive, securing the porous base to the skin adjacent to the scar and wherein the film-former and active ingredient are placed on the scar to be treated. The composition used in the method of the present invention is a relatively viscous liquid which can be applied directly and accurately onto the scar tissue and does not require the application of additional pressure or rubbing as do certain oils and greases which have been previously utilized. Accordingly, it is believed that the use of the Collodion-based film-former with one or more medicaments to treat hypertrophic scars is novel.
In a second aspect of the present invention, a composition is provided to treat hypertrophic scars so as to reduce the size of the scars and improve the appearance thereof. In this aspect of the invention, an active ingredient in the form of a steroid is added to the Collodion-type film-forming carrier. Thus, it has been found that dermatologically active steroids which can be applied topically, such as hydrocortisone, betamethasone, and any other known corticosteroids and the like, as well as pharmaceutically acceptable salts thereof including chloride, acetate, etc., can be added to the Collodion film-forming carrier in amounts of from about 0.25% to about 70% by weight to yield a composition which can be readily and directly applied to the affected scar tissue. The composition dries to a clear film and maintains the steroid active ingredient in contact with the scar tissue and provides an advantageous and continuous healing effect of the steroid. As previously disclosed, adjuvants typically used for topical compositions can be added, including solvents, penetration enhancers, emollients, buffers, etc. as long as such addition does not adversely interfere with the effectiveness of the steroid.
The invention is further directed to a topical composition which can be used to readily and effectively treat a variety of adverse skin conditions including hypertrophic scars, eczema, psoriasis, atopic dermatitis, and other immunological skin disorders. In this aspect of the invention, topical actives such as steroids, including corticosteroids, silicone gels, i.e. non-volatile polysiloxanes, vitamins, including vitamins A and E, or mixtures thereof, are incorporated into a Collodion or Flexible Collodion film-forming carrier. The levels of each active component will vary depending on the skin disorder being treated and can be readily determined from known usages of the actives which have been contained in other carriers such as lotions, greases, oils or porous structures, e.g. bandages, gauze, etc. In general, levels of 0.25 wt. % to 75 wt. % are most practical but, variations are acceptable within the scope of this invention.
In still another aspect of the present invention, there is provided a composition which is useful to improve the size and appearance of hypertrophic scars. The composition again is based upon the Collodion-type film-forming carrier. In this aspect of the invention, three components which are active to improve hypertrophic scars and which have been used on an individual basis are now combined in the Collodion-type film-forming carrier which dries as a clear film on the affected area and provides a base in which the three components can act upon the scar tissue and provide the desired improvement. Thus, in accordance with this invention, the Collodion-type carrier has incorporated therein the dermatologically active steroid, a silicone gel and, optionally, vitamin E.
The dermatologically active steroid which can be used is that described above, in particular, corticosteroids such as hydrocortisone, betamethasone, and the like, including pharmaceutically acceptable salts thereof.
Additionally, it has been found that the Collodion-type carrier can still remain film-forming and a particularly advantageous composition can be formed by the further addition of silicone to the composition in addition to the dermatologically active steroid. The silicones which can be added to the composition of this invention are those which have been found effective to improve the appearance and size of hypertrophic scars. Silicones are a group of completely synthetic polymers containing the recurring group xe2x80x94SiR2Oxe2x80x94 wherein R is a radical such as an alkyl, phenyl, or vinyl group which may be substituted or unsubstituted. The simpler silicones are oils of very low melting point, while at the other end of the scale of physical properties are highly cross-linked silicones which form rigid solids. Intermediate physical properties are silicone elastomers such as gels and rubbers. A variety of silicone gels have been used as wound dressings as disclosed in U.S. Pat. No. 4,838,253 assigned to Johnson and Johnson and U.S. Pat. No. 4,991,574 assigned to Dow. An example of a useful silicone gel which has been used is marketed under the tradename SILASTIC(copyright).
While it has not been proven conclusively as to how the silicone gels act on the scar tissue to improve them, based on experiments involving the measurement of physical parameters associated with the use of such gels, investigators have concluded that the mode of operation of the silcone gel and scar treatment did not involve, pressure, temperature, oxygen, tension or occlusion. Rather, as reported, the likely mechanism involved both hydration of the stratum corneum and the release of a low molecular weight silicone fluid from the gel.
Any of the known silicone gels which have been previously used for wound dressings as described above can be used in the composition of this invention. In general, the silicone gel will have a viscosity at 25xc2x0 C. of about 100-30,000 cps. Preferably, a phenyl trimethicone such as Dow Corning 556 fluid or a non-volatile polydimethylsiloxane can be used.
Although optional, it is preferred to include vitamin E (xcex1-tocopherol) to the composition. In this most preferred embodiment, three active ingredients which have been known to treat hypertrophic scars on an individual basis have been found to be extremely useful in combined form in a single film-forming carrier without disadvantageous interactions between the components. Useful compositions can comprise from about 0.25-50% by weight of the steroid such as hydrocortisone, preferably from about 0.5-5% of the steroid; 2-70%, preferably 5-25% silicone and 0-25%, preferably 0.25-10% vitamin E. The balance is the Collodion-type film-forming carrier, whether Collodion or Flexible Collodion. Although the Collodion film-forming carrier is preferred, it is possible that other film-formers can be used. Examples include polyvinyl-pyrrolidone polymers and copolymers, polyacylate polymers and copolymers, etc.
As previously stated, other adjuvants can be added to enhance penetration of the active ingredients, control moisture levels on the scar tissue, provide preservative and antibacterial effects, etc. In a most preferred embodiment, small amounts of xanthan gum can be added which provides both thickening qualities and acts as a dispersion enhancer for the active ingredients, including the steroids such as hydrocortisone and the silicone component. If xanthan gum is added, it should be present in amounts of from about 0.5-4%, preferably from about 0.75-2.5% by weight.
The compositions of the present invention are believed to be novel. As the carrier system, the Collodion-type film-forming material containing the steroid and silicone has not been used to treat hypertrophic scars. While hydrocortisone is available as a topical ointment or cream and silicone is available as a liquid, an ointment or as a bandage sheet that must be cut and adhered to the skin with tape or other mechanism, the composition of the present invention combines these two active agents and disperses such agents into a matrix of an occlusive dressing that when brushed or otherwise applied onto the skin, dries immediately, keeps the active ingredients in contact with the skin to exert their intended action, and can easily be peeled off, either at completion of therapy or to apply subsequent doses. The compositions of this invention require no mechanical aid, i.e. adhesive bandage, gauze or impregnated sheet coverings. Application is simply accomplished by brushing the medicated viscous base onto the scar area and allowing to dry. The liquid base fully dries within one minute, creating a clear, flexible occlusive bandage covering. While the compositions can be easily brushed on, other applicators can be used including a dispensing-type device which will roll the material onto the scar, as well as eye dropper-type mechanisms. What is important, is that the carrier which contains the active ingredients of this invention does not need to be rubbed or massaged onto the scar area which can be painful in certain circumstances. Further, the carrier dries to a completely dry film which will not stick to clothing. Compositions of this invention have been found useful when applied once or twice daily for 3-4 months to yield the best results of softening, shrinking and lightening hypertrophic scars.

Method and composition for the treatment of scars


The game hanger apparatus is attachable to a tow hitch of a pickup truck. The folded game hanger can be taken to the site in the bed of the truck and speedily installed in the tow hitch for hanging, cleaning and butchering large game, such as deer and small bears. The apparatus comprises a mast and fixed boom of square cross-section, and having a winch, pulleys and a gambrel with a pair of end hooks and a pair of pins which engage a jib at the end of the boom to prevent the game from twisting. The horizontal bottom and top bars are locked in place by removable pins for operation, and unlocked by removing the pins for folding the unit for storage. The bottom bar is inserted into a tow hitch and locked in place with the hitch pin.

1. Field of the Invention
The present invention relates generally to hoists. More specifically, the invention is a collapsible game hanger which prevents the game from twisting, installable on the trailer hitch drawbar of a pickup truck, and enables an open tailgate while utilizing the game hanger apparatus.
2. Description of Related Art
The related art of interest describes various hoists attachable to vehicles, but none discloses the present invention. There is a need for a game hoist apparatus which can be readily attached with the tailgate open, subsequently detached from a trailer hitch drawbar, and folded for transport or storage. The relevant art will be discussed in the order of perceived relevance to the present invention.
U.S. Pat. No. 4,338,703, issued on Jul. 13, 1982, to James M. Tanner, describes a game supporting device placed in a slot in a sidewall of a bed of a pickup truck or attached to the bumper of a truck. An upright cylindrical member has a perpendicular cylindrical member supported by a cylindrical brace. The upright member has a winch and a hand crank attached which supplies a cable through two rollers to a structure for hanging an animal carcass consisting of an upper horizontal crossbar connected by a pair of chains to a lower movable horizontal crossbar. The crossbars have perpendicular ends which point upward. The upright cylindrical member passes through a sleeve two sets of peripheral bores for insertion of pins to position the supporting device in various positions. A solid cylindrical member at the bottom of the support is inserted into the sidewall of a bed of a pickup truck. The apparatus is distinguishable for requiring a sleeve member, external roller linkages for the cable and two crossbars connected by chains.
U.S. Pat. No. 5,791,858, issued on Aug. 11, 1998 to Kenneth W. Sasser, describes a vehicle mounted game skinning device that is separable and connected to a receiver hitch assembly via a pin. The apparatus includes a winch and pulley assembly, an adjustable boom assembly and a gambrel for hoisting an animal. The apparatus is distinguishable for a game gambrel device which can readily twist when the game is hoisted and does not allow room for the tailgate to be lowered.
U.S. Pat. No. 4,806,063, issued on Feb. 21, 1989 to W. Clifton York, describes a portable wild game hoist that is separable for storage and comprises a winch and pulley assembly with a gambrel that attaches to the ball hitch. The assembly is stabilized by straps that attach to the vehicle fender wells and a torsion bar on the boom which bears against the closed tailgate or a plate which rests on the hitch ball. The hoist is distinguishable for having a twistable gambrel and anchoring elements which do not permit the lowering of the gate.
U.S. Pat. No. 5,540,537, issued on Jul. 30, 1996 to Wilmer M. Welch, describes a portable hoist which mounts to a trailer hitch drawbar receiver of a pickup truck that can use either a block and tackle or a pulley to support the winch cable. The hoist is distinguishable for its proximity to the tailgate, which must be closed, and the swinging terminal hook of the block and tackle or pulley system.
U.S. Pat. No. 4,746,263, issued on May 24, 1988 to Larry D. Cook, describes a vehicle bumper stored telescopic crane hoist comprising a mast telescopically receiving a boom which supports a power head or winch assembly. The mast is supported by a jack. The tailgate can be lowered. The crane hoist is distinguishable for its required telescopic structure and jack.
U.S. Pat. No. 5,205,700, issued on Apr. 27, 1993 to Jhy-hong Lin et al., describes a load carrying attachment for any motor vehicle for transporting a personal mobility vehicle comprising a load carrying frame pivotally attached to a first frame member and which is pivotable from a storage position to an extended load carrying position transverse to and extending rearward from the first frame member. A hoist mechanism is attached to one end of the first frame member rotatable on the support about a vertical axis and pivotable thereon in a vertical plane. The apparatus is distinguishable for its limitation to carrying another smaller vehicle.
U.S. Pat. No. 5,211,526, issued on May 18, 1993 to Larry Robinette, describes a modular, readily assembled crane for mounting on a vehicle trailer hitch drawbar and reconfigurable for stand alone, rollabout operation. A receptacle rotatably supports a vertical column, a boom arm, and a hydraulic jack or a winch as the lifting device. An optional pair of outriggers support the crane against a closed tailgate. The crane is distinguishable for its required versatile structure utilizable as a mobile crane.
U.S. Pat. No. 5,419,672, issued on May 30, 1995 to Jimmy Poe, describes a tailgate hanger apparatus for hanging objects from and lifting objects onto the bed of a pickup truck, comprising a telescopic rod having a base end for supporting the rod, a tip end with a pulley system for lifting objects, and an intermediate portion for holding the tip in an upright pivotal position. The apparatus is supported by two chains attached to the sides of the pickup truck bed with an open tailgate and bolted at its bottom end to an angle iron. The tailgate hanger is distinguishable for its telescopic structure including a unique chain and bolted anchor system.
U.S. Pat. No. 5,662,451, issued on Sep. 2, 1997 to Vincent Muzzi et al., describes a game hoist attached to an all-terrain vehicle (ATV) comprising a horizontal boom on a vertical support shaft which telescopes and supports a winch and two-pulley system ending in a freely rotatable safety hook. The hoist is attached to a side of the ATV either in front or in back. The game hoist is distinguishable for its freely rotatable safety hook.
U.S. Pat. No. 5,993,137 issued on Nov. 30, 1999, to Robert E. Harr describes an adjustable hoist for introducing or removing objects from a vehicle. A main boom having a terminal hook is supported by two steel plates having a rearward support column and a forward hydraulic double action cylinder. A bottom mounting bracket supporting the boom is based on a turntable supported by the receiver mount to the vehicle, two outrigger legs and a jack opposite the receiver mount. The hoist is distinguishable for its required rotatable support system comprising a jack, receiver mount and outrigger legs.
None of the above inventions and patents, taken either singly or in combination, is seen to describe the instant invention as claimed.
The present invention is a foldable game hanger apparatus for attachment to the tow hitch of a pickup truck. The folded game hanger can be taken to the site in the bed of the truck and speedily installed in the tow hitch for hanging, cleaning and butchering large game, such as deer and small bears. The apparatus comprises a mast and fixed boom of square cross-section, and having a winch, pulleys and a gambrel with a pair of end hooks and a pair of pins which engage an apertured horizontal bar at the end of the boom to prevent the game from twisting. The horizontal bottom and top bars are locked in place by removable pins for operation and unlocked by removing the pins for folding the unit for storage. The bottom bar is inserted into a tow hitch and locked in place with the hitch pin. The bottom bar is preferably long enough to accommodate a lowered gate of the pickup truck. The game hanger apparatus has a loading capacity of at least 500 pounds.
Accordingly, it is a principal object of the invention to provide a game hanger apparatus for attachment to a pickup truck""s trailer hitch.
It is another object of the invention to provide a game hanger apparatus that is foldable and readily removable from the truck.
It is a further object of the invention to provide a game hanger apparatus which has a gambrel that eliminates twisting of the game.
Still another object of the invention is to provide a game hanger apparatus having a fixed boom and a winch raising and lowering a gambrel at the end of the boom.
It is an object of the invention to provide improved elements and arrangements thereof in an apparatus for the purposes described which is inexpensive, dependable and fully effective in accomplishing its intended purposes.
These and other objects of the present invention will become readily apparent upon further review of the following specification and drawings.

Collapsible game hanger for pickup truck