|Publication number||US3711602 A|
|Publication date||Jan 16, 1973|
|Filing date||Oct 30, 1970|
|Priority date||Oct 30, 1970|
|Publication number||US 3711602 A, US 3711602A, US-A-3711602, US3711602 A, US3711602A|
|Original Assignee||Crown Zellerbach Corp|
|Export Citation||BiBTeX, EndNote, RefMan|
|Patent Citations (6), Non-Patent Citations (2), Referenced by (121), Classifications (7), Legal Events (3)|
|External Links: USPTO, USPTO Assignment, Espacenet|
United States Patent Herschler 51 *Jan. 16, 1973 [5 COMPOSITIONS FOR TOPICAL 3,592,936 7 1971 Marcus ct al ..424 337 APPLICATION FOR ENHANCING 3,499,961 3 1970 Dobson et al. 3,011,950 i2/l96l Mehaffcy ..424/8l PHYSIOLOGICAL ACTIVE AGENTS FOREIGN PATENTS OR APPLICATIONS WITH DMSO 655,363 10/!965 South Africa Inventor: Robert John Herschler, Camas,
 Assignee: Crown Zellerbach Corporation, San
[ 1 Notice: The portion of the term of this patent subsequent to Dec. 28, 1987, has been disclaimed.
 Filed: Oct. 30, 1970  Appl. N0.: 85,697
Related U.S. Application Data  Continuation-in-part of Ser. No. 753,23l, Aug. 16, I968, abandoned, which is a continuation-in-part of Ser. No. 329,151, Dec. 9, I963, abandoned.
 U.S. Cl ..424/45, 424/337 [5 1] Int. Cl. A6lk 9/00  Field of Search ..424/45, 337
 References Cited UNITED STATES PATENTS 155L554 l2/l970 Herschler ..424/7 3,549,770 l2/l970 Herschler ..424/337 OTHER PUBLICATIONS Marson Bull. Chimicofarm l 02zl09-l24 February 1963. Fitzpatrick D&Cl 96(2):254 February 1965.
Primary Examiner-Shep K. Rose Attorney-Corwin R. Horton and Robert E. Howard  ABSTRACT Compositions for topical application for enhancing tissue penetration of physiologically active agents with dime'thyl sulfoxide (DMSO). Such agents include physiologically active steroids, antineoplastic agents, antigens, antihistaminic agents, neuropharmacologic agents, antiinflammatory agents, anticoagulants, vasodilators, ultra-violet screening agents and nutrients. Such compositions, which may be in the form of lotions, ointments and suppositories, include the physiologically active agent, at least l0% by weight of DMSO and a pharmaceutically acceptable thickening agent. Liquid formulations for topical application of DMSO and the physiologically active agent in spray containers are also provided.
11 Claims, N0 Drawings COMPOSITIONS FOR TOPICAL APPLICATION FOR ENHANCING TISSUE PENETRATION OF PHYSIOLOGICALLY ACTIVE AGENTS WITH DMSO CROSS REFERENCES TO RELATED APPLICATION This is a continuation-in-part of co-pending application Ser. No. 753,231, filed Aug. 16, 1968, now abandoned, which is, in turn, a continuation in part of application Ser. No. 329,151, filed Dec. 9, 1963, now abandoned.
BACKGROUND OF THE INVENTION A predominant and limiting problem in the development and use of physiologically active agents is the inability to administer them as effectively as is desired. In particular, there is often a limitation as to the routes of administration because of the following factors:
I. Some agents are inactivated in the gastrointestinal tract or they are absorbed poorly into the body from the tract. Also, undesirable side effects may result which prevent effective oral administration.
2. ln every case where injection must be resorted to, there is a risk of needle injury, infection, and other trauma (including the emotional trauma inevitably associated with injections).
3. Few agents are absorbed through the skin or mucous membranes in effective quantities and the rate of absorption is less than would be desirable for those that do.
. A local concentration for a local effect is often desired but a larger systemic dose must be given to achieve an effective concentration at the local area when the agent can only be injected or given orally, (but not topically). This higher dose often causes undesirable side effects, since dosage related side effects are very prevalent for many agents.
Animal tissues comprise various membranes which are selectively permeable and which allow some substances to pass freely, while rejecting others or permitting only slight passage. Such membranes comprise the body coverings and externally communicating cavities, including the skin and mucous membranes ofthe body cavities, e.g. alimentary tract, respiratory tract, genitourinary tract, oral cavity, eyes, etc. (collectively defined herein as external membranes). They also include internal membranes such as the linings of the various organs and other internal body structures, e.g., peritoneum and pleura, and the membranes surrounding cellular and intracellular structures. It is desirable in overcoming the aforementioned problems in drug administration, to increase the passage or penetration of agents across such membranes and further to enhance their intercellular and intracellular diffusion in order for them to reach their situs of activity more rapidly to achieve the desired response more quickly and often more effectively. It is exceptionally desirable to do this in a reversible manner, by which is meant penetration of the agents into tissue without adversely affecting or impairing the function or structure of the tissue. It is known that certain substances will penetrate tissue only after the tissue has been irreversibly damaged which is certainly undesirable. Certain agents, such as surfactants, have been known previously for increasing penetration of various agents. However, again, such penetration was effected only through irreversible damage of the tissue.
It has been a major rule in medicine that the vehicles or carriers have relatively little effect on the penetration rate for a given agent and this rule generally still holds true. Thus, with conventional carriers for medicines, such as alcohol, carbowax, water, etc., few agents will adequately penetrate such formidable external membrane barriers as the intact skin or mucous membrane. It is to be expected that this would be true of all potential vehicles" or materials combined with physiologically active agents. However, surprisingly, it has been discovered that dimethyl sulfoxide (DMSO) has the unusual ability to greatly enhance the penetration of agents when they are applied to such membrane barriers along with dimethyl sulfoxide. The penetration of agents which previously have not penetrated these membranes to an effective degree may be enhanced sufficiently so that a useful result may be obtained. The penetration of agents which have been known to penetrate to a limited degree in conventional vehicles may be significantly enhanced. New and convenient routes of administration, often with a decrease in side effects of the agents, better localized concentration and a more sustained activity, may thereby be created for many agents.
In my co-pending application (Ser. No. 6l5,377 filed Feb. 13, i967) is disclosed my related discovery that DMSO enhances the penetration of plant-active agents (pesticides, dyes, nutrients, hormones, herbicides, and the like) into plant tissue in a highly unusual manner.
Dimethyl sulfoxide (DMSO) is a water-white liquid at room temperature having a freezing point of approximately l8.5C and a specific gravity of approximately 1.1. Dimethyl sulfoxide is a well known industrial solvent and it has been available in commercial quantities for at least a decade (from Crown Zellerbach Corporation, San Francisco, Calif). DMSO was originally synthesized in 1866 and since that time it has been extensively investigated for possible industrial and biological utility and a considerable amount of literature has developed on its properties and uses. Over the last 25 years it has found widespread use as a solvent in industry and in the laboratory.
DMSO has been investigated in the past for various biochemical uses, for example as a reaction solvent for preparing derivatives of various proteins, and antibiotics, as an extraction solvent for various proteins, as an analytical solvent and as a solvent'for various other laboratory uses. It has also been suggested as a solvent for certain pesticides.
DMSO has been investigated as a preservative agent for in vitro storage of chilled or frozen tissue and it has also been determined to have a protective effect in experimentalanimals subjected to X-irradiation following injection of DMSO into such animals.
In connection with topical application of the antifungal griseofulvin, DMSO has been listed along with various inert materials as bland, high boiling fluids to be used as carriers for the griseofulvin in applying it to the skin to control fungus growth in the skin. DMSO has been employed as a solvent for preparation of certain injectable formulations, namely chloramphenicol and an anthelminic preparation.
SUMMARY OF THE INVENTION By a mechanism or mechanisms not yet fully understood, DMSO, when applied to animal tissue, increases the permeability of the tissue in a reversible manner to cause a much greater penetration rate for conjointly applied physiologically active agents. Although the mode of activity is still unclear, it is definitely not that of the simple vehicle" or carrier" since the effect may be obtained to some extent even when the DMSO is applied to the tissue separately and the enhanced penetrability of the tissue may last for as much as three hours after the DMSQ treatment.
When applied to the intact skin along with dimethyl sulfoxide, particularly at a DMSO concentration of 50 percent by weight and above, or to skin pretreated with the dimethyl sulfoxide, an agent such as a steroid, may penetrate rapidly to and saturate the stratum corneum (the highly resistant horny layer of the skin which is the major barrier to penetration). The steroid continues to penetrate through the skin from this reservoir" in the stratum corneum to the underlying tissue and into the circulatory system.
Similarly, penetration into underlying tissues and into the circulatory system may be obtained from topical application to the mucous membranes of the body cavities as in the case of intraoral, conjuctival sac, rectal, vaginal, and bladder instillation administration, particularly where the DMSO is utilized at a concentration of 10 percent by weight and above. It is thus seen that a particularly'important aspect of this invention is that penetration of agents may be effectively enhanced following topical administration. As used in this connection herein, the term topical is intended to include application to all external membrane barriers including the cutaneous or epidermis regions and the mucous membranes including the gastrointestinal tract, the respiratory tract and the genitourinary tract.
As previously indicated, the mechanisms of penetration enhancement are as yet not fully elucidated. Accordingly, it is not intended to be bound to one specific theory of operation. However, it is believed that DMSO acts by several mechanisms in enhancing penetration. DMSO is believed to act directly on tissue to alter the general permeability of the tissue membrane. More specifically, DMSO when applied thereto, is believed to decrease'the natural resistance of tissue membranes to penetration by foreign agents. DMSO is also believed to promote penetration by a direct transport effect, perhaps by the mechanism of complexing with the agent. This mechanism is believed more applicable to cationic and anionic agents.
By the present invention compositions are provided which are uniquely suitable for the purpose of utilizing the penetration enhancement of DMSO, which compositions include the physiologically active agent, an amount of DMSO effective to enhance topical penetration of such agent and a pharmaceutically acceptable thickening agent. For application to mucous membranes, the DMSO concentration may be 10 percent by weight and higher. For application to the intact skin DMSO concentrations of 50 percent or higher are suitable. The thickened composition forms of this invention permit more sustained contact of the composition with the treated surface and more accurate and controlled dosing. Accidental spilling, run off and undesired contact with the composition can also be minimized. Pharmaceutically acceptable hydrophillic diluents, particularly water, may also be employed in these compositions to lessen the tissue irritation affects which may result from application of higher concentrations of DMSO.
Liquid formulations for topical application comprising at least 10 percent by weight DMSO, the physiologically active agent and, optionally, diluents, thickening agents, etc. in spray containers are also provided. Such dosage forms are useful for topical application to prevent accidental spilling and undesired contact with the composition. They are particularly suitable for application to mucous membranes of various body orifices. They are also advantageous in providing a more uniform application to both dermal and mucous membrane surfaces.
GENERAL DESCRlPTlON OF THE INVENTION This invention is applicable to the tissue or organisms of all animal phyla, DMSO having differing degrees of influence on penetration of various tissue types of a given animal. Animals of particular importance in the practice of the invention are the mammalians, especially man and veterinary animals. However, the invention may also be practiced with other vertebrates, as for example the amphibians, fishes, reptiles, etc., and with the lower species comprising the non-vertebrates.
Penetration enhancement is generally non-selective in terms of the type of physiological effect or effects of agents to be transported across membrane barriers. The extent of penetration enhancement will depend upon' many factors, the predominant factors being the relative natural permeability of the particular membrane, the concentration of DMSO applied, the extent of solubility of the agent in DMSO and the chemical and physicalproperties of the agent.
The thickened dosage forms of this invention for topical application include lotions, ointments (including creams and gels) and suppositories. These compositions comprise the physiologically active agent combined with the DMSO and a base comprising a thickening agent for the composition and such pharmaceutical diluents as may be indicated.
Lotions and ointments may contain the usual ingredients to provide the thickening base, as for example cetyl alcohol, an emulsifier such as lauryl sulfate and water. Another base may be formulated by combining equal weight amounts of stearic acid, cetyl alcohol, triethanolamine and glycerol monostearate with water. Still other thickening bases may utilize polyethylene glycols of different viscosities, depending upon the desired consistency. DMSO may be added to the lotion or ointment base in varying amounts as desired, generally up to around 50 percent by weight or higher.
A suppository form may be made from a high viscosity polyethylene glycol 4,000, water and DMSO, which may be present in an amount of about percent by weight.
The spraying and misting dosage forms of the invention constitute nasal spray bottles, aspirators, misting devices, aerosol bombs and other dispensing containers having liquid spray or mist dispensing means, which containers are charged with fluid formulations comprising the physiologically active agent, at least l0 percent by weight DMSO and, optionally, water or diluent, thickening agents and the like. The compositions for this purpose are sufficiently fluid to permit dispensing by spray or mist from the container. Normally the DMSO component will provide adequate fluidity. However, the usual liquid diluents may be provided where desired to enhance sprayability.
The term physiologically active" in describing the agents contemplated herein is used in a broad sense to comprehend not only agents having a direct pharmacological effect on the host but also those having an indirect or observable effect which is useful in the medical arts, e.g., the screening of U.V. radiation from the tissues, etc., Agents, penetration of which across external membrane barriers may be beneficially enhanced upon direct application of the compositions of this invention include: physiologically active steroids, antineoplastic agents, antigens, antihistaminic agents, neuropharmacologic agents, antiinflammatory agents, anticoagulants, vasodilators, ultra-violet screening agents and nutrients.
The concentration of physiologically active agent in the various dosage forms is, of course, commensurate with that normally utilized for the particular agent in conventional formulations for effective results for the intended route. Both the amount of physiologically active agent and the amount of DMSO will be influenced by the type of effect desired. If a more localized effect is required, lower amounts of physiologically active agents and lower concentrations of DMSO may be called for. Where deeper penetration is desired, as in the case of local anaesthesia, a higher concentration of DMSO may be desirable to promote adequate penetration. Where general systemic concentration of an agent is desired for a topical preparation, generally higher concentrations of DMSO are desirable and the amount of agent as, for example, a steroid, may be included in the composition sufficient to provide the blood level desired.
The concentration of the DMSO in the compositions to enhance penetration may vary over wide limits. The concentration selected is desirably related to the route of administration to be employed. For cutaneous application, compositions including at least about 50 percent by weight DMSO are preferable in that they have been found to increase percutaneous penetration in a highly significant manner. Maximum cutaneous penetration is generally attained with DMSO concentrations closely approaching 100 percent (excluding the agent), but with concentrations much above 90 percent by weight the incremental increase in penetration rate over that achieved at 90 percent often is relatively small. On the other hand, above a percent concentration of dimethyl sulfoxide the side effects of a burning sensation and erythema increase significantly. Accordingly, for topical use, it may be desirable, consistent with physical stability of the composition, to formulate the DMSO in compositions containing a DMSO concentration of between about 50 and 90 percent by weight and containing water, preferably 10 percent by weight or greater.
Application to mucous membranes follows generally the procedure for cutaneous administration. However, lower concentrations of DMSO in the compositions, for example as low as 10 percent by weight, may be preferred since penetration of mucous membrane is more easily affected.
The usual pharmaceutical compounding agents, diluents or carriers, especially water, may be included in the compositions of this invention as desirable for the particular route of administration and dosage form. As discussed previously in relation to the concentration of DMSO in the formulations, the amount and type of diluent or carrier used should, of course, be consistent with the compatability of the agent in DMSO and the diluent. A cosolvent or other standard adjuvant, such as a surfactant, may be called for to maintain the agent in solution or suspension at the desired concentration. Where stability of the agent in the presence of DMSO at the desired concentration is a problem, it may be desirable to prepare the formulation immediately before administration.
The various pharmaceutical forms are desirably provided in determined amounts, as in containers of a given volume. Cotton tipped stick applicators, squeeze tubes may all be utilized for topical application of the thickened formulations.
The amount of the composition, and thus of the physiologically active agent therein, to be administered will obviously be an effective amount for the desired result expected therefrom. This, of course, will be ascertained by the ordinary skill of the practitioner. Due to enhanced activity which may be achieved through better penetration, the dosage of agent may often be decreased from that generally applicable. In accordance with the usual prudent formulating practices, a dosage near the lower end of the useful range of the particular agent may be employed initially and the dosage increased as indicated from the observed response, as in the routine procedure of the physician.
The examples which follow illustrate the compositions of the present invention. For an additional discussion of the various physiologically active agents and exemplification of the compositions of this invention, reference is made to copending application Ser. No. 753,231, filed Aug. 16, I968, the disclosure of which is incorporated herein by reference.
EXAMPLE 1 The following lotion formulation may be prepared containing about 0.01 to 1.0 percent, with preferably 0.1 percent fluocinolone acetonide:
. Gm. Fluocinolone acetonide 0.1-4.0 Cetyl alcohol 200 Propylene glycol Sodium lauryl sulfate 15 DMSO 300 Water q.s. 1000 cc.
EXAMPLE 2 The following ointment (gel) formulation may be prepared containing about 0.2 to 1.0 percent, and preferably 0.6 percent triamcinilone acetonide:
Gm. Triamcinilone acetonide 0.240 Polyethylene glycol 400 400 Dimethyl sulfoxide 598 Carboxy vinyl polymer powder I Triethanolamine 0.4
The corticosteroid is dissolved in a mixture of the first two ingredients, and the carboxy vinyl polymer gelling agent is sprinkled on the surface of the combined liquids and stirred until all the particles have been wetted and dispersed. The triethanolamine is then added dropwise to the mixture until it has gelled, care being taken to minimize the air entrapment. This gel is particularly effective in the treatment of seborrhea and other scalp and hair inflammatory conditions and may be applied in amount and frequency conventionally used for topical application of this steroid. Better penetration and thereby an increased anti-inflammatory active is obtained for the amount of steroid applied than results from its application in conventional formulations.
EXAMPLE 3 The following ointment formulations may be prepared containing about 0.1 to 1.0 percent prednisone and preferably 0.5 percent:
Prednisone gm 0.1-l Glyceryl monostearate, acid type gm I80 Stearyl alcohol gm 50 Polysorbate 80 cc 20 Water cc 450 Dimethyl sulfoxide cc 300 The product is prepared as described in Example 1. The ointment is a valuable base for application of the corticosteroid to inflammatory dermatological areas, particularly when they require inunction. Application is in accordance with that usual for topical application of this steroid in conventional bases.
EXAMPLE 4 The following cream formulations may be prepared Water q.s. 1000 cc.
As above, the product is prepared as directed in Example l and is useful in severe dermatoses requiring inunction. I
EXAMPLE 5 The following ointment formulation may be prepared containing about 0.5 to 2.5 percent preferably 1.0 percent, desoxycorticosterone acetate:
Water, q.s. 1000 cc.
The product is prepared as specified in Example 1. The product may be employed in treatment of pigmentation in Addisons disease by topical application to the affected area. Penetration may be increased sufficiently so that effective results may be obtained. In conventional bases this steroid has had very limited effectiveness topically and injection usually must be resorted to.
EXAMPLE 6 A suppository formulation may be prepared as follows containing about 1 to 5 percent, preferably 2 per- The solid constituents are melted, added to the solution of the steroid in DMSO and poured into an appropriate mold. The product is recommended for rectal application as replacement therapy.
EXAMPLE 7 A suppository formulation may be prepared as follows containing about 1 to 5 percent, preferably 2 percent, l7-methyl testosterone:
l7-Methyl testosterone gm 1050 Hydrogenated castor oil gm 400 Stearic acid gm I00 Dimethyl sulfoxide cc 500 The product is prepared as noted in Example 5 and used in a similar manner.
EXAMPLE 8 A cream formulation may be prepared as follows containing about'l to 10 percent, preferably 3 percent, 1 7a-ethyll 9-nortestosterone:
l7a-ethyll9-nortestosterone gm l0-100 Cetyl alcohol gm 250 Stearyl alcohol gm 200 Polysorbate cc 20 Water cc 250 Dimethyl sulfoxide, q.s. cc 1000 This cream may be prepared as noted in Example 1. It may be applied topically for stimulation of epithelization and connective tissue regeneration.
EXAMPLE 9 The following cream may be formulated with the following composition containing about 1 to 10 percent, and preferably 3%, 2a-methyl-dihydrotestosterone The cream is prepared as directed in Example I. The product is useful in the treatment of muscle wasting l5 and weakness followed breast cancer surgery and may be applied topically to the affected area. Penetration of the steroid is greatly improved over that obtained in conventional formulations.
EXAMPLE The following ointment (gel) may be formulated containing about 1 to 5 percent, preferably 2 percent, steroid:
2-hydroxymethylene-17a-methyldihydrotestosterone gm 10-50 Propylene glycol cc 500 Dimethyl sulfoxide cc 498 Carboxy vinyl polymer powder gm 1 Triethanolamine gm 0.5
The product is prepared as specified in Example 2. The product is useful in topical anabolic treatment, particularly in preventing thinning of the skin and in inducing blood vessel thickening.
EXAMPLE 1 l The following lotion may be formulated as follows containing about 0.1 to 1.0 percent, preferably 0.4 percent, estradiol valerate:
Estradiol valerate gm l-10 Cetyl alcohol grn 200 Propylene glycol gm 100 Sodium lauryl sulfate gm 15 Water cc 400 Dimethyl sulfoxide cc 300 This product is prepared as noted in Example '1. The product is designed as a means of establishing systemic replacement therapy for estrogens during menopause by simple topical application to the skin or mucous membrane. The DMSO enhances penetration of the estrogen sufficiently to obtain a systemic effect. This has not been possible in conventional formulations.
. EXAMPLE 12 A suppository may be formulated as follows to contain 0.1 to 1.0 percent, preferably 0.5 percent, of 3- methyl ether of ethynylestradiol:
J-methyl ether of ethynylestradiol gm l0-l00 Polyethylene glycol 4000 gm 400 Propylene glycol monostearate gm I00 Dimethyl sulfoxide (DMSO) cc 500 The suppositories are prepared as noted in Example 7. The product is used in estrogenic replacement therapy and may be used by rectal or vaginal application.
EXAMPLE 13 The following ointment (gel) may be formulated containing 0. 1 percent diethylstilbesterol:
Diethylstilbesterol Propylene glycol cc 500 Dimethyl sulfoxide cc 498 Carboxy vinyl polymer powder gm 1 Triethanolamine gm 0.5
This gel is prepared as detailed in Example 2. The preparation is particularly suitable for topical application in the treatment of adolescent acne.
EXAMPLE 14 A cream may be formulated as follows to contain about 0.72 percent norethynodrel and about 0.0286 percent mestranol:
Norethynodrel gm 10.5 Mestranol gm 0.42 Cetyl alcohol gm 100 Stearyl alcohol gm 100 Polysorbate cc 20 Water cc 250 Dimethyl sulfoxidc, q.s. cc 1000 This cream is prepared as noted in Example 1. This formulation is to be used as a contraceptive agent applied cutaneously twice monthly at a dosage of 10 grams.
EXAMPLE 15 A suppository formulation may be prepared as follows:
Chlormadinone mg 5 Stilbesterol mg l Polyethylene glycol 4000 gm 400 Propylene glycol monostearate gm Dimethyl sulfoxide cc 500 The suppositories are formed as in Example 7. The product may be employed for treatment of irregular or prolonged bleeding.
EXAMPLE 16 The following ophthalmic formulation may be prepared containing about 0.1 to 0.75 percent, preferably 0.3 percent, spironolactone:
Spironolactone gm [-7.5 Polyethylene glycol 4000 cc 200 Dimethyl sulfoxide cc 200 Water, q.s. I000 cc.
The formulation is prepared by melting the polyethylene glycol 4000, dissolving the steroid in the DMSO, mixing the two liquids together and diluting to volume with water while stirring. The preparation is applied topically to the eye by eye dropper, or similar applicator, for treatment of glaucoma.
EXAMPLE 17 A 5-fluorouracil formulation may be prepared by blending the following:
S-fluorouracil 10 grams DMSO 80 grams Water 10 grams Carboxymethyl cellulose 0.25 grams The formulation is particularly useful in topical treatment of skin tumors or other localized superficial tumors. A typical dose is grams. lt is also useful intreating viral disorders such as warts.
EXAMPLE 18 A suppository formulation may be prepared by melting together the following:
Gm. Estradiol valerate 2.75 Guiacol glycerol stearate I00 DMSO 300 Diglycol laurate 150 The melted blend is poured into a suppository mold to provide gm. suppositories for treatment of prostatic cancer.
EXAMPLE 19 EXAMPLE 20 A topical ointment formulation of tripelennamine base particularly suitable for treatment of itching dermatoses (applied to the affected area several times daily), may be formulated as follows:
Percent Tripelennamine base percent 2 DMSO 70 Sodium carboxymethylcellulose 4 Water 24 EXAMPLE 21 A chloral hydrate suppository formulation may be prepared by blending together:
Gms. Chloral hydrate 10 DMSO 4.7 Stearic acid 1 Water 0.5
The melt is poured into a suppository mold and cooled to form l0 suppositories each supplying a l gram dose. One or two suppositories, as indicated, may be administered as a general sedative.
EXAMPLE 22' A unit dose suppository form of imipramine can be prepared by melting together:
lmipramine base mg. 50 DMSO gm 4.5 Sodium stearate gm 1.0 Glycerine gm 4.5 Water 1.0
and cooling the melt in a suppository mold. This dosage may be administered rectally T.l.D. to relieve depression.
EXAMPLE 23 The following formulation maybe melted together, placed in a suppository mold and cooled to form a unit dose for rectal application as a monoamine oxidase inhibitor for treatment of depressive states:
N-benzyl-N-methyl-2-propynylamine mg v100 DMSO gm 4 Diglycol laurate gm 1.5 Carbopol 934 gm 0.25 Triethanolamine gm 0.01
EXAMPLE 24 Mecamylamine is representative of agents having a site of activity at the autonomic ganglia (ganglionic stimulating and blocking agents). It may be formulated as follows to provide a single dose in suppository form for rectal application in treatment of hypertension:
Mecamylamine base mg 15 Propylene glycol stearate gm 4.5 DMSO gm 4.5 Triethanol amine gm 0.3 Stearic acid gm 1.5
Melt ingredients together and pour into cooled suppository mold.
EXAMPLE 25 A glycerol trinitrate ointment may be prepared by blending the following ingredients:
Gms. Glycerol trinitrate 2 DMSO Ethanol 8 Carbowax 1500 20 A typical dosage of 10 mg. of glycerol trinitrate is provided with one-half gram of this ointment. The dosage may be applied topically as, for example, to the intact skin of the upper arm, or sublingually.
EXAMPLE 26 A male subject had a skin markedly sensitive to ultraviolet light. A test solution was made containing 1 percent ultraviolet absorber in percent dimethyl sulfoxide. A control solution was made containing the ultraviolet-absorber in 100 percent ethanol, and both solutions were similarly thickened with Carbowax 4000 to provide lotion forms. The ultraviolet absorber was 2,2-dihydroxy-4,4'-dimethoxy benzophenone. The two lotions were applied to different sides of the subjects face. After one day of severe sun exposure, the subject was examined. The side with the control application showed marked redness. The side with the test application showed only slight redness. Two days later, the control side was blistered, whereas the test side was normal and free of redness.
EXAMPLE 27 An ointment base may be prepared from the follow. ing:
Parts by wt. Lanolin 90 DMSO 10 lsopropyl myistate to which is added L800 U.S.P. units of Vitamin A and 300 U.S.P. units of Vitamin D per gram of ointment base. This ointment is applied topically for the treatment of burns, skin irritation, diaper rash and pruritis.
What I claim is:
1. A composition suitable for topical application to external membranes of a human or animal subject for enhanced penetration of a physiologically active agent in said composition which comprises an amount of a physiologically active agent effective to produce the desired physiological effect on topical application of the composition to an external membrane of the subject, said agent being selected from the group consisting of physiologically active steroids, antineoplastic agents, antigens, antihistaminic agents, neuropharmacologic agents, antiinflammatory agents, anticoagulants, vasodilators, ultra-violet screening agents and nutrients, an amount of DMSO effective to enhance external membrane penetration of said agent and comprising at least about percent by weight of said composition, and a pharmaceutically acceptable thickening agent in an amount sufficient to materially increase the viscosity of said composition, whereby to facilitate controlled topical application thereof.
2. A composition as in claim 1 for dermal application and wherein said DMSO comprises at least about 50 percent by weight of said composition.
3. A composition as in claim 2 and wherein said agent is selected from the group consisting of physiologically active steroids, antineoplastic agents,
antigens, antihistaminic agents, analgesics, local anaesthetics and antiinflammatory agents;
4. A composition as in claim 1 and wherein said composition is in the form of a lotion.
5. A composition as in claim 1 and wherein said composition is in the form of an ointment.
6. A composition as in claim 1 and wherein said composition is in the form of a suppository.
7. A container provided with liquid spray dispensing means and containing a fluid, sprayable composition which comprises an amount of a physiologically active agent effective to produce the desired physiological effeet on topical application of the composition to an external membrane of a human or animal, said agent being selected from the group consisting of physiologically active steroids, antineoplastic agents, antigens, antihistaminic agents, neuropharmacologic agents, antiinflammatory agents, anticoagulants, vasodilators, ultra-violet screening agents and nutrients, and an amount of DMSO effective to enhance external membrane penetration of said agent and comprising at least about 10 percent by weight of said composition.
8. A container as in claim 7 and wherein said DMSO in the composition charged therein comprises at least about 50 percent by weight of said composition.
9. A container as in claim 7 and wherein said container is an aerosol bomb containing a halocarbon propellant.
10. A container as in claim 7 and wherein said container is a squeeze bottle.
11. A container as in claim 7 and wherein the composition therein contains a substantial amount of water asadiluent.
|Cited Patent||Filing date||Publication date||Applicant||Title|
|US3011950 *||May 19, 1959||Dec 5, 1961||Colgate Palmolive Co||Liquid composition containing discrete gaseous bodies|
|US3499961 *||Dec 9, 1963||Mar 10, 1970||Crown Zellerbach Corp||Dimethyl sulfoxide-enhanced astringent aluminum,zinc or zirconium antiperspirant salt cosmetics|
|US3549770 *||Nov 28, 1967||Dec 22, 1970||Crown Zellerbach Corp||Therapeutic administration of effective amounts of dimethyl sulfoxide to human and animal subjects|
|US3551554 *||Aug 16, 1968||Dec 29, 1970||Crown Zellerbach Corp||Enhancing tissue penetration of physiologically active agents with dmso|
|US3592936 *||Apr 25, 1969||Jul 13, 1971||Merck & Co Inc||Method of treatment using pharmaceutical composition containing dimethyl sulfoxide|
|ZA655363A *||Title not available|
|1||*||Fitzpatrick D&CI 96(2):254 February 1965.|
|2||*||Marson Bull. Chimicofarm 102:109 124 February 1963.|
|Citing Patent||Filing date||Publication date||Applicant||Title|
|US4296104 *||Aug 30, 1979||Oct 20, 1981||Herschler R J||Therapeutic dimethyl sulfoxide composition and methods of use|
|US4442089 *||Jul 6, 1982||Apr 10, 1984||E. R. Squibb & Sons, Inc.||Method for treating glaucoma with topical or systemic ACE inhibitor compositions|
|US4499084 *||Feb 3, 1983||Feb 12, 1985||Dixon Glen J||Ara-A Antiviral composition and method of administering the same|
|US4505901 *||Mar 22, 1983||Mar 19, 1985||Orvet B.V.||Compositions and methods for topical treatment of cutaneous leishmaniasis with paromomycin|
|US4507287 *||Jun 20, 1983||Mar 26, 1985||Dixon Glen J||Preparation and method for the treatment of acne|
|US4575515 *||May 15, 1984||Mar 11, 1986||Clark Pharmaceutical Laboratories Ltd.||Pharmaceutical solutions comprising dimethyl sulfoxide|
|US4652557 *||Oct 24, 1985||Mar 24, 1987||Clark Pharmaceutical Laboratories Ltd.||Pharmaceutical solutions comprising dimethyl sulfoxide|
|US5262165 *||Feb 4, 1992||Nov 16, 1993||Schering Corporation||Transdermal nitroglycerin patch with penetration enhancers|
|US5486509 *||May 27, 1994||Jan 23, 1996||University Of Miami||Method of preventing and treating chemotherapy-induced alopecia|
|US5702361 *||Jan 31, 1996||Dec 30, 1997||Micro Therapeutics, Inc.||Method for embolizing blood vessels|
|US5789399 *||Oct 2, 1996||Aug 4, 1998||Strube; Marilyn E.||Treatment of pruritus with vitamin D and analogs thereof|
|US5814599 *||Aug 4, 1995||Sep 29, 1998||Massachusetts Insitiute Of Technology||Transdermal delivery of encapsulated drugs|
|US5947921 *||Dec 18, 1995||Sep 7, 1999||Massachusetts Institute Of Technology||Chemical and physical enhancers and ultrasound for transdermal drug delivery|
|US6002961 *||Jul 25, 1995||Dec 14, 1999||Massachusetts Institute Of Technology||Transdermal protein delivery using low-frequency sonophoresis|
|US6017977 *||Jun 4, 1997||Jan 25, 2000||Micro Therapeutics, Inc.||Methods for embolizing blood vessels|
|US6018678 *||Oct 19, 1995||Jan 25, 2000||Massachusetts Institute Of Technology||Transdermal protein delivery or measurement using low-frequency sonophoresis|
|US6041253 *||Apr 1, 1996||Mar 21, 2000||Massachusetts Institute Of Technology||Effect of electric field and ultrasound for transdermal drug delivery|
|US6190315||Jan 8, 1999||Feb 20, 2001||Sontra Medical, Inc.||Sonophoretic enhanced transdermal transport|
|US6234990||Jun 30, 1997||May 22, 2001||Sontra Medical, Inc.||Ultrasound enhancement of transdermal transport|
|US6281263||Nov 12, 1999||Aug 28, 2001||Scott Evans||Methods for embolizing blood vessels|
|US6335384||Oct 10, 2000||Jan 1, 2002||Micro Therapeutics, Inc.||Methods for embolizing blood vessels|
|US6491657||May 21, 2001||Dec 10, 2002||Sontra Medical, Inc.||Ultrasound enhancement of transdermal transport|
|US6795727||Oct 17, 2001||Sep 21, 2004||Pedro Giammarusti||Devices and methods for promoting transcutaneous movement of substances|
|US7015210||Dec 12, 2002||Mar 21, 2006||Pharmacia Corporation||Methods of treating ophthalmic disorders with epoxy-steroidal aldosterone receptor antagonists|
|US7066884||Mar 16, 2001||Jun 27, 2006||Sontra Medical, Inc.||System, method, and device for non-invasive body fluid sampling and analysis|
|US7135191 *||Mar 1, 2000||Nov 14, 2006||Zsolt Istvan Hertelendy||Urogenital or anorectal transmucosal vaccine delivery system|
|US7432069||Dec 5, 2005||Oct 7, 2008||Sontra Medical Corporation||Biocompatible chemically crosslinked hydrogels for glucose sensing|
|US7544714||Jul 15, 2005||Jun 9, 2009||University Of Massachusetts||Lipid-amino acid conjugates and methods of use|
|US7758561||Feb 6, 2004||Jul 20, 2010||Altea Therapeutics Corporation||Microporation of tissue for delivery of bioactive agents|
|US8016811||Oct 24, 2003||Sep 13, 2011||Altea Therapeutics Corporation||Method for transdermal delivery of permeant substances|
|US8116860||Jan 22, 2008||Feb 14, 2012||Altea Therapeutics Corporation||Transdermal porator and patch system and method for using same|
|US8224414||Sep 13, 2005||Jul 17, 2012||Echo Therapeutics, Inc.||System and method for analyte sampling and analysis with hydrogel|
|US8287483||Mar 5, 2004||Oct 16, 2012||Echo Therapeutics, Inc.||Method and apparatus for enhancement of transdermal transport|
|US8386027||Apr 25, 2008||Feb 26, 2013||Echo Therapeutics, Inc.||Skin permeation device for analyte sensing or transdermal drug delivery|
|US8517958||Nov 12, 2010||Aug 27, 2013||Nitto Denko Corporation||Transdermal integrated actuator device, methods of making and using same|
|US8561795||Nov 15, 2012||Oct 22, 2013||Seventh Sense Biosystems, Inc.||Low-pressure packaging for fluid devices|
|US8641689||Oct 13, 2011||Feb 4, 2014||Nitto Denko Corporation||Transdermal porator and patch system and method for using same|
|US8706210||Jan 27, 2009||Apr 22, 2014||Nitto Denko Corporation||Transdermal integrated actuator device, methods of making and using same|
|US8808202||Nov 9, 2011||Aug 19, 2014||Seventh Sense Biosystems, Inc.||Systems and interfaces for blood sampling|
|US8812071||Mar 6, 2008||Aug 19, 2014||Echo Therapeutics, Inc.||Transdermal analyte monitoring systems and methods for analyte detection|
|US8821412||Nov 19, 2012||Sep 2, 2014||Seventh Sense Biosystems, Inc.||Delivering and/or receiving fluids|
|US8827971||Apr 26, 2012||Sep 9, 2014||Seventh Sense Biosystems, Inc.||Delivering and/or receiving fluids|
|US8870810||Sep 13, 2012||Oct 28, 2014||Echo Therapeutics, Inc.||Method and apparatus for enhancement of transdermal transport|
|US9033898||Jun 22, 2011||May 19, 2015||Seventh Sense Biosystems, Inc.||Sampling devices and methods involving relatively little pain|
|US9033950||Jul 29, 2011||May 19, 2015||Nitto Denko Corporation||Method for transdermal delivery of permeant substances|
|US9041541||Jan 28, 2011||May 26, 2015||Seventh Sense Biosystems, Inc.||Monitoring or feedback systems and methods|
|US9066913||Sep 25, 2014||Jun 30, 2015||Hznp Limited||Diclofenac topical formulation|
|US9101591||Jan 14, 2015||Aug 11, 2015||Hznp Limited||Diclofenac topical formulation|
|US9113836||Mar 2, 2010||Aug 25, 2015||Seventh Sense Biosystems, Inc.||Devices and techniques associated with diagnostics, therapies, and other applications, including skin-associated applications|
|US9119578||Apr 26, 2012||Sep 1, 2015||Seventh Sense Biosystems, Inc.||Plasma or serum production and removal of fluids under reduced pressure|
|US9132110||Oct 31, 2012||Sep 15, 2015||Hznp Limited||Treatment of pain with topical diclofenac|
|US9168304||May 6, 2015||Oct 27, 2015||Hznp Limited||Diclofenac topical formulation|
|US9168305||May 6, 2015||Oct 27, 2015||Hznp Limited||Diclofenac topical formulation|
|US9220784||May 6, 2015||Dec 29, 2015||Hznp Limited||Diclofenac topical formulation|
|US9295417||Apr 26, 2012||Mar 29, 2016||Seventh Sense Biosystems, Inc.||Systems and methods for collecting fluid from a subject|
|US9339551||May 6, 2015||May 17, 2016||Hznp Limited||Diclofenac topical formulation|
|US9339552||Oct 26, 2015||May 17, 2016||Hznp Limited||Diclofenac topical formulation|
|US9370501||Jul 21, 2015||Jun 21, 2016||Hznp Limited||Treatment of pain with topical diclofenac|
|US9375412||Jul 27, 2015||Jun 28, 2016||Hznp Limited||Treatment of pain with topical diclofenac|
|US9415029||Oct 26, 2015||Aug 16, 2016||Hznp Limited||Treatment of pain with topical diclofenac|
|US9486616||Mar 5, 2014||Nov 8, 2016||Nitto Denko Corporation||Transdermal integrated actuator device, methods of making and using same|
|US9539335||Apr 6, 2016||Jan 10, 2017||Hznp Limited||Diclofenac topical formulation|
|US9572527||Jan 22, 2013||Feb 21, 2017||Echo Therapeutics, Inc.||Skin permeation device for analyte sensing or transdermal drug delivery|
|US9579380||Mar 16, 2005||Feb 28, 2017||Ntt Denko Corporation||Microporation of tissue for delivery of bioactive agents|
|US20030022938 *||Jun 25, 2002||Jan 30, 2003||Burstein Sumner H.||N-fatty acid-amino acid conjugates and therapeutic uses|
|US20030092982 *||Oct 31, 2002||May 15, 2003||Eppstein Jonathan A.||Microporation of tissue for delivery of bioactive agents|
|US20030138455 *||Mar 1, 2000||Jul 24, 2003||Hertelendy, Pharm.D.,Ph.D Zsolt Istvan||Urogential or anorectal transmucosal vaccine delivery system|
|US20040039342 *||Mar 11, 2003||Feb 26, 2004||Jonathan Eppstein||Transdermal integrated actuator device, methods of making and using same|
|US20040127476 *||Nov 12, 2003||Jul 1, 2004||Alvin Kershman||Oral testosterone delivery system with improved sustained release|
|US20040171980 *||Mar 5, 2004||Sep 2, 2004||Sontra Medical, Inc.||Method and apparatus for enhancement of transdermal transport|
|US20040197399 *||Dec 23, 2003||Oct 7, 2004||University Of Massachusetts, A Massachusetts Corporation||N-fatty acid-amino acid conjugates and therapeutic uses|
|US20040210184 *||May 5, 2004||Oct 21, 2004||Massachusetts Institute Of Technology||Effect of electric field and ultrasound for transdermal drug delivery|
|US20040220456 *||Feb 6, 2004||Nov 4, 2004||Altea Therapeutics Corporation||Microporation of tissue for delivery of bioactive agents|
|US20040236268 *||Mar 5, 2004||Nov 25, 2004||Sontra Medical, Inc.||Method and apparatus for enhancement of transdermal transport|
|US20050165393 *||Mar 16, 2005||Jul 28, 2005||Eppstein Jonathan A.||Microporation of tissue for delivery of bioactive agents|
|US20060014820 *||Jul 15, 2005||Jan 19, 2006||Burstein Sumner H||Lipid-amino acid conjugates and methods of use|
|US20060015058 *||Feb 25, 2005||Jan 19, 2006||Kellogg Scott C||Agents and methods for enhancement of transdermal transport|
|US20060094944 *||Sep 13, 2005||May 4, 2006||Sontra Medical Corporation||System and method for analyte sampling and analysis with error correction|
|US20060094946 *||Sep 13, 2005||May 4, 2006||Sontra Medical Corporation||System and method for analyte sampling and analysis with hydrogel|
|US20070082010 *||Oct 12, 2006||Apr 12, 2007||Protein Express, Inc.||Urogenital or anorectal transmucosal vaccine delivery system|
|US20070128681 *||Dec 5, 2005||Jun 7, 2007||Sontra Medical Corporation||Biocompatible chemically crosslinked hydrogels for glucose sensing|
|US20080208107 *||Jan 22, 2008||Aug 28, 2008||Mcrae Stuart||Transdermal porator and patch system and method for using same|
|US20080275468 *||Apr 25, 2008||Nov 6, 2008||Echo Therapeutics, Inc.||Skin permeation device for analyte sensing or transdermal drug delivery|
|US20080281178 *||Mar 6, 2008||Nov 13, 2008||Echo Therapeutics, Inc.||Transdermal analyte monitoring systems and methods for analyte detection|
|US20090104235 *||Feb 24, 2006||Apr 23, 2009||Heinrich Exner||Method for Producing of a Preparation of a Solid Dmso-Containing Silicone Oil Emulsion for the Binding of Reactive Oxygen Compounds in Human and Animal Bodies|
|US20090264810 *||Jan 27, 2009||Oct 22, 2009||Eppstein Jonathan A||Transdermal Integrated Actuator Device, Methods of Making and Using Same|
|US20090311290 *||Aug 17, 2009||Dec 17, 2009||Protein Express, Inc.||Urogenital or anorectal transmucosal vaccine delivery system|
|US20100069491 *||Jun 5, 2009||Mar 18, 2010||University Of Massachusetts||Lipid-amino acid conjugates and methods of use|
|US20100069726 *||Jun 4, 2009||Mar 18, 2010||Seventh Sense Biosystems, Inc.||Compositions and methods for rapid one-step diagnosis|
|US20100217212 *||Feb 24, 2010||Aug 26, 2010||Eppstein Jonathan A||Microporation of Tissue for Delivery of Bioactive Agents|
|US20100256465 *||Mar 2, 2010||Oct 7, 2010||Seventh Sense Biosystems, Inc.||Devices and techniques associated with diagnostics, therapies, and other applications, including skin-associated applications|
|US20100256524 *||Mar 2, 2010||Oct 7, 2010||Seventh Sense Biosystems, Inc.||Techniques and devices associated with blood sampling|
|US20110105872 *||Oct 29, 2010||May 5, 2011||Seventh Sense Biosystems, Inc.||Systems and methods for application to skin and control of actuation, delivery, and/or perception thereof|
|US20110105951 *||Oct 29, 2010||May 5, 2011||Seventh Sense Biosystems, Inc.||Systems and methods for treating, sanitizing, and/or shielding the skin or devices applied to the skin|
|US20110105952 *||Oct 29, 2010||May 5, 2011||Seventh Sense Biosystems, Inc.||Relatively small devices applied to the skin, modular systems, and methods of use thereof|
|US20110125058 *||Nov 24, 2010||May 26, 2011||Seven Sense Biosystems, Inc.||Patient-enacted sampling technique|
|US20110172508 *||Jan 13, 2011||Jul 14, 2011||Seventh Sense Biosystems, Inc.||Sampling device interfaces|
|US20110172510 *||Jan 13, 2011||Jul 14, 2011||Seventh Sense Biosystems, Inc.||Rapid delivery and/or withdrawal of fluids|
|US20110181410 *||Jan 28, 2011||Jul 28, 2011||Seventh Sense Biosystems, Inc.||Monitoring or feedback systems and methods|
|US20150231113 *||Feb 23, 2015||Aug 20, 2015||Morvus Technology Limited||Use of alpha-hydroxy carbonyl compounds as reducing agents|
|US20150359767 *||Aug 26, 2015||Dec 17, 2015||Cmpd Licensing, Llc||Composition and method for compounded therapy|
|US20150359768 *||Aug 26, 2015||Dec 17, 2015||Cmpd Licensing, Llc||Composition and method for compounded therapy|
|DE4018919A1 *||Jun 13, 1990||Dec 19, 1991||Sanol Arznei Schwarz Gmbh||Nitroglycerin-spray|
|DE19519056A1 *||May 24, 1995||Jan 16, 1997||Klinge Co Chem Pharm Fab||Verwendung von Antidepressiva zur Behandlung von Asthma und/oder Atemwegserkrankungen mittels inhalatorischer Applikation|
|DE102005009515A1 *||Feb 25, 2005||Sep 7, 2006||Exner, Heinrich, Dr.||Verfahren zur Herstellung einer Zubereitung einer DMSO-haltigen festen Silikonölemulsion zur Bindung von reaktiven Sauerstoffverbindungen im Körper von Menschen und Tieren|
|EP0028525A2 *||Oct 31, 1980||May 13, 1981||Orion-Yhtymä Oy||Hair treatment agent promoting the growth of hair and preventing dandruff|
|EP0028525A3 *||Oct 31, 1980||Oct 28, 1981||Orion-Yhtymä Oy||Hair treatment agent promoting the growth of hair and preventing dandruff|
|EP0036138A2 *||Mar 5, 1981||Sep 23, 1981||Merck & Co., Inc.||Composition of matter for topical application comprising a bio-affecting agent and N,N-diethyl-m-toluamide|
|EP0036138A3 *||Mar 5, 1981||Nov 25, 1981||Merck & Co. Inc.||Composition of matter for topical application comprising a bio-affecting agent|
|EP0191357A2 *||Jan 29, 1986||Aug 20, 1986||Thomas L. Dr. Schulte||Treatment of eye inflammation with biphenamine|
|EP0191357A3 *||Jan 29, 1986||May 24, 1989||Thomas L. Dr. Schulte||Treatment of eye inflammation with biphenamine|
|EP0410348A1 *||Jul 23, 1990||Jan 30, 1991||G.D. Searle & Co.||Topical spironolactone composition|
|EP1465563A1 *||Dec 20, 2002||Oct 13, 2004||Duramed Pharmaceuticals, Inc.||METHOD OF SYSTEMICALLY DELIVERING SSRIs|
|EP1465563A4 *||Dec 20, 2002||Jun 30, 2010||Duramed Pharmaceuticals Inc||METHOD OF SYSTEMICALLY DELIVERING SSRIs|
|EP2305195A1||Jun 21, 1996||Apr 6, 2011||Theratech, Inc.||Drug delivery compositions for improved stability of steroids|
|EP2767163A1||Feb 17, 2006||Aug 20, 2014||Abbott Laboratories||Transmucosal administration of drug compositions for treating and preventing disorders in animals|
|EP2921111A1||Aug 29, 1996||Sep 23, 2015||Nitto Denko Corporation||Microporation of human skin for drug delivery and monitoring applications|
|WO1998000194A2||Jun 30, 1997||Jan 8, 1998||Sontra Medical, L.P.||Ultrasound enhancement of transdermal transport|
|WO1999002182A2 *||Jul 10, 1998||Jan 21, 1999||Biotech Australia Pty. Limited||Non-aqueous vaccines|
|WO1999002182A3 *||Jul 10, 1998||Apr 1, 1999||Biotech Australia Pty Ltd||Non-aqueous vaccines|
|WO2010101625A2||Mar 2, 2010||Sep 10, 2010||Seventh Sense Biosystems, Inc.||Oxygen sensor|
|U.S. Classification||424/45, 514/711|
|Cooperative Classification||A61K47/20, A61K9/0014|
|European Classification||A61K9/00M3, A61K47/20|
|Aug 5, 1988||AS||Assignment|
Owner name: GAYLORD CONTAINER CORPORATION
Free format text: CHANGE OF NAME;ASSIGNOR:GC ACQUISITION CORPORATION;REEL/FRAME:004941/0061
Effective date: 19861203
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:GAYLORD CONTAINER LIMITED;REEL/FRAME:004941/0056
Effective date: 19861117
|Jul 21, 1988||AS||Assignment|
Owner name: BANKERS TRUST COMPANY, A NY BANKING CORP.
Free format text: SECURITY INTEREST;ASSIGNOR:GAYLORD CONTAINER CORPORATION, A CORP. OF DE;REEL/FRAME:004922/0959
Effective date: 19880329
|Sep 24, 1986||AS||Assignment|
Owner name: GAYLORD CONTAINER LIMITED, ONE BUSH STREET, SAN FR
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST. SUBJECT TO CONDITIONS RECITED;ASSIGNOR:CROWN ZELLERBACH CORPORATION, A CORP OF NV.;REEL/FRAME:004610/0457
Effective date: 19860429