Source: http://www.google.com/patents/US8062660?dq=7493558
Timestamp: 2014-07-13 03:21:36
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Matched Legal Cases: ['Application No. 60', 'Application No. 01976586', 'Application No. 01976586', 'Application No. 155097', 'Application No. 164191', 'Application No. 199236', 'Application No. 164191', 'Application No. 155097', 'Application No. 164191', 'Application No. 155097', 'Application No. 155097', 'Application No. 155097', 'Application No. 199236', 'Application No. 164191', 'Application No. 155097', 'Application No. 164191', 'Application No. 01976586', 'Application No. 199236', 'Application No. 164191', 'Application No. 155097', 'art 3', 'Application No. 01976586']

Patent US8062660 - Methods compositions and devices utilizing stinging cells/capsules for ... - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign in<nobr>Advanced Patent Search</nobr>PatentsA delivery device including at least one stinging capsule and methods of use are described....http://www.google.com/patents/US8062660?utm_source=gb-gplus-sharePatent US8062660 - Methods compositions and devices utilizing stinging cells/capsules for delivering a therapeutic or a cosmetic agent into a tissueAdvanced Patent SearchPublication numberUS8062660 B2Publication typeGrantApplication numberUS 11/374,969Publication dateNov 22, 2011Filing dateMar 15, 2006Priority dateSep 28, 2000Also published asEP1379127A2, EP1379127A4, EP1379127B1, US6613344, US6923976, US7338665, US8486441, US20020039592, US20030202995, US20040224013, US20060159769, US20110070224, WO2002026191A2, WO2002026191A3Publication number11374969, 374969, US 8062660 B2, US 8062660B2, US-B2-8062660, US8062660 B2, US8062660B2InventorsTamar Lotan, Shimon EckhouseOriginal AssigneeNanocyte Inc.Export CitationBiBTeX, EndNote, RefManPatent Citations (66), Non-Patent Citations (119), Referenced by (4), Classifications (28), Legal Events (1) External Links: USPTO, USPTO Assignment, EspacenetMethods compositions and devices utilizing stinging cells/capsules for delivering a therapeutic or a cosmetic agent into a tissueUS 8062660 B2Abstract A delivery device including at least one stinging capsule and methods of use are described.
1. A composition-of-matter comprising a nucleic acid construct and at least one stinging capsule.
2. The composition-of-matter of claim 1, wherein said nucleic acid construct is disposed in a pharmaceutically acceptable carrier surrounding, or stored within, said at least one stinging capsule.
3. The composition-of-matter of claim 1, wherein said nucleic acid construct encodes a polypeptide, an enzyme, a hormone, an antibody, a ligand or a peptide.
4. The composition-of-matter of claim 1, wherein said nucleic acid construct encodes an antisense RNA or a ribozyme.
5. The composition-of-matter of claim 1, wherein said at least one stinging capsule is capable of delivering said nucleic acid construct into tissue of a metazoan.
6. The composition-of-matter of claim 1, wherein said at least one stinging capsule is derived from an organism of a class selected from the group consisting of Anthozoa, Hydrozoa and Scyphozoa.
7. The composition-of-matter of claim 1, wherein said at least one stinging capsule is derived from an organism of a phylum selected from the group consisting of Cnidaria, Dinoflagellata and Myxozoa.
8. The composition-of-matter of claim 1, wherein said stinging capsule forms a part of a stinging cell.
9. A method of delivering a molecule which delivery is desired into a tissue, the method comprising:
(a) applying a composition-of-matter which comprises the molecule which delivery is desired and at least one stinging capsule to the tissue, wherein the molecule is disposed in a pharmaceutically acceptable carrier surrounding, or stored within, said at least one stinging capsule; and
(b) triggering a discharge of said at least one stinging capsule to thereby deliver the molecule which delivery is desired into the tissue.
10. The method of claim 9, wherein said composition-of-matter is formulated as a topical formulation, an aerosol spray, a spray or a gel.
11. The method of claim 9, wherein the molecule which delivery is desired is disposed in a pharmaceutically acceptable carrier surrounding, or stored within, said at least one stinging capsule.
12. The method of claim 9, wherein the molecule which delivery is desired is selected from the group consisting of a nucleic acid construct, a polypeptide and a peptide.
13. The method of claim 12, wherein said nucleic acid construct encodes a polypeptide, an enzyme, a hormone, an antibody, a ligand or a peptide.
14. The method of claim 12, wherein said nucleic acid construct encodes an antisense RNA or a ribozyme.
15. The method of claim 9, wherein said tissue is of a metazoan.
RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 10/868,802, filed on Jun. 17, 2004, now U.S. Pat. No. 7,338,665, which is a divisional of U.S. patent application Ser. No. 10/406,202, filed on Apr. 4, 2003, now U.S. Pat. No. 6,923,976, which is a divisional of U.S. patent application Ser. No. 09/963,672, filed on Sep. 27, 2001, now U.S. Pat. No. 6,613,344, which claims the benefit of U.S. Provisional Patent Application No. 60/235,910, filed on Sep. 28, 2000. The contents of the above applications are all incorporated by reference.
FIELD AND BACKGROUND OF THE INVENTION The present invention relates to stinging cells or capsules and to the use thereof in compositions, devices and methods for delivering a therapeutic, cosmetic or diagnostic agent into a tissue. More particularly, the present invention relates to the use of stinging cells or capsules as transdermal/intradermal, transmembranal or transcuticular delivery devices.
To traverse such barriers, drugs targeted at internal tissues are often administered via a transdermal injection, using a syringe and a needle or other mechanical devices. A transdermal injection delivers drugs into the subcutaneous space thus traversing the epidermis-dermis layers.
Anatomically, the skin of a human body is subdivided into three compartments: an epidermis, a dermis and a subcutaneous layer, of which the epidermis plays a key role in blocking drug delivery via the skin (the dourest layer of the epidermis is the stratum comeum which is called also the horny layer). The epidermis is 0.1 mm or more in thickness and consists mainly of protein surrounded by lipid, thus rendering the epidermis hydrophobic.
Non-invasive methods, which overcome some of the limitations inherent to the invasive delivery methods described above, have also been described. Such methods utilize preparations, which include an active ingredient disposed within lipid vehicles (e.g., liposomes) or micelles or accompanied with skin permeation agent such that absorption of the active ingredient through the skin is enhanced. Such preparations can be directly applied to a skin region or delivered via transdermnal devices such as membranes, pressure-sensitive adhesive matrices and skin patches.
To overcome the limitations of invasive and non-invasive delivery devices, the present inventors propose the use of �stinging cells� (e.g. cnidocytes, nematocytes and the like) or �stinging capsules� (e.g., cnidocysts, nematocysts and polar capsules) isolated therefrom for tissue delivery of a therapeutic or cosmetic agents.
SUMMARY OF THE INVENTION According to one aspect of the present invention there is provided a composition of matter comprising a therapeutic or a cosmetic agent and at least one stinging capsule.
According to still further features in the described preferred embodiments the step of treating the stinging capsule under conditions which inactivate an endogenous toxin stored in the stinging capsule yet do not trigger discharge or breakdown of the stinging capsule to thereby obtain the delivery capsule) is effected by incubating the stinging capsule at a temperature of 37-45� C. for at least two hours.
FIGS. 1 a-d illustrate the structure and release mechanism of a cnidocyst;
FIG. 2 a is a schematic illustration of a delivery device according to the teachings of the present invention;
FIG. 2 b is a prior art scanning electron micrograph showing stinging cells of Cyanea capillata following activation via human skin contact;
FIG. 3 is a microscope image of capsules (stinging capsules) isolated from Rhopilema nomadica tentacles;
FIG. 4 is a microscope image of capsules isolated from Rhopilema nomadica tentacles. The folded tubule inside some of the capsules is marked with an arrow;
FIG. 5 is a microscope image of capsules isolated from Rhopilema nomadica following discharge activation with NaSCN;
FIG. 6 illustrates capsules isolated from Rhopilema nomadica (Arrow B) and loaded with a pigment (arrow A);
FIG. 7 illustrates capsules isolated from Rhopilema nomadica and loaded with a pigment of a molecular weight of 306 daltons, prior to (arrow A) and following (arrow B) discharge activation with NaSCN;
FIG. 8 illustrates capsules isolated from Rhopilema nomadica and loaded with a pigment of a molecular weight of 306 daltons, prior to (arrow A) and following (arrow B) discharge activation with NaSCN;
FIG. 9 illustrates dermal penetration of a tubule discharged from an isolated cnidocyst (tubule indicated by arrows); and
DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention is of compositions, devices and methods utilizing stinging cells or capsules, which can be used, for example, for transdermal/intradermal, transmucosal or transcuticular delivery of an agent, such as for example a biologically active agent. Specifically, the present invention relates to the use of stinging cells (cnidocytes) or to stinging capsules isolated therefrom (cnidocysts) for transdermal/intradermal, transmucosal, transcuticular or transmembranal delivery of a therapeutic or a cosmetic agent.
Throughout history man has exploited or imitated naturally occurring processes, e.g., biological processes, for the advancement of scientific fields such as medicine or engineering. As is further described herein, the present invention exploits the unique delivery mechanism of stinging cells, such as cnidocytes or isolated stinging capsules such as cnidocysts, for the delivery of therapeutic, diagnostic or cosmetic agents into tissues of a metazoan organism, such as, for example, a manmmal.
As used herein, the phrase �stinging cell� refers to the specialized cells (e.g. cnidocytes or nematocytes) present in, for example, all members of the phylum Cnidaria, Myxozoa, and Dinoflagellata. A stinging cell contains the �stinging capsule� which houses the delivery tubule.
As is further described in the Examples section, which follows, toxins endogenous to cnidocysts can be efficiently and easily inactivated by incubating isolated cnidocysts at 45� C. for several hours. Alternatively, incubation at a high temperature of 70-95� C. for several minutes can also be utilized by the present invention.
As demonstrated herein, incubation of cnidocysts at 45� C. for 22 hours does not damage or trigger activation of the cnidocyst. Such conditions are effective in denaturing polypeptides stored within the cnidocyst, such as the polypeptide toxins and enzymes delivered by the tubule of the cnidocyst. It will be appreciated that since organisms of, for example, the phylum Cnidaria habitat aquatic environments, which are characterized by temperatures well below 30� C., polypeptides stored within their stinging capsules can be denatured via incubation in temperatures well above 30� C.
The therapeutic agent can also be a prodrug, which is activatable prior to, during, or following discharge of the stinging capsule. As used herein in the specification and in the claims section which follows, the term �prodrug� refers to an agent which is inactive but which is convertible into an active form via enzymatic, chemical or physical activators.
Hereinafter, the phrase �pharmaceutically acceptable carrier� refers to a carrier, which does not cause significant irritation to the individual treated and does not abrogate the biological activity and properties of the active ingredient.
For topical, transmucosal or transnasal administration, the active ingredient and stinging cells can be conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or a nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane or carbon dioxide. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount.
Although, for some applications, contact mediated discharge suffices, such activation can be inefficient since it enables discharge of only, the portion of stinging cells, which come into physical contact with the tissue following application.
Device 10 includes at least one stinging cell/capsule 12 (several are shown). Upon discharge, stinging cell/capsule 12 is capable of delivering (via it's tubule) liquid disposed in or around stinging cell/capsule 12 into a tissue region (as described hereinabove). Device 10 further includes a support 14, which serves for supporting stinging cell/capsule 12 and for applying stinging cell/capsule 12 to an outer surface of the tissue region into which delivery is desired.
Stinging cells 12 can be secured to support 14 via, for example, biological glue (e.g. BIOBOND�), polylysine, a mesh support or the like.
As is further described in Example 2 of the Examples section below, Sodium thiocyanate (NaSCN) is capable of triggering discharge of cnidocysts. In addition, Lubbock and Amos (1981) have shown that isolated cnida (cnidocysts) can discharge normally when placed in buffered EGTA or 10 mM citrate solution; Weber (1989) demonstrated the effect of dithioerthritol or proteases on discharging isolated cnida and Hidaka (1993) discussed various agents which can trigger cnida discharge.
The present invention can be also used for delivering pigments, such as photosensitizers utilizable in photo dynamic therapy (PDT), into cells of skin cancer or other skin disorders. Photosensitizers are chemical compound which produce a biological effect upon photoactivation, or a biological precursor of a compound that produces a biological effect upon photoactivation. Examples of photosensitizers which can be delivered by the stinging cells/capsules of the present invention include, but are not limited to, hematoporphyrins (Batlle 1993 J. Photochem. Photobiol. Biol. 20:5-22 and Kessel 1988 Cancer Let. 39:193-198), uroporphyrins and phthalocyanines (Kreimer-Birnbaum, 1989 Seminars in Hematology 26:157-173), purpurins (Morgan et al. 1990 Photochem. Photobiol. 51:589-592 and Kessel, 1989 Photochem. Photobiol. 50:169-174), acridine dyes and bacteriochlorophylls (Beems et al. 1987 Photochem. Photobiol. 46:639-643 and Kessel et al. 1989 Photochem. Photobiol. 49:157-160), and bacteriochlorins (Gurinovich et al. 1992 J. Photochem. Photobiol. Biol. 13:51-57).
Anaesthetics can be used for alleviating pain for example during suturing, or in infections, which are accompanied with pain sensation. Examples of topical anaesthetic drugs include without limitation benzocaine, lidocaine, biupivacaine, chlorprocaine, dibucaine, etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine, procaine, cocaine, ketamine, pramoxine, phenol, and pharmaceutically acceptable salts thereof all of which are deliverable via the delivery device or method of the present invention.
Allternatively, the stinging cells/capsules of the present invention can be utilized to deliver, directly into hair follicles, a hair follicle suppressing agent capable of suppressing hair growth. Examples of agents capable of suppressing hair growth include, but are not limited to, non-steroidal suppressors of angiogenesis and inhibitors of 5-alpha reductase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, gamma-glutamyl transpeptidase, and transglutaminase.
Example 1 Isolation of Capsules Fresh tentacles of Rhopilema nomadica were homogenized in seawater. 300 l of the homogenate was added to 300 l Percoll in a microfuge tube. The tube was shaken over ice for 30 min and then centrifuged for 10 minutes, at 1000 rpm. The pellet was washed 3 times with H2O and resuspended in 50 l H2O. The tube was kept at 4� C. until use.
Example 2 Discharging the Capsules A 2 l sample of the above-described preparate was applied to a microscopic slide, and the isolated capsules were photographed under a light microscope (Leitz Laborlux S) (See FIG. 3 and FIG. 4). Two l of Sodium thiocyanate were added to the isolated capsules. Following the NaSCN administration capsules immediately discharged to release their tubules. The discharged capsules were photographed under a light microscope (FIG. 5).
Example 3 Inactivation of Capsule-Stored Polypeptides The temperature range, which is tolerated by Rhopilema nomadica, is between 16� C.-30� C. Therefore, it is possible to perform denaturation and inactivation of an endogenous polypeptide at 45� C. Isolated capsules were incubated for 22 hours in 45� C. Following the heat inactivation process the capsules were intact and their round shape was unchanged. Moreover, the heated capsules were able to discharge normally upon treatment with NaSCN.
Example 4 Altering the Content of the Isolated Capsules Isolated capsules were treated with 0.1% Toluidine Blue O for 3 minutes and than washed 3 times with H20. The pigment penetrated the intact capsules and the stained capsules were photographed (FIGS. 6-8, A arrow). Upon activation with NaSCN the capsules containing the pigment discharged normally and released the pigment through the tubule to the surrounding solution (FIGS. 7-8, B arrow).
To demonstrate intraepidermal penetration of the delivery tubule, capsules isolated from Rhopilema nomadica were loaded with a pigment (0.1% Toluidine Blue O, MW-306 daltons) and discharged using NaSCN. As specifically shown in FIG. 10, which depicts an experiment performed on a 15 micron thick human skin section, following discharge, the tubule penetrated the stratum corneum and delivered the pigment stored by the capsule into the squamous cell layer of the epidermis. The tubule penetration path is depicted in more detail in FIG. 9.
Example 5 Drug Delivery Using Stinging Capsules�Theoretical Considerations Psoralen:
Since hydra cnidocysts are spherical in shape, with a diameter of approximately 10 micrometers, their volume can be calculated as 4/3� �r3�4�53=500 μm3 When filled, the capsule contains approximately 0.5 nanograms of water. Since a loaded drug, such as psoralen, can occupy 5-10% of the capsule volume, a single loaded capsule contains about 0.05 nanograms of the drug. Since 2�104 to 106 cnidocysts can penetrate a 1 cm2 region of skin, the amount of drug which can be delivered by capsules into 1 cm2 of skin is: 0.05 nanograms of the drug�2�104 to 106 cnidocysts which equal to 1-50 μg of the drug per 1 cm2 of skin, which is 20-1000 fold higher than the amount deliverable by oral administration. Thus, the present invention can provide targeted delivery of psoralen at high concentrations while at the same time not inducing toxicity in other tissues of the body.
Diphenhydramine hydrochloride is an antihistamine used in the treatment of allergies, stings and skin irritations. An oral dose of 120 mg/kg results in a peak plasma concentration of 0.2 g/ml.
2 hours following administration. Although the same drug can be administered topically by the application of 1-2% diphenhydramine hydrochloride this pharmaceutical formulation is known to have low penetration and thus a slow therapeutic effect.
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