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(12) United States Patent (10) Patent No.: US 8,937,074 B2 Meyer (45) Date of Patent: Jan

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(12) United States Patent (10) Patent No.: US 8,937,074 B2 Meyer (45) Date of Patent: Jan US008937074 B2 (12) United States Patent (10) Patent No.: US 8,937,074 B2 Meyer (45) Date of Patent: Jan. 20, 2015 (54) ENHANCEMENT OF THE ACTION OF 9/4866 (2013.01); A61K 31/133 (2013.01); ANT-INFECTIVE AGENTS AND OF A6 IK3I/4409 (2013.01); A61 K3I/496 CENTRAL AND PERPHERAL NERVOUS (2013.01); A61 K3I/4965 (2013.01); A61 K SYSTEMIAGENTS ANDTRANSPORTATION 38/02 (2013.01); A61 K39/39533 (2013.01); OF NUCLECACID SUBSTANCES CI2N 15/63 (2013.01) USPC ........................................ 514/256; 514/258.1 (71) Applicant: North West University, Potchefstroom (58) Field of Classification Search (ZA) None See application file for complete search history. (72) Inventor: Petrus Johannes Meyer, George (ZA) (56) References Cited (73) Assignee: North West University, Potchefstroom (ZA) U.S. PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this 5,633,284 A 5/1997 Meyer patent is extended or adjusted under 35 6,416.740 B1* 7/2002 Unger .......................... 424,952 U.S.C. 154(b) by 0 days. FOREIGN PATENT DOCUMENTS (21) Appl. No.: 13/709,596 DE 2647 671 A1 4f1978 WO 9606152 A2 2, 1996 (22) Filed: Dec. 10, 2012 * cited by examiner (65) Prior Publication Data Primary Examiner — Alton Pryor US 2013/0336990 A1 Dec. 19, 2013 (74) Attorney, Agent, or Firm — Rothwell, Figg, Ernst & Manbeck, P.C. Related U.S. Application Data (63) Continuation of application No. 10/345.204, filed on (57) ABSTRACT Jan. 16, 2003, now Pat. No. 8,329,685, which is a The invention provides a method of enhancing the action of a continuation-in-part of application No. pharmaceutical agent selected from the group consisting of PCT/ZAO1/00098, filed on Jul. 19, 2001, and a the anti-infective agents, the group comprising of the antimi continuation-in-part of application No. crobial agents, the anthelmintic agents and the anti-ectopara PCT/ZAO1/00099, filed on Jul. 19, 2001, and a sitic agents, but excluding coaltar Solution and H1-antagonist continuation-in-part of application No. antihistamines, and from the group consisting of the CPNS PCT/ZAO1/00100, filed on Jul. 19, 2001. agents selected from the group of compounds acting on the central or peripheral nervous system, but excluding coal tar (30) Foreign Application Priority Data Solution and H1-antagonistantihistamines and also excluding anti-inflammatory, analgesic and antipyretic agents and also Jul. 19, 2000 (ZA) ................................... 2OOO/3643 provides an enhanced method for the administration of a Jul. 19, 2000 (ZA) ................................... 2000/3644 nucleic acid Substance to the cells of an animal, a plant or a micro-organism. The method is characterized in that the (51) Int. Cl. agent or nucleic acid Substance is formulated with an admin AOIN 43/54 (2006.01) istration medium which comprises a solution of nitrous oxide AOIN 43/90 (2006.01) gas in a pharmaceutically acceptable carrier solvent for the A6 IK3I/7088 (2006.01) gas and which administration medium includes at least one A6 IK9/00 (2006.01) fatty acid or ester or other suitable derivative thereof selected A6 IK 47/02 (2006.01) from the group consisting of oleic acid, linoleic acid, alpha A6 IK9/48 (2006.01) linolenic acid, gamma-linolenic acid, arachidonic acid, A6 IK3I/33 (2006.01) eicosapentaenoic acid C20:5c)3], decosahexaenoic acid A6 IK3I/4409 (2006.01) C22:603, ricinoleic acid and derivatives thereof selected A6 IK3I/496 (2006.01) from the group consisting of the C1 to C6 alkyl esters thereof, A6 IK3I/4965 (2006.01) the glycerol-polyethylene glycol esters thereof and the reac A6 IK38/02 (2006.01) tion product of hydrogenated natural oils composed largely of A 6LX39/395 (2006.01) ricinoleic acid based oils, such as castor oil with ethylene CI2N 15/63 (2006.01) oxide. The formulations of Such agents or Substances form (52) U.S. Cl. part of the invention. CPC ........... A61 K3I/7088 (2013.01); A61 K9/0019 (2013.01); A61 K47/02 (2013.01); A61 K 18 Claims, 8 Drawing Sheets U.S. Patent Jan. 20, 2015 Sheet 2 of 8 US 8,937,074 B2 Zone inhibition by different therapies Submicron lipid Free active vesicle Saline aSSOCiated active SS Aureus OP Aeruginosa Figure 2 U.S. Patent Jan. 20, 2015 Sheet 3 of 8 US 8,937,074 B2 AbSOrbance/Cut- CD4 T-cell and viral growth Off ratioS 14 2 10 l Lind 1:256 - O. 1 nMAZT 8 ss. s indi 1.512 + O. nMAZT DAZT (1nM) 6 OAZT (0.1nM) 4. Control 2 O 2 3 Lindi 1.256 - O.1nMAZT FIGURE 3 U.S. Patent Jan. 20, 2015 Sheet 4 of 8 US 8,937,074 B2 Viability of Mel1 cells 90% 80% 70% 60% D E 50% sO 40% g 30% 20% 10% O% g CN as S. SQ CN CD s 9. Cells CN 5 s N d s S Fungi Therapeutic s O) C FIGURE 4 U.S. Patent Jan. 20, 2015 Sheet 5 of 8 US 8,937,074 B2 Zone inhibition of yeasts and molds Zone inhibition measured S - C Albicans Control T Mententagrophytes h E FOCOSSum Control Nano lipid vesicle with active Figure 5 U.S. Patent Jan. 20, 2015 Sheet 6 of 8 US 8,937,074 B2 Bioavailability:Rifamzaloid Time (minutes) -0-MZL Rifamzaloid HRifampin Figure 6 U.S. Patent Jan. 20, 2015 Sheet 7 of 8 US 8,937,074 B2 Bioavailability of Rifampicin in the MZL formulated Rifamzaloid vs its comparator Rifampin BIOAVAILABLITY OF IZONAZID O 60 120 180 240 3OO Time (minutes) mNH in MZL formula as NH in Rifafour Figure 7 U.S. Patent Jan. 20, 2015 Sheet 8 of 8 US 8,937,074 B2 Bioavailability of IZONIAZID BOAVAILABLITY OF PYRAZINAMIDE 5O 45 3 5 3 O 2 5 2 O 5 1 O O - -op- r O 30 60 120 180 24O 3OO 360 Time (minutes) PZA in MZL formula Figure 8 Bioavailability of Pyrazinamide US 8,937,074 B2 1. 2 ENHANCEMENT OF THE ACTION OF of these conditions are caused by viral infections, the disclo ANT-INFECTIVE AGENTS AND OF sures in these patents do not refer to that fact. CENTRAL AND PERPHERAL NERVOUS It is also disclosed in these patents that, in addition to the SYSTEMIAGENTS ANDTRANSPORTATION coal tar Solution the composition may also contain an H1-an OF NUCLECACID SUBSTANCES tagonistantihistamine (e.g. diphenhydramine hydrochloride) and may in that form be used in the treatment of atopic and This application is a divisional of U.S. Ser. No. 10/345.204 allergic conditions manifesting in skin irritations such as filed Jan. 16, 2003 (which will issue as U.S. Pat. No. 8.329, eczema, dermatitis and ringworm. The latter of these condi 685 on Dec. 11, 2012), which is a continuation-in-part of PCT tions is caused by a fungal infection. Again the disclosures in International Applications PCT/ZAO1/00098, PCT/ZAO1/ 10 issue do not refer specifically to that fact. O0099 and PCT/ZAO1/00100, all filed on Jul.19, 2001 and all It further disclosed an alternative composition in which the designating the U.S., which claims the benefit of South Africa coal tar solution formulation is further provided with collagen Patent Application Nos. 2000/3643 and 2000/3644 filed on and lanolin and this formulation was found to be useful in the Jul.19, 2000, the disclosure of which are incorporated herein 15 treatment of persons Suffering from acne Vulgaris. Bacteria in their entirety by reference. are involved in the condition but no mention was made of such involvement in those patents. FIELD OF THE INVENTION Since coal tar solution is in itself not known to be an anti-viral, anti-fungal or antibacterial agent, and has merely This invention relates to pharmaceutical preparations been mentioned as being weakly antiseptic, the aforemen (which expression is herein intended to include veterinary tioned disclosures would not have been understood as Sug preparations) for use in combating infective organisms gesting that the nitrous oxide and fatty acid combination has afflicting the animal body (which expression is herein any beneficial effect on the anti-viral or anti-fungal or anti intended to include the human body). bacterial activity of any recognised anti-viral oranti-fungalor This invention also relates to pharmaceutical preparations 25 anti-bacterial agent or to have disclosed that such properties (which expression is also herein intended to include veteri are displayed by coal tar solution. As will appear below the nary preparations) for use in treating afflictions of the animal enhancement of the anti-bacterial, anti-fungal or anti-viral body affecting the central and/or peripheral nervous system properties of known agents lie at the very heart of this inven of an animal (which expression is again herein intended to tion. include the human body) in need of treatment. 30 Within the context of the disclosure in the abovementioned This invention further relates to preparations for use in patent family the notional addressee most likely would, as did transporting nucleic acid substances to and into cells of a the inventor, have understood the role of the coal tar solution plant or an animal body (which expression is again herein to sooth the itching and to assist in the repairing and healing intended to include the human body), either in vivo or invitro, of the skin which was damaged as a result of the infections/ or of a micro-organism. This invention is more particularly 35 conditions in issue. concerned with the administration of Substances based on No agent known for having an effect on the central or nucleic acid to patients for the purpose of the transportation peripheral nervous system, was amongst the active ingredi thereof through the body of the patient and the ultimate deliv ents specifically mentioned in these patents.
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