Delivery system

Abstract

In accordance with the present disclosure, there are provided formulations comprising: (a) at least one active agent; (b) an oil, and optionally a thickener therefor; (c) an organic solvent, and a thickener therefor; and (d) an oil and/or solvent soluble skin penetration enhancer; wherein: said formulation comprises <10 wt % water; and said formulation optionally forms a thixotropic thinning gel. Also provided are gels comprising oil and organic solvent, methods for preparing same and methods for the topical delivery of an active agent to a subject in need thereof.

Claims

1. A formulation for human or veterinary use, said formulation comprising: (a) diclofenac; (b) oleic acid; (c) at least one organic solvent selected from the group consisting of dimethyl isosorbide, dimethyl formamide, ethanol, ethyl acetate, 1,2-propanediol, 1,3-propanediol, and glycerin; (d) dimethylsulfoxide; and (e) hydroxypropyl cellulose; wherein: said formulation is a non-aqueous transparent gel.

2. The formulation of claim 1 wherein said formulation further comprises 2.0 wt % to 5.0 wt % of at least one compound selected from the group consisting of Dibutyl Lauroyl Glutamide, Dibutyl Ethylhexanol Glutamide, Poloxamer 124, Poloxamer 188, Poloxamer 237, Poloxamer 337, Poloxamer 408, and Polyamide 8.

3. The formulation of claim 1 wherein component (c) of the formulation comprises ethanol and the combined concentration of dimethylsulfoxide and component (c) in the formulation is 30 wt % to 60 wt %.

4. The formulation of claim 1, further comprising propylene glycol.

5. A gel formulation, comprising: (a) diclofenac or a salt thereof; (b) oleic acid; (c) ethanol (d) hydroxypropyl cellulose; (e) propylene glycol; and (f) dimethylsulfoxide; wherein: said formulation is a nonaqueous transparent gel and comprises 2-5 wt % hydroxypropyl cellulose, 1-10 wt % diclofenac or a salt thereof, and a combined concentration of dimethylsulfoxide and ethanol of 30-60 wt %.

6. A formulation of claim 1, wherein component (a) of the formulation comprises 1-10 wt % diclofenac or a salt thereof.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

(1) In accordance with certain aspects and embodiments of the present disclosure, there are provided formulations wherein: the active agent employed herein is at least one NSAID; the oil phase contemplated for use herein is oleic acid and/or palmitic acid, or a high oleic acid/palmitic acid vegetable oil and/or a castor oil; the thickener for oil phase contemplated for use herein is a dibutyl lauroyl glutamide; the organic solvent contemplated for use herein is dimethyl sulfoxide (DMSO), dimethyl formamide (DMF) and/or dimethyl isosorbide (DMI); the thickener for organic solvent phase contemplated for use herein is a Polyamide or a Poloxamer (e.g., Polyamide-2, Polyamide-3, Polyamide-4, Polyamide-6, Polyamide-8, and the like); the oil and/or solvent soluble skin penetration enhancer contemplated for use herein is Caprylic/Capric Triglyceride; and optionally the pharmaceutical excipient that will work in the oil phase contemplated for use herein is phosphatidylcholine or menthol.

(2) In accordance with certain aspects and embodiments of the present disclosure, there are provided formulations wherein: the active agent employed herein is at least one opioid; the oil phase contemplated for use herein is oleic acid and/or palmitic acid, or a high oleic acid/palmitic acid vegetable oil, or castor oil; the thickener for oil phase contemplated for use herein is optional, but when present is dibutyl lauroyl glutamide; the organic solvent contemplated for use herein is dimethyl sulfoxide (DMSO) and/or dimethyl isosorbide (DMI) or any combination thereof; the thickener for organic solvent phase contemplated for use herein is a Polyamide or Poloxamer (e.g., Polyamide-2, Polyamide-3, Polyamide-4, Polyamide-6, Polyamide-8, and the like); the oil and/or solvent soluble skin penetration enhancer contemplated for use herein is Caprylic/Capric Triglyceride; and optionally the pharmaceutical excipient that will work in the oil phase contemplated for use herein is phosphatidylcholine or menthol.

(3) The following examples are provided to further illustrate aspects of the present disclosure. These examples are non-limiting and should not be construed as limiting any aspect of the disclosure.

Example 1

Preparation of Exemplary Formulations for Topical Application of Active(s)

(4) Numerous exemplary formulations as contemplated herein are summarized in Table 2 below, and are prepared as follows: A. Weigh and mix OIL PHASE ingredients, heat until dissolved up to 100° C.; B. Weigh, mix and heat SOLVENT PHASE ingredients to 75° C.-80° C. or until all SOLVENT PHASE ingredients dissolve; C. Maintain temperature at 65° C. Add Active to solution (B), mix until dissolved; D. Add (A) oil phase mixture to (C) solvent phase mixture with active, keep mixing at low RPM until gel forms; Cool mixture to RT and package.

(5) TABLE-US-00002 TABLE 2 Formulation* 1A 1B 1C 1D 1E 1F 1G 1H 1I Oil Phase Ingredients Sesame oil 0 0 0 23.0 0 5.0 0 23.0 0 Oleic Acid 0 0 20.0 0 0 0 0 0 0 Palmitic Acid 0 0 0 0 0 0 0 0 0 Menthol 2.0 0 0 0 2.0 2.0 2.0 0 2.0 Wintergreen oil 1.0 0 0 0 1.0 1.0 1.0 0 1.0 Olive oil 8.0 25.0 0 0 6.0 0 6.0 0 8.0 Castor oil 1.0 0 0 0 0 1.0 1.0 0 1.0 Cetyl Alcohol 3.0 0 0 0 2.0 3.0 3.0 0 3.0 Cetearyl Alcohol 3.0 0 0 0 2.0 3.0 3.0 0 0 Median Chain Triglyceride 8.0 15.0 10.0 12.0 4.0 6.0 0 12.0 8.0 Squalane 0 0 0 0 0 0 0 0 0 Glyceryl Layrate 0 0 0 0 0 0 0 0 0 Cetearyl Glucoside 0 0 0 0 0 0 5.0 0 3.0 Dibutyl Lauroyl Glutamide 2.0 3.0 0 0 0 2.0 0 0 2.0 Dibutyl Ethylhexanol Glutamide 0 0 0 0 0 0 2.0 0 0 Polyamide 8 0 0 0 0 0 0 0 0 0 Polyamide-3 0 0 0 0 0 0 0 0 0 Poloxamer 108 0 0 0 0 6.0 0 0 0 0 Poloxamer 408 0 0 6.0 10.0 0 0 10.0 10.0 0 Solvent Phase Ingredients DMSO 35.0 0 0 18.0 30.0 30.0 0 19.0 26.0 DMI 0 22.0 5.0 0 15.0 8.0 0 0 0 DMF 0 0 24.0 0 0 0 20.0 0 0 Water 0 0 0 0 0 0 0 0 0 1,2-Propanediol 0 0 0 1.0 0.5 0 0 0 1.0 Ethanol 10.0 0 0 0 0 0 6.0 0 0 Glycerin 0 0 0 0 0 0 0 0 0 Polyamide 3 10.0 10.0 0 0 0 8.0 8.0 0 10.0 Poly(1-vinyl-2-pyrrolidinone), 1.0 0 0 0 0 0 0 0 0 PVP Poloxamer 108 0 0 0 0 16.0 0 2.0 0 0 Polomamer 408 0 0 10.0 10.0 0 0 0 10.0 0 Phophatdyl choline 1.0 0 0 1.0 0.5 1.0 1.0 1.0 10.0 Actives Naproxen 15.0 0 0 0 15.0 0 0 0 0 Ibuprofen 0 25.0 25.0 25.0 0 0 30.0 25.0 0 Acetaminophen 0 0 0 0 0 30.0 0 0 0 Lidocaine 0 0 0 0 0 0 0 0 0 Acyclovir 0 0 0 0 0 0 0 0 0 Dichlofenac sodium 0 0 0 0 0 0 0 0 0 R-Lipoic acid 0 0 0 0 0 0 0 0 25.0 Tetracaine 0 0 0 0 0 0 0 0 0 Tetracycline 0 0 0 0 0 0 0 0 0 Vitamin B12 cyanocobalamin 0 0 0 0 0 0 0 0 0 TOTAL 15 25 25 25 15 30 3030 25 25 *All values are given in Wt %

Example 2

Preparation of Additional Exemplary Formulations

(6) Additional exemplary formulations as contemplated herein are prepared as described above, and are summarized in Table 3 below.

(7) TABLE-US-00003 TABLE 3 Formulation* 2A 2B 2C 2D 2E 2F 2G 2H Oil Phase Ingredients Sesame oil 0 0 0 0 0 5.0 0 0 Oleic Acid 0 15.0 20.0 23.0 0 0 0 13.0 Palmitic Acid 0 10.0 0 0 0 0 0 10.0 Menthol 2.0 0 0 0 2.0 2.0 2.0 0 Wintergreen oil 1.0 0 0 0 1.0 1.0 1.0 0 Olive oil 8.0 0 0 0 6.0 0 6.0 0 Castor oil 1.0 0 0 0 0 1.0 1.0 0 Cetyl Alcohol 3.0 0 0 0 2.0 3.0 3.0 0 Cetearyl Alcohol 3.0 0 0 0 2.0 3.0 3.0 0 Median Chain Triglyceride 8.0 15.0 10.0 12.0 4.0 6.0 0 12.0 Squalane 0 0 0 0 0 0 0 0 Glyceryl Layrate 0 0 0 0 0 0 0 0 Cetearyl Glucoside 0 0 0 0 0 0 5.0 0 Dibutyl Lauroyl Glutamide 2.0 0 0 0 0 2.0 0 0 Dibutyl Ethylhexanol Glutamide 0 3.0 0 0 0 0 2.0 0 Polyamide 8 0 0 0 0 0 0 0 0 Polyamide-3 0 0 0 0 0 0 0 0 Poloxamer 108 0 0 0 0 6.0 0 0 0 Poloxamer 408 0 0 6.0 10.0 0 0 6.0 10.0 Solvent Phase Ingredients DMSO 35.0 22.0 24.0 18.0 30.0 30.0 24.0 19.0 DMI 0 0 5.0 0 15.0 8.0 0 0 DMF 0 0 0 0 0 0 0 0 Water 0 0 0 0 0 0 0 0 1,2-Propanediol 0 0 0 1.0 0.5 0 0 0 Ethanol 10.0 0 0 0 0 0 6.0 0 Ethyl acetate 0 0 0 0 0 0 0 0 Glycerin 0 0 0 0 0 0 0 0 1,3-Propanediol 0 0 0 0 0 0 0 0 Polyamide 3 10.0 10.0 0 0 0 8.0 8.0 0 Poly(1-vinyl-2-pyrrolidinone), 1.0 0 0 0 0 0 0 0 PVP Poloxamer 108 0 0 0 0 16.0 0 2.0 0 Polomamer 408 0 0 10.0 10.0 0 0 0 10.0 Phophatdyl choline 1.0 0 0 1.0 0.5 1.0 1.0 1.0 Actives Naproxen 15.0 0 0 0 15.0 0 0 0 Ibuprofen 0 25.0 25.0 25.0 0 0 30.0 25.0 Acetaminophen 0 0 0 0 0 30.0 0 0 Lidocaine 0 0 0 0 0 0 0 0 Acyclovir 0 0 0 0 0 0 0 0 Dichlofenac sodium 0 0 0 0 0 0 0 0 Cyclosporin 0 0 0 0 0 0 0 0 R-Lipoic acid 0 0 0 0 0 0 0 0 Guaifensin 0 0 0 0 0 0 0 0 Tetracaine 0 0 0 0 0 0 0 0 Vitamin B12 cyanocobalamin 0 0 0 0 0 0 0 0 TOTAL 15 25 25 25 15 30 30 25 *All values are given in Wt %

Example 3

Preparation of Additional Exemplary Formulations

(8) Additional exemplary formulations as contemplated herein are prepared as described above, and are summarized in Table 4 below.

(9) TABLE-US-00004 TABLE 4 Formulation* 3A 3B 3C 3D 3E 3F 3G 3H 3I Oil Phase Ingredients Sesame oil 0 7.0 0 0 0 0 0 0 0 Oleic Acid 12.0 0 7.0 7.0 14.0 0 0 13.0 20.0 Palmitic Acid 8.0 7.0 0 0 11.0 0 0 10.0 5.0 Menthol 0 0 0 0 0 2.0 2.0 0 3.0 Wintergreen oil 0 0 0 0 0 1.0 1.0 0 0 Olive oil 0 0 0 0 0 10.4 6.0 0 0 Castor oil 0 0 0 0 0 1.0 1.0 0 0 Cetyl Alcohol 0 0 0 0 0 4.0 3.0 0 0 Cetearyl Alcohol 0 0 0 0 0 4.0 3.0 0 0 Median Chain Triglyceride 10.0 7.0 0 0 5.0 10.0 10.0 12.0 5.0 Squalane 0 0 0 0 0 0 0 0 0 Glyceryl Layrate 0 0 0 0 0 0 0 0 0 Cetearyl Glucoside 0 0 0 0 0 0 0 0 0 Dibutyl Lauroyl Glutamide 2.5 0 0 0 2.5 2.0 0 3.0 2.5 Dibutyl Ethylhexanol Glutamide 0 2.5 0 0 0 0 2.0 0 0 Polyamide 8 0 0 0 0 0 0 0 0 0 Polyamide-3 0 0 0 0 0 0 0 0 0 Poloxamer 108 0 0 0 0 0 0 0 0 0 Poloxamer 408 0 0 0 0 0 0 0 0 0 Vitamin D3, 1.0M IU/gm 0 0 0 0 0 0 1.0 0 0 Urea 0 0 9.0 9.0 0 0 0 0 0 Boswellia serrata, 90% 0 0 0 0 1.0 0 0 0 0 Solvent Phase Ingredients DMSO 31.1 39.5 44.0 42.0 42.1 39.595 37.0 32.8 35.0 DMI 0 0 0 12.0 0 13.0 13.0 0 0 DMF 0 0 0 0 0 0 0 0 0 Water 0 0 0 0 0 0 0 0 0 1,2-Propanediol 0 0 12.0 0 3.0 1.5 2.5 2.00 0 Ethanol 10.0 0 0 0 0 0 6.0 10.0 0 Ethyl acetate 0 0 0 0 0 0 0 0 0 Glycerin 0 0 0 0 0 0 0 0 0 1,3-Propanediol 0 0 0 0 0 0 0 0 0 Polyamide 3 10.0 0 0 0 10.0 10.0 10.0 0 10.0 Poly(1-vinyl-2-pyrrolidinone), 0 10.0 8.0 0 0 0 0 0 0 PVP Poloxamer 108 0 0 0 0 0 0 0 0 0 Polomamer 408 0 0 0 10.0 0 0 0 10.0 0 Phophatdyl choline 0 0 0 0 3.0 1.5 2.5 2.0 0 Aloe 0.2 0 0 0 0 0 0 0.2 0.2 Urea 8.0 8.0 0 0 8.0 0 0 0 5.3 Actives Naproxen 0 15.0 15.0 15.0 0 0 0 0 0 Ibuprofen 0 0 0 0 0 0 0 0 0 Acetaminophen 0 0 0 0 0 0 0 0 0 Lidocaine 4.0 4.0 5.0 5.0 0 0 0 0 7.0 Acyclovir 0 0 0 0 0 0 0 5.0 0 Betamethasone dipropionate 0 0 0 0 0 0 0 0 0 Dichlofenac sodium 4.2 0 0 0 0 0 0 0 0 Cyclosporin 0 0 0 0 0 0 0 0 0 R-Lipoic acid 0 0 0 0 0 0 0 0 0 Guaifensin 0 0 0 0 0 0 0 0 0 Tetracaine 0 0 0 0 0 0 0 0 7.0 Tetracycline 0 0 0 0 0 0 0 0 0 Vitamin B12 cyanocobalamin 0 0 0 0 0 0.005 0 0 0 Cannabinoids, 99% 0 0 0 0 0.4 0 0 0 0 TOTAL 8.2 19 20 20 0.4 0.005 0 5 14 *All values are given in Wt %

Example 4

Preparation of Additional Exemplary Formulations

(10) Additional exemplary formulations as contemplated herein are prepared as described above, and are summarized in Table 5 below.

(11) TABLE-US-00005 TABLE 5 Formulation* 4A 4B 4C 4D 4E 4F 4G 4H Oil Phase Ingredients Sesame oil 0 7.0 0 0 0 0 0 0 Oleic Acid 12.0 0 12.0 0 0 10.0 7.0 16.0 Palmitic Acid 8.0 7.0 8.0 0 0 0 0 11.0 Menthol 0 0 0 3.0 0 2.0 0 0 Wintergreen oil 0 0 0 0 1.0 1.0 0 0 Olive oil 0 0 0 0 0 0 0 0 Castor oil 0 0 0 0 0 1.0 0 0 Cetyl Alcohol 0 0 0 0 0 4.0 0 0 Cetearyl Alcohol 0 0 0 4.0 0 4.0 0 0 Median Chain Triglyceride 0 0 10.0 25.0 19.0 10.0 0 0 Squalane 10.0 7.0 0 6.0 4.0 0 0 0 Glyceryl Layrate 0 0 0 2.0 0 0 0 0 Cetearyl Glucoside 0 0 0 4.0 0 0 0 0 Dibutyl Lauroyl Glutamide 2.5 0 2.5 1.0 2.0 2.0 0 2.0 Dibutyl Ethylhexanol Glutamide 0 1.0 0 1.0 1.0 0 0 0 Polyamide 8 0 5.0 0 0 0 0 0 0 Polyamide-3 0 0 0 0 0 0 0 0 Poloxamer 108 0 0 0 0 5.0 0 0 0 Poloxamer 408 0 0 0 0 0 0 0 0 Vitamin D3, 1.0M IU/gm 0 0 0 0 0 2.0 0 0 Urea 0 0 8.0 0 0 0 8.0 0 Boswellia serrata, 90% 0 0 0 0 0 0 0 0 Solvent Phase Ingredients DMSO 34.3 26.0 30.1 25.0 31.0 30.0 42.0 44.0 DMI 0 10.0 0 9.0 11.0 21.0 5.0 0 DMF 0 0 0 0 0 0 0 0 Water 2.0 0 0 0 0 0 0 0 1,2-Propanediol 0 0 3.0 1.5 3.0 1.5 0 3.0 Ethanol 10.0 0 0 0 0 0 0 0 Ethyl acetate 0 0 0 0 0 0 0 0 Glycerin 0 0 0 2.0 1.0 0 0 1.0 1,3-Propanediol 0 0 0 0 1.0 0 0 0 Polyamide 3 10.0 0 10.0 0 5.0 10.0 0 10.0 Poly(1-vinyl-2-pyrrolidinone), 0 0 0 0 0 0 0 0 PVP Poloxamer 108 0 0 0 0 0 0 0 0 Polomamer 408 0 10.0 0 0 0 0 18.0 0 Phophatdyl choline 0 0 0 1.5 1.0 1.5 0 3.0 Aloe 0.2 0 0.2 0 0 0 0 0 Urea 8.0 8.0 8.0 0 0 0 0 8.0 Actives Naproxen 0 15.0 0 15.0 15.0 0 15.0 0 Ibuprofen 0 0 0 0 0 0 0 0 Acetaminophen 0 0 0 0 0 0 0 0 Lidocaine 0 4.0 4.0 0 0 0 5.0 0 Acyclovir 0 0 0 0 0 0 0 0 Dichlofenac sodium 0 0 4.2 0 0 0 0 0 R-Lipoic acid 0 0 0 0 0 0 0 0 Tetracaine 3.0 0 0 0 0 0 0 0 Vitamin B12 cyanocobalamin 0 0 0 0 0 0 0 0 Cannabinoids, 99% 0 0 0 0 0 0 0 2.0 TOTAL 3 19 8.2 15 15 0 20 2 *All values are given in Wt %

Example 5

Case Study of 15% Naproxen Gel and 30% Acetaminophen Gel

(12) The use of all topical gels was done with physician oversight and the informed consent of the subject.

(13) For the Naproxen Pain Gel, 15 wt % (see Formulation 1A in Table 2 above), one pump from an airless container equals 0.4 grams, which contains 60 mg of Naproxen.

(14) For the Acetaminophen Pain Gel, 30 wt % (see Formulation 1F in Table 2 above), one pump from an airless container equals 0.4 grams, which contains 120 mg of Acetaminophen.

(15) Details Regarding Topical Application of Naproxen

(16) Subject: Male, 59 yr. old.

(17) Localized Topical Application Area: Groin, right hip area

(18) Use Frequency: Morning and bedtime

(19) Dosage: One pump, 0.4 grams, 60 mg Naproxen

(20) Duration of pain relief: 10-12 hours

(21) Pain level before application: 7 (scale 1-10 worst)

(22) Pain level after application: 2 (scale 1-10 worst)

(23) Time to effectiveness: 30 to 60 minutes

(24) Side effects: none

(25) Details Regarding Topical Application of Acetaminophen

(26) Localized Topical Application Area: Groin, right hip area

(27) Use Frequency: Morning and bedtime

(28) Dosage: One pump, 0.4 grams, 120 mg Acetaminophen.

(29) Duration of pain relief: 0

(30) Pain level before application: 7 (scale 1-10 worst)

(31) Pain level after application: 7 (scale 1-10 worst)

(32) Side effects: none

(33) The subject was seen by an orthopedic specialist due to decreased mobility and range of motion in the hip joint. Physical therapy and Celebrex were ordered as a precursor to future hip surgery.

(34) The Celebrex was initiated and stopped after 3 days due to drowsiness and GI side effects. No other oral or topical products were used or taken for hip discomfort—including opioids, analgesics, and topical pain relievers.

(35) The subject is in continuous discomfort due to intense physical labor at work.

(36) The subject started on 15 wt % Naproxen gel, 0.4 grams (60 mg of Naproxen), before work and at bedtime for 2 days, and felt a reduction on the pain scale from 7 down to 2 after 2 applications of the gel. Pain was much improved over the course of the therapy; and the subject was able to perform activities at work with pain relief. Continued use has allowed the subject to use only 60 mg twice a day of the 15% Naproxen Gel to maintain significant pain relief.

(37) After 1 full day of not using the naproxen gel, the subject began using the 30% Acetominophen gel by applying 1 full pump of the acetaminophen gel (0.4 gm or 120 mg of Acetaminophen) from an airless container. The gel was applied once in the morning before work, and again at bedtime. Prior to application, the pain level was at a 7 (on a scale of 1-10, with zero being no pain). The pain level remained at 7 after application. The subject felt little relief after applying the acetaminophen gel. The pain continued throughout the day at a 7 level. After 2 days of using the acetaminophen gel with little pain relief, the acetominophen gel was discontinued and the use of the naproxen gel was reinstated. Using the 15% naproxen gel, pain relief was controlled at a 2 level during the course of naproxen gel therapy.

(38) This example demonstrates that the formulations contemplated herein are useful for topical delivery of actives such as the NSAID naproxen.

Example 6

Case Study of Vitamin B12 Gel

(39) The use of all topical gels was done with physician oversight and the informed consent of the subject.

(40) A topical Vitamin B12 formula containing 200 mcg of methyl cobalamin per pump of 200 mg (see Formulation 3F in Table 4) was applied to the thighs of a test subject once in the morning and once in the evening. The subject's blood was analyzed for Vitamin B12 and recorded a blood concentration of 278 pg/ml. The topical Vitamin B12 gel formulation was applied for 14 days and the Vitamin B12 blood concentration was recorded as 441 pg/ml. The test subject followed his normal daily routine with no other supplements taken and no changes to his normal diet.

(41) The invention illustratively described herein may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

(42) The contents of the articles, patents, and patent applications, and all other documents and electronically available information mentioned or cited herein, are hereby incorporated by reference in their entirety to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference. Applicants reserve the right to physically incorporate into this application any and all materials and information from any such articles, patents, patent applications, or other documents.

(43) The inventions illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising”, “including,” containing”, etc. shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the inventions embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention.

(44) The invention has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the invention. This includes the generic description of the invention with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

(45) In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group.

(46) Other embodiments are set forth within the following claims.