HERBAL MEDICINES FOR TREATING POLYCYSTIC KIDNEY DISEASES

Abstract

A method for treating all types of polycystic kidney disease using the herbs Phytolacca americana (poke), Fouquieria splendens (ocotillo), Parietaria judaica, and a Ceanothus species (red root) is detailed.

Claims

1. A composition comprising two or more extracts of Phytolacca americana, Fouquieria splendens, Parietaria judaica, a species of the Ceanothus genus or combinations thereof.

2. The composition of claim 1, wherein the extract is a water-ethanol extract.

3. The composition of claim 1, wherein the composition comprises a extract of Phytolacca americana, Fouquieria splendens, Parietaria judaica, and a species of the Ceanothus genus.

4. The composition of claim 1, wherein the composition further comprises powders or crude dried plant parts of Phytolacca americana, Fouquieria splendens, Parietaria judaica, a species of the Ceanothus genus or combinations thereof.

5. The composition of claim 1, wherein the species of the Ceanothus genus is selected from the group consisting of Ceanothus greggii, Ceanothus cuneatus, Ceanothus fendleri, and Ceanothus integerrimus.

6. The composition of claim 1, wherein the concentration of the Phytolacca americana extract ranges from about 10-30% by volume of the composition.

7. The composition of claim 1, wherein the concentration of the extract of the species of the Ceanothus genus ranges from about 20-40% by volume of the composition.

8. The composition of claim 1, wherein the concentration of the Fouquieria splendens extract ranges from about 1-20% by volume of the composition.

9. The composition of claim 1, wherein the concentration of the Parietaria judaica extract ranges from about 40-60% by volume of the composition.

10. The composition of claim 1, wherein the concentration of the Phytolacca americana extract ranges from about 10-20%, the concentration of the extract of the species of the Ceanothus genus ranges from about 20-40%, the concentration of the Fouquieria splendens extract ranges from about 1-20%, the concentration of the Parietaria judaica extract ranges from about 40-60% by volume of the composition.

11. The composition of claim 1, wherein the concentration of the Phytolacca Americana extract is about 20%, the concentration of the extract of the species of the Ceanothus genus is about 30%, the concentration of the Fouquieria splendens extract is about 10%, the Parietaria judaica extract ranges from about 50% by volume of the composition.

12. The composition of claim 1, wherein the species of the Ceanothus genus is Ceanothus greggii.

13. A method for treating polycystic kidney disease, the method comprising administering a composition comprising one or more extracts from the group consisting of Phytolacca americana, Fouquieria splendens, Parietaria judaica, and a species of the Ceanothus genus to a mammal in need thereof.

14. The method of claim 13, wherein administering is oral administration.

15. The method of claim 13, wherein the extract is a water-ethanol extract.

16. The method of claim 13, wherein the composition further comprises powders or crude dried plant parts of Phytolacca americana, Fouquieria splendens, Parietaria judaica, a species of the Ceanothus genus or combinations thereof.

17. The method of claim 13, wherein the polycystic kidney disease is autosomal dominant polycystic kidney disease.

18. The method of claim 13, wherein the polycystic kidney disease is autosomal recessive polycystic kidney disease.

19. A method for treating a polycystic ovarian syndrome, the method comprising administering a composition comprising one or more extracts from the group consisting of Phytolacca americana, Fouquieria splendens, Parietaria judaica and a species of the Ceanothus genus to a mammal in need thereof.

20. The method of claim 19, wherein the administering is oral administration.

21. The method of claim 19, wherein the extract is a water-ethanol extract.

22. The method of claim 19, wherein the composition further comprises powders or crude dried plant parts of Phytolacca americana, Fouquieria splendens, Parietaria judaica, a species of the Ceanothus genus or combinations thereof.

Description

DETAILED DESCRIPTION

[0015] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the disclosure. However, one skilled in the art will understand that the invention may be practiced without these details.

[0016] Unless the context requires otherwise, throughout the present specification and claims, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to”.

[0017] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0018] In brief, the present disclosure provides compositions and methods of administering four medicinal plants together or separately for treatment of patients with PKDs. In certain embodiments, the medicinal plants are Phytolacca americana (poke) root, Fouquieria splendens (ocotillo) bark, Parietaria judaica and a Ceanothus species (red root). In particular embodiments, compositions are provided that are formulated as powders, other extracts, encapsulations, tablets, liquids, gels, or other methods of delivering the herbs orally.

Compositions

[0019] As detailed above, one particular embodiment provides a composition comprising two or more extracts of Phytolacca americana, Fouquieria splendens, Parietaria judaica, a species of the Ceanothus genus or combinations thereof. Certain embodiments comprise a pharmaceutically acceptable carrier or excipient and two or more extracts of Phytolacca americana, Fouquieria splendens, Parietaria judaica, a species of the Ceanothus genus or combinations thereof.

[0020] In some embodiments, the composition comprises 2 extracts. In some embodiments, the composition comprises 3 extracts. In certain embodiments, the composition comprises 4 extracts. In some embodiments, the composition comprises 4 or more extracts. In certain embodiments, the composition comprises an extract of Phytolacca americana, Fouquieria splendens, Parietaria judaica, and a species of the Ceanothus genus. Examples of a species of the Ceanothus genus include Ceanothus greggii, Ceanothus cuneatus, Ceanothus fendleri, and Ceanothus integerrimus. In some specific embodiments, the species of the Ceanothus genus is Ceanothus greggii.

[0021] In some embodiments, the pharmaceutical composition is formulated for oral administration. In other embodiments, the pharmaceutical composition is formulated for injection. Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.

[0022] The composition can be prepared according to methods known in the art and is not particularly limited with respect to the methods used for extraction. Accordingly, in certain embodiments, the extract is a water-ethanol extract. In some embodiments, the extract is a vegetable glycerin extract. In some embodiments, the extract is an oil extract. In some embodiments, the extract is an extract of an organic solvent, including but not limited to alcohols, esters, and ethers. The organic solvent may also include acetonitrile, dichloromethane, ethanol, methanol, diethyl ether, ethyl acetate, acetone, DMSO and the like.

[0023] Additionally, plant parts from which the extracts were taken can be included in the composition. In certain embodiments, powders or crude dried plant parts of Phytolacca americana, Fouquieria splendens, Parietaria judaica, a species of the Ceanothus genus or combinations thereof. In some embodiments, the composition further comprises crushed fresh plant parts Phytolacca americana, Fouquieria splendens, Parietaria judaica, a species of the Ceanothus genus (e.g., Ceanothus greggii, Ceanothus cuneatus, Ceanothus fendleri, and Ceanothus integerrimus) or combinations thereof.

[0024] In some embodiments, the concentration of the Phytolacca americana extract ranges from about 10-30% (e.g., about 10%, about 15%, about 20%, about 25% or about 30%) by volume of the composition.

[0025] In some more specific embodiments, the concentration of the extract of the species of the Ceanothus genus (e.g., Ceanothus greggii) ranges from about 20-40% (e.g., about 20%, about 25%, about 30%, about 35% or about 40%) by volume of the composition. In some embodiments, the concentration of the Fouquieria splendens extract ranges from about 1-20% (e.g., about 5%, about 10%, about 12%, about 15% or about 20%) by volume of the composition.

[0026] In some embodiments, the concentration of the Parietaria judaica extract ranges from about 40-60% (e.g., about 40%, about 45%, about 50%, about 55% or about 60%) by volume of the composition.

[0027] In certain more specific embodiment, the concentration of the Phytolacca Americana extract ranges from about 10-20%, the concentration of the extract of the species of the Ceanothus genus (e.g., Ceanothus greggii) ranges from about 20-40%, the concentration of the Fouquieria splendens extract ranges from about 1-20%, the concentration of the Parietaria judaica extract ranges from about 40-60% by volume of the composition.

[0028] In other more specific embodiments, the concentration of the Phytolacca Americana extract is about 20%, the concentration of the extract of the species of the Ceanothus genus (e.g., Ceanothus greggii) is about 30%, the concentration of the Fouquieria splendens extract is about 10%, the concentration of the Parietaria judaica extract ranges from about 50% by volume of the composition.

[0029] In one embodiment, the extract(s) are formulated in an aqueous solution. In specific embodiments, the aqueous solution is selected from, by way of example only, a physiologically compatible buffer, such as Hank's solution, Ringer's solution, or physiological saline buffer. In specific embodiments, such solutions include physiologically compatible buffers and/or excipients.

[0030] In another embodiment, extracts described herein are formulated for oral administration. Compounds described herein are formulated by combining the active extracts with, e.g., pharmaceutically acceptable carriers or excipients. In various embodiments, the extracts described herein are formulated in oral dosage forms that include, by way of example only, tablets, powders, pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries, suspensions and the like.

[0031] In certain embodiments, pharmaceutical preparations for oral use are obtained by mixing one or more solid excipient with one or more of the extracts (or dried powder form thereof) described herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as: for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others such as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. In specific embodiments, disintegrating agents are optionally added. Disintegrating agents include, by way of example only, cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0032] In one embodiment, dosage forms, such as dragee cores and tablets, are provided with one or more suitable coating. In specific embodiments, concentrated sugar solutions are used for coating the dosage form. The sugar solutions, optionally contain additional components, such as by way of example only, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs and/or pigments are also optionally added to the coatings for identification purposes. Additionally, the dyestuffs and/or pigments are optionally utilized to characterize different combinations of active compound doses.

Administration

[0033] A composition described herein above can be administered according to any of the methods of administration described herein. In particular, certain embodiments provide a method for treating polycystic kidney disease, the method comprising administering a composition comprising one or more extracts from the group consisting of Phytolacca americana, Fouquieria splendens, Parietaria judaica, and a species of the Ceanothus genus (e.g., Ceanothus greggii, Ceanothus cuneatus, Ceanothus fendleri, and Ceanothus integerrimus) to a mammal in need thereof. The extracts may be formulated together or separately according to methods known in the art.

[0034] In certain embodiments, the administration is oral. In some related embodiments of the method, the extract is a water-ethanol extract. In some embodiments of the method, the composition further comprises powders or crude dried plant parts of Phytolacca americana, Fouquieria splendens, Parietaria judaica, a species of the Ceanothus genus (e.g., Ceanothus greggii, Ceanothus cuneatus, Ceanothus fendleri, and Ceanothus integerrimus) or combinations thereof.

[0035] The compositions are effective in a variety of cystic diseases. Accordingly, in certain specific embodiments, the polycystic kidney disease is autosomal dominant polycystic kidney disease, for example, type 1 or type 2. In other embodiments, the polycystic kidney disease is autosomal recessive polycystic kidney disease.

[0036] Other embodiments provide a method for treating a polycystic ovarian syndrome, the method comprising administering a composition comprising one or more extracts from the group consisting of Phytolacca americana, Fouquieria splendens, Parietaria judaica and a species of the Ceanothus genus (e.g., Ceanothus greggii, Ceanothus cuneatus, Ceanothus fendleri, and Ceanothus integerrimus) to a mammal in need thereof.

[0037] In more specific embodiments of the foregoing, the administering is oral administration. In some embodiments of the foregoing, the extract is a water-ethanol extract.

[0038] In certain related embodiments, the composition further comprises powders or crude dried plant parts of Phytolacca americana, Fouquieria splendens, Parietaria judaica and a species of the Ceanothus genus (e.g., Ceanothus greggii, Ceanothus cuneatus, Ceanothus fendleri, and Ceanothus integerrimus) or combinations thereof.

[0039] Administration of the composition may continue as long as necessary. In some embodiments, a composition is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a composition is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a composition is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

[0040] In some embodiments, the composition is administered in dosages. Due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is provided in certain embodiments. Dosing for a composition of embodiments of this disclosure may be found by routine experimentation in light of the instant disclosure and/or can be derived by one of ordinary skill in the art.

[0041] In some embodiments, the composition is formulated into pharmaceutical compositions. In specific embodiments, pharmaceutical compositions are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any pharmaceutically acceptable techniques, carriers, and excipients are used as suitable to formulate the pharmaceutical compositions described herein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

Example 1

Preparation of Compositions

[0042] A representative composition was prepared by extracting a fresh plant mixture by coarsely chopping plant parts and macerating the resultant mixture in a solvent mixture of water, ethanol, and vegetable glycerin. Specifically, 600 g of fresh, coarsely chopped Phytolacca americana (poke) root was mixed with 900 mL ethanol, 180 mL water, and 120 mL vegetable glycerin and macerated for 30 days. Of Ceanothus greggii (red root), 470 g of coarsely chopped fresh root was mixed with 850 mL ethanol, 420 mL water, and 140 mL vegetable glycerin and macerated for 30 days. Of Fouquieria splendens (ocotillo), 470 g of coarsely chopped fresh bark was mixed with 1,270 mL ethanol and 140 mL vegetable glycerin and macerated for 30 days. Of Parietaria judaica (pellitory-of-the-wall), 470 g of coarsely chopped leaf, stem, and flower were mixed with 560 mL ethanol, 700 mL water, and 140 mL vegetable glycerin.

[0043] The resultant composition in each case was then pressed to excrete the liquid extract and strained to remove any residual solid material. All four extracts were then combined in a ratio of 20% Phytolacca americana, 30% Ceanothus greggii, 10% Fouquieria splendens, and 50% Parietaria Judaica.

Example 2

Administration of Representative Compositions (1.SUP.ST .Study)

[0044] Shrinkage of kidney and other cysts caused by ADPKDs was observed upon administration of the composition in two patients (numbers A1 and A4) who had pre- and post-total kidney volume (TKV) assessed. The shrinkage represents halting and reversal of progression of ADPKD. All four patients report an improvement in their estimated glomerular filtration rate (eGFR) since starting treatment with a minimum six-month follow-up. eGFR is the standard for assessing overall kidney function and its improvement is a clear indication that as their kidneys and cysts are shrinking and damage is being repaired.

TABLE-US-00001 TABLE A1 Representative results from administration of compositions of the present disclosure eGFR eGFR TKV TKV Patient CKD pre-tx post-tx pre-tx post-tx number Age Sex Race stage (mL/min) (mL/min) (mL) (mL) A1 35 M P G3a — — 1038 840 A3 35 F W G2b 72.4 — * — A4 37 M W G2b 72 — 783.5 — A7 29 M P G3a — — — — Abbreviations: Sex: F = female, M = male Race: P = Persian, W = White CKD = chronic kidney disease eGFR = estimated glomerular filtration rate TKV = total kidney volume. * = both kidneys were 15.3 cm in the longitudinal axis

Example 3

Administration of Representative Compositions (2.SUP.ND .Study)

[0045] Shrinkage or stabilization of kidney and other cysts caused by ADPKD was observed upon administration of the composition in two patients (numbers B1 and B5) who had pre- and post-total kidney volume (TKV) assessed. This represented a halting and reversal of progression of ADPKD. The one other patient with pre- and post-TKV measurements had an approximate 11% increase, but treatment duration was only three months. TKV is recognized in the art as a biomarker for efficacy of therapies for PKD. Eight of 11 treated patients had an improvement or stabilization in their estimated glomerular filtration rate (eGFR) since starting treatment with a minimum three-month follow-up (allowing for an error of ±1 mL/min in eGFR measurement). eGFR is the standard for assessing overall kidney function and its improvement is an indication that kidneys and cysts are shrinking and damage is being repaired. Even patients who had worsening of their eGFR over time (particularly patients B2 and B6), their initial kidney disease (stage G4) was relatively severe (and patient B6's kidneys were enormous on initial imaging, though no post-treatment sizing information was available) and the degree of progression was remarkably low for such situations. The deterioration of patient B1's eGFR was most mysterious, as imaging showed his TKV significantly improved with treatment.

TABLE-US-00002 TABLE B1 Representative results from administration of compositions of the present disclosure eGFR eGFR TKV TKV Tx Patient Sex, CKD stage pre-tx post-tx pre-tx post-tx duration number Age Race (baseline) (mL/min) (mL/min) (mL) (mL) (years) B1 35 M, P   G2 A1 84 76 1038 840 2.75 B2 47  F, W G3b A1 37 29 — — 3.5 B3 37 M, W G2  72 74 783.5 — 0.5 B4 38  M, AA G3a 58 67 1153 — 0.5 B5 42 M, W G3b A3 42 46 3140 3151 1 B6 63 M, W G4  23 20 5240 — 2.5 B7 65 M, W G3b A1a 40 51 — — 0.67 B8 66  F, W G2  72 74 524 580 0.25 B9 46 M, W G3b 31 30 — — 1.5  B10 71  M, AA G5d 4 5 — — 1  B11 38  F, W G2 A2 66 66 1773 — 1.25 Abbreviations: Sex: F = female, M = male Race: AA = African American, P = Persian, W = White Stage: A = albumin-based, d = on dialysis, G = glomerular-filtration rate-based CKD = chronic kidney disease eGFR = estimated glomerular filtration rate TKV = total kidney volume

[0046] All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet, including U.S. Provisional Patent Application No. 62/664,709, filed Apr. 30, 2018, are incorporated herein by reference, in their entirety to the extent not inconsistent with the present description.

[0047] From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.