Combinations of extracts of Serenoa repens and lipophilic extracts of Zingiber officinalis and Echinacea angustifolia, the use thereof, and formulations containing them

Abstract

Disclosed are compositions containing an extract of Serenoa repens, a lipophilic extract of Zingiber officinalis and a lipophilic extract of Echinacea angustifolia or Zanthoxylum bungeanum.

Claims

1. A method of treating urinary incontinence, benign prostate hypertrophy, prostatitis and prostatism, and pelvic pain in a patient in need thereof, said method comprising: administering to said patient an effective amount of a composition comprising a Serenoa repens extract, a Zingiber officinalis lipophilic extract and an Echinacea angustifolia or Zanthoxylum bungeanum lipophilic extract; wherein the ratio of the Serenoa repens extract to the Zingiber officinalis lipophilic extract to the Echinacea angustifolia or Zanthoxylum bungeanum lipophilic extract is 1:0.25-0.5:0.05-01.

2. The method according to claim 1 wherein the extracts of Serenoa repens, Zingiber officinalis, Echinacea angustifolia and Zanthoxylum bungeanum are prepared by extraction with supercritical carbon dioxide.

3. The method according claim 1 further comprising oils rich in ω-3 fatty acids.

4. The method according to claim 3 wherein the oils are selected from Oenothera biennis, Linum usitatissimum or Ribes nigrum oils and natural or semi-synthetic fish oils.

5. The method according to claim 1 further containing antioxidants and trace elements.

6. The method according to claim 1, wherein said effective amount comprises 120 mg of said Serenoa repens extract, 25 mg of said Zingiber officinalis lipophilic extract and 5 mg of said Echinacea angustifolia or of said Zanthoxylum bungeanum lipophilic extract.

Description

DESCRIPTION OF THE INVENTION

(1) It has now surprisingly been found that by combining Serenoa repens extract with a lipophilic extract of Zingiber officinalis and a lipophilic extract of Echinacea angustifolia or Zanthoxylum bungeanum, the urogenital symptoms of both men and woman regress completely, with a rapid reduction of inflammation in prostatism and pelvic pain in general which has never been observed with the sole use of the extracts administered individually.

(2) The present invention therefore relates to compositions containing a Serenoa repens extract, a lipophilic extract of Zingiber officinalis and a lipophilic extract of Echinacea angustifolia or Zanthoxylum bungeanum.

(3) The invention also relates to said compositions for use in the treatment of urinary incontinence, benign prostate hypertrophy, prostatitis and prostatism, and pelvic pain.

(4) Serenoa repens extract, which is rich in fatty acids, lipophilic extract of Zingiber officinalis and lipophilic extract of Echinacea angustifolia or Zanthoxylum bungeanum are preferably obtained by extraction with carbon dioxide under supercritical conditions.

(5) The Zingiber officinalis extract used in the present invention, prepared by extraction from the rhizomes with carbon dioxide under supercritical conditions, is characterised by the fact that it contains 20 to 35% gingerols, preferably 25%.

(6) The Serenoa repens extracts according to the invention contain between 60 and 90% fatty acids, preferably about 80%. The extracts can also be prepared with solvents selected from hexane, ethanol and acetone. Alternatively, the extract obtained by pressing the fresh fruit can be used. An example of a lipophilic extract of Serenoa is disclosed in EP 0250953.

(7) The lipophilic extracts of Echinacea angustifolia or Zanthoxylum bungeanum contain between 15 and 35%, preferably 25%, of isobutylamides, and are prepared with carbon dioxide under supercritical conditions as reported in EP 0464298 and WO 00/02570. Isobutylamides are ligands of the cannabinoid receptors, particularly CB2, and agonists of TRPV1, the vanilloid receptor with a painkilling function.

(8) The extracts of Serenoa repens, Zingiber officinalis and Echinacea angustifolia or Zanthoxylum bungeanum are preferably present in the compositions according to the invention in the ratios of 1:0.25-0.5:0.05-01, which minimise the side effects and consequently allow safe chronic treatment.

(9) The therapeutic effect was evaluated on the basis of internationally accepted scores according to the NIH-CPSI (National Institute of Health—Chronic Prostatitis Symptoms Index) which monitors CP-CPPS (chronic prostatitis/chronic pelvic pain syndrome), which is associated with urinary symptoms such as pollakiuria, dysuria, nocturia and sexual dysfunctions which have lasted for at least three to six months and are present in the absence of urogenital infections, tumours or anatomical abnormalities. The evaluations are functional in the absence of specific markers, and require an adequate number of patients. The scale comprises an NIH-CPSI range of 0 to 43 (43 for the most serious cases). A population with variations of 0 to 30 in the inclusion criteria was evaluated.

(10) The trial was carried out on 80 patients aged between 55 and 70 years (63±7) with category IIIB CPPS. The patients were divided into 4 groups after randomisation; the first group was treated with capsules of Serenoa repens lipophilic extract (120 mg, 3 capsules a day), the second with the combination described in example 1 (3 capsules a day), the third with the mixture of Echinacea angustifolia/Zingiber officinalis lipophilic extract (3 capsules a day) prepared as described in EP 2379095 and administered in groundnut oil, and the fourth with a placebo. The data are reported in Table 1.

(11) TABLE-US-00001 TABLE 1 Variations in NIH-CPSI for pelvic pain and quality of life after treatment with Combination 1 and the ingredients thereof NIH-CPSI NIH-CPSI NIH-CPSI QUALITY OF TOTAL PAIN LIFE Serenoa repens Start 23.1 (1.8) 9.8 (1.6) 8.0 (0.9) 3 months 14.3 (1.3) 7.3 (1.1) 3.8 (1.1) 6 months 10.2 (1.1) 6.5 (1.2) 4.5 (0.8) Combination 1 Start 22.4 (1.5) 9.7 (1.5) 7.8 (0.9) 3 months 11.3 (1.1) 3.2 (1.0) 2.2 (0.9) 6 months  8.2 (1.2) 1.5 (1.1) 2.1 (0.8) Echinacea/ginger Start  22.7 (11.4) 9.1 (1.1) 7.9 (1.2) 3 months 17.4 (1.5) 8.2 (1.2) 6.2 (1.1) 6 months 12.6 (1.4) 7.3 (1.1) 6.2 (1.1) Placebo Start 24.2 (1.7) 9.2 (1.3) 7.6 (1.1) 3 months 15.1 (1.6) 7.3 (1.2) 6.9 (0.8) 6 months 11.2 (1.5) 6.5 (1.1) 5.9 (1.0)

(12) A second group of 60 patients was treated similarly to the first, evaluating the changes in the IPSS (International Prostate Symptom Score) and quality of life; the Serenoa repens extract, the combination and the placebo were compared for six months. The results are reported in Table 2.

(13) TABLE-US-00002 TABLE 2 Start 2 months 4 months Final MODIFICATIONS SYMPTOMS (score) Serenoa repens 16.5 ± 4.7 12.9 ± 4.4  11.9 ± 5.0  12.1 ± 5.3  −4.4 ± 5.0 (p < 0.036) Combination 1 17.1 ± 4.6 9.5 ± 4.2 8.6 ± 5.2 7.6 ± 5.8 −9.5 ± 5.2 (p < 0.001) Placebo 15.9 ± 4.5 12.3 ± 5.2  13.2 ± 5.3  13.5 ± 6.4  −2.4 ± 5.4 QUALITY OF LIFE (score) Serenoa repens  3.3 ± 1.2 3.1 ± 1.3 2.7 ± 1.1 2.6 ± 1.4 −0.7 ± 1.3 Combination 1  3.2 ± 1.2 2.8 ± 1.1 2.0 ± 1.2 1.8 ± 1.1 −1.4 ± 1.1 (p < 0.05) Placebo  3.1 ± 1.2 2.9 ± 1.0 2.8 ± 1.2 2.8 ± 1.1 −0.3 ± 1.1 Values expressed as mean ± S.D. p < 0.05 (significance vs. placebo)

(14) The results of the studies demonstrate the synergy of the composition compared with the individual ingredients.

(15) The pharmaceutical compositions mainly take the form of soft gelatin or cellulose capsules suitable for oils that disperse rapidly in the stomach, or capsules or tablets after microencapsulation of the oils.

(16) A preferred lipophilic formulation uses as dispersing agent oils rich in ω-3 fatty acids, which promote rapid absorption of the active ingredient. Examples of said oils include Oenothera biennis oil, Linum usitatissimum oil and Ribes nigrum oil, and natural or semi-synthetic fish oils. Said compositions are mainly used in curative and maintenance treatments, and to reduce pelvic pain.

(17) According to a preferred aspect, the compositions according to the invention will also contain antioxidants, such as palmitoyl ascorbate, catechin and gallic polyphenols, or lycopene and extracts containing it, and trace elements such as zinc, selenium and manganese.

(18) These compositions can be prepared according to conventional methods, as described in “Remington's Pharmaceutical Handbook”, Mack Publishing Co., N.Y., USA, using suitable excipients. Some formulation examples are reported below.

EXAMPLE 1

Soft Gelatin Capsules

(19) TABLE-US-00003 Serenoa repens extract 120 mg Zingiber officinalis lipophilic extract 25 mg Echinacea angustifolia lipophilic extract 5 mg Soya lecithin 10 mg Palmitoyl ascorbate 20 mg Oenothera biennis lipophilic extract 150 mg

EXAMPLE 2

Cellulose Capsules for Oils

(20) TABLE-US-00004 Serenoa repens extract 120 mg Zingiber officinalis lipophilic extract 50 mg Echinacea angustifolia lipophilic extract 10 mg Soya lecithin 10 mg Oenothera biennis lipophilic extract 150 mg

EXAMPLE 3

Tablets

(21) TABLE-US-00005 Serenoa repens extract 120 mg Zingiber officinalis lipophilic extract 50 mg Echinacea angustifolia lipophilic extract 10 mg Soya lecithin 10 mg Palmitoyl ascorbate 20 mg Oenothera biennis lipophilic extract 150 mg

EXAMPLE 4

Soft Gelatin Capsules

(22) TABLE-US-00006 Serenoa repens extract 130 mg Zingiber officinalis lipophilic extract 25 mg Echinacea angustifolia lipophilic extract 5 mg Soya lecithin 10 mg Palmitoyl ascorbate 20 mg Lycopersicon aesculentum extract (10% lycopene) 50 mg Oenothera biennis lipophilic extract 150 mg

EXAMPLE 5

Soft Gelatin Capsules

(23) TABLE-US-00007 Serenoa repens extract 120 mg Zingiber officinalis lipophilic extract 25 mg Zanthoxylum bungeanum lipophilic extract 5 mg Soya lecithin 10 mg Palmitoyl ascorbate 20 mg Oenothera biennis lipophilic extract 150 mg