A powder composition of serenoa repens extract

Abstract

The present invention relates to a powder composition consisting essentially of a lipid extract of Serenoa repens also called as Saw palmetto, polyethylene glycol, colloidal silicone dioxide, silicified microcrystalline cellulose and magnesium stearate. The said powder composition has a desirable flow property that provides easy capsule filling. The invention further relates to a process for the preparation of said powder composition and use thereof as medicament in the treatment of benign prostatic hyperplasia in adult men.

Description

[0001] A POWDER COMPOSITION OF SERENOA REPENS EXTRACT

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a powder composition consisting essentially of a lipid extract of Serenoa repens also called as Saw palmetto, polyethylene glycol, colloidal silicone dioxide, silicified microcrystalline cellulose and magnesium stearate. The said powder composition has a desirable flow property that provides easy capsule filling. The invention further relates to a process for the preparation of said powder composition and use thereof as medicament in the treatment of benign prostatic hyperplasia in adult men.

[0004] BACKGROUND OF THE INVENTION

[0005] Saw palmetto, commonly known as Serenoa repens is the only species currently classified in the genus Serenoa.

[0006] Serenoa repens is a small palm and that grows to a maximum height around 7-10 ft (2.1-3.0 m). It is endemic to the subtropical Southeastern United States, most commonly along the south Atlantic and Gulf Coastal plains and sand hills. The fruits of the plant are commonly used in supplements to improve prostate health, balance hormone levels, prevent hair loss in men, improves urinary tract function and may decrease inflammation. Especially, Saw palmetto extract has been studied as possible treatment for people with prostate cancer and for men with lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). In vitro studies indicated, Saw palmetto extract inhibits both 5-alpha reductase and aromatase enzymes. 5-alpha reductase enzyme catalyzes the conversion of testosterone to dihydrotestosterone in prostate gland cells. Aromatase enzyme provides the catalyzation of testosterone to 17-betaestradiole in prostate gland cells.

[0007] In addition to above therapeutic activity, Serenoa repens is also included in the composition of many nutritional supplements. Sanz palmetto or sterol lipid extract of Serenoa repens is marketed under the tradename of Permixon® by Pierre Fabre as a capsule for the treatment of moderate urinary tract symptoms associated with benign prostatic hyperplasia in adult men. For adults, Permixon® can be taken for 160 mg twice a day in the morning and evening with meal. Although, the results of animal experiments showed that Saw palmetto extract has very low acute toxicity, the maximum duration of the treatment has been limited with 6 months.

[0008] Permixon® is available on the market as 60 mg or 180 mg capsules in a box. It contains Saw palmetto extract, polyethylene glycol 10000, titanium dioxide, gelatin & iron oxide.

[0009] EP 0265338 B1 discloses a stable pharmaceutical composition comprising 10 to 40% of a lipid-sterolic extract of Serenoa repens by weight and 60 to 90% of one or more polyethylene glycols (or PEG) selected from PEG 6000, PEG 10,000 and PEG 20,000 by weight and is exemplified by a preferred unit formula containing 160 mg of extract and 290 mg of polyoxyethylene glycol 10,000. This composition can be administered orally, particularly in capsule form containing the said composition.

[0010] EP 1165108 B1 discloses the use of a lipid-sterol extract of Serenoa Repens to manufacture a medicinal product to be administered individually or in combination, simultaneously, separately or sequentially over time, with a prostatectomy, radiotherapy and / or a hormone therapy, for the prevention and / or treatment of prostate cancer.

[0011] US 20060121129 A1 discloses a dietary supplement for treating or preventing prostate disease and / or vascular disease including saw palmetto, d-alpha tocopherol, d-gamma tocopherol, d-delta tocopherol, d-beta tocopherol, selenium, lycopene, zinc, folic acid, vitamin B12, and vitamin B6, each in a therapeutically effective amount. A composition containing, inter alia, the above-mentioned compounds may contain 320 mg Saw palmetto in oblong tablets i.e. caplet.

[0012] WO 2009103477 A1 disclose compositions containing: a) lipophilic extract of Serenoa repens, b) lipophilic extract of Echinacea, c) a component selected from lipophilic extract of Hypericum perforatum, hydrogenated lipophilic extract of Hypericum perforatum and octahydrohyperforin, and d) selenium compounds. This composition can be administered orally, particularly in capsule form containing the said composition.

[0013] US 20040247619 A1 discloses a therapeutic herbal composition comprising Sanz Palmetto, Bromelain, Willow Herb, Grape Seed Complex, Wild Rosella, Liquorice, Passionfruit Seed and Selenium Yeast. The composition can be used as a health promotant but it is also useful as a treatment for cancer and inflammation. Additionally, this composition may be beneficial especially for prostate cancer and hyperplasia.

[0014] EP 2600845 B1 discloses a pharmaceutical composition in the form of a capsule comprising with 50 - 90 % of Serenoa repens extract and 10 - 50 % of polyethylene glycol (PEG) 10000 by weight in relation to the total weight of composition. According to EP ‘845, the mixing of PEG & active by co-melting makes it possible to obtain a filling composition in liquid form at a moderate temperature, which becomes a solid at room temperature. In EP ‘845, the capsules are filled at a moderate temperature, when the filling composition is in liquid form. After cooling, the composition becomes solid. Thus, the manufacturing process of EP ‘845 comprising the heating of pre-filled composition before filling into the capsule, which makes capsule filling process very attentive and laborious as compared to the powder filling.

[0015] TR 2021 / 015689 discloses a powder composition comprising Saw palmetto, hyroxypropylmethyl cellulose, vegetable oil and at least one additional excipient for the treatment of benign prostatic hyperplasia.

[0016] According to above mentioned prior art, it is evident that preparing a stable powder composition with a sterol lipid extract of Serenoa repens and filling into capsules needs more conscious efforts.

[0017] Various attempts have been made in the art to get the stable composition of Serenoa repens in the powder form with desirable physico-chemical properties. However, there still exist need to obtain a powder composition of Serenoa repens through a very simple process, which overcome the problems associated with above prior art and still provides desired flowing properties and easy capsule filling.

[0018] In a totally unexpected manner, the inventors have shown that it is possible to obtain a solid powder composition comprising of Serenoa repens, which is easy to scale up, easy to manufacture and easy to fill into capsules by using few numbers of excipients. The inventors of the present invention have surprisingly found that when specific excipients, such as silicified microcrystalline cellulose and at least one additional excipient have been used in specific amounts, it is possible to obtain a Serenoa repens in powder composition having desired flowing properties and doesn’t allow to form a clumps during the capsule filling process.

[0019] OBJECTS OF THE INVENTION

[0020] The main object of the present invention to obtain a powder composition of Serenoa repens eliminating all aforesaid problems and bringing additional advantages to the relevant prior art.

[0021] Another object of the present invention is to develop a powder composition of Serenoa repens with enhanced stability.

[0022] Another object of the present invention is to provide proper flowability and decrease in agglomeration.

[0023] Yet another object of the present invention is to obtain a powder composition of Serenoa repens with increased uniformity.

[0024] Yet another object of the present invention is to provide a powder composition of Serenoa repens, which is easy to fill in the capsule.

[0025] Yet another object of the present invention is to develop a formulation that eliminates the problems that may occur during the capsule filling process. Yet another object of the present invention to provide a powder composition of Serenoa repens, which is easy to scale up, easy to manufacture and easy to fill into capsules.

[0026] SUMMARY OF THE INVENTION

[0027] In one aspect, the present invention provides a powder composition consisting essentially of Serenoa repens, polyethylene glycol, colloidal silicone dioxide, silicified microcrystalline cellulose, and magnesium stearate.

[0028] In another aspect, the present invention provides a powder composition consisting essentially of

[0029] - 30 - 50 % by weight of Serenoa repens,

[0030] - 1 .0 - 7.0 % by weight of polyethylene glycol,

[0031] - 20 - 35 % by weight of colloidal silicone dioxide,

[0032] - 27 - 45 % by weight of silicified microcrystalline cellulose, and

[0033] - 0.5 - 5.0 % by weight of magnesium stearate by weight based on the total weight of the capsule.

[0034] In yet another aspect, the present invention provides a powder composition consisting essentially of

[0035] - 30 - 50 % by weight of Serenoa repens,

[0036] 1 .0 - 7.0 % by weight of polyethylene glycol,

[0037] 20 - 35 % by weight of colloidal silicone dioxide,

[0038] 27 - 45 % by weight of silicified microcrystalline cellulose, and

[0039] 0.5 - 5.0 % by weight of magnesium stearate by weight based on the total weight of the capsule, wherein said powder composition is prepared by wet granulation.

[0040] In yet another aspect, the present invention provides a powder composition consisting of

[0041] - 30 - 50 % by weight of Serenoa repens,

[0042] 1 .0 - 7.0 % by weight of polyethylene glycol,

[0043] 20 - 35 % by weight of colloidal silicone dioxide, 27 - 45 % by weight of silicified microcrystalline cellulose, and

[0044] 0.5 - 5.0 % by weight of magnesium stearate by weight based on the total weight of the capsule.

[0045] In yet another aspect, the present invention provides a powder composition consisting of

[0046] - 30 - 50 % by weight of Serenoa repens,

[0047] 1 .0 - 7.0 % by weight of polyethylene glycol,

[0048] 20 - 35 % by weight of colloidal silicone dioxide,

[0049] 27 - 45 % by weight of silicified microcrystalline cellulose, and

[0050] 0.5 - 5.0 % by weight of magnesium stearate by weight based on the total weight of the capsule, wherein said powder composition is prepared by wet granulation.

[0051] In yet another aspect, the present invention provides a process for the preparation of powder composition comprises steps of: a. loading Serenoa repens extract to tank and heating to 50-60 °C b. adding polyethylene glycol to the solution obtained in step (a) and mixing until dissolved, c. granulating colloidal silicone dioxide with the granulation solution obtained in step (b), d. sieving the granules obtained in step (c) with a suitable sieving system, e. adding silicified microcrystalline cellulose to the granules obtained in step (d) and mixing, f. adding magnesium stearate to the granules obtained in step (e) and mixing, and g. filling the powder mixture obtained in step (f) into the capsules.

[0052] In yet another aspect, the present invention provides a process of the preparation of abovementioned powder composition, which is easy to scale up, easy to manufacture and easy to fill into capsules. In yet another aspect, the present invention provides a pharmaceutical composition of any of the above aspects, wherein the said composition remains stable after storage for at least 3 months at 40°C and 75% relative humidity (RH).

[0053] In yet another aspect, the present invention discloses a use of such pharmaceutical composition as medicament for the treatment of moderate urinary tract symptoms associated with benign prostatic hyperplasia in adult men.

[0054] The details of one or more embodiments of the present invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description.

[0055] DETAILED DESCRIPTION OF THE PRESENT INVENTION

[0056] The present invention will now be more specifically illustrated as hereunder.

[0057] In the present invention, unless indicated otherwise, all ingredient concentrations are presented in units of % weight.

[0058] The term “Serenoa repens" as used in the present invention containing a sterol lipid extract from the fruit of the Saw palmetto tree. The Saw palmetto tree produces dark berries that contain a large seed. The Saw palmetto fruit has long been used by Native Americans for its nutritional, diuretic, sedative, aphrodisiac, and coughreducing properties. In the present invention Saw palmetto extract is taken orally in the form of a capsule twice a day.

[0059] In one embodiment of the present invention, a powder composition comprising Serenoa repens in an amount of 30 - 50 %, preferably 40 % by weight based on the total composition.

[0060] The term “powder” as used in the present invention means a composition that consists of finely dispersed solid particles that are free flowing. The powder composition of the present invention is intended for oral use and it is in the form of a capsule.

[0061] In the present invention, colloidal silicon dioxide, as adsorbent, is generally employed in an amount of 20 - 35 %, preferably 27.5 % by weight based on the total composition.

[0062] Instead of colloidal silicone dioxide, adsorbent can be selected from, but are not limited to, microcrystalline cellulose, calcium silicate, magnesium aluminium silicate, magnesium carbonate, polycarbophil or mixture thereof.

[0063] In the present invention magnesium stearate, as lubricant, is employed in an amount of 0.5 - 5.0 %, preferably 1 .5 % by weight based on the total composition.

[0064] Instead of magnesium stearate, lubricant can be selected from, but are not limited to, metallic stearates such as calcium stearate, zinc stearate, stearic acid, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, com starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc and mixtures thereof.

[0065] In the present invention, polyethylene glycol or its derivatives, as a solubility enhancer, is employed in an amount of 1.0 to 7.0% by weight, preferably 2.5% by weight, based on the total composition. In the present invention, the preferred polyethylene glycol derivative is polyethylene glycol 10000 (PEG 10000).

[0066] In the present invention silicified microcrystalline cellulose, as diluent, is employed in an amount of 27 - 45 %, by weight based on the total composition.

[0067] Instead of silicified microcrystalline cellulose, diluent can be selected from, but are not limited to, lactose monohydrate, corn starch, spray dried lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, sodium chloride, sorbitol and mixtures thereof.

[0068] The composition of the invention may be prepared as is known in the art. In some embodiments the powder composition may be prepared as described in the examples herein. In some embodiments the powder composition may be granulated prior to being filled into capsules. In some embodiments the granules of the invention are manufactured by wet granulation.

[0069] In general aspect, the present invention provides a process for the preparation of powder composition comprises steps of: a. loading Serenoa repens extract to tank and heating to 50-60 °C b. adding polyethylene glycol to the solution obtained in step (a) and mixing until dissolved, c. granulating colloidal silicone dioxide with the granulation solution obtained in step (b), d. sieving the granules obtained in step (c) with a suitable sieving system, e. adding silicified microcrystalline cellulose to the granules obtained in step (d) and mixing, f. adding magnesium stearate to the granules obtained in step (e) and mixing, and g. filling the powder mixture obtained in step (f) into the capsules.

[0070] Serenoa repens is an oily substance, hence it is challenging to obtain the pre-filled composition in suitable form, particularly powder form, for filing into the capsule and get the stable composition.

[0071] Due to oily structure of Serenoa repens, it is adsorbed on colloidal silicon dioxide and granules are obtained. These granules are then sieved and mixed with silicified microcrystalline cellulose and magnesium stearate. However, it has come to the observation that use of specific excipient like silicified microcrystalline cellulose is required to be used in specific amount to obtain the powder composition with desired powder properties like having appropriate content uniformity with adequate powder flow property to allow the smooth capsule filling process. The inventors surprisingly invented the aforementioned properties of powder has been obtained by using silicified microcrystalline cellulose in amount of 27 - 45 % by weight based on the total composition. The powder composition in accordance with the present invention may be used as a medicament. The pharmaceutical composition preferably can be used in treatment of moderate urinary tract symptoms associated with benign prostatic hyperplasia in adult men.

[0072] The following examples are intended to illustrate the scope of the present invention but not to limit it thereto.

[0073] Examples:

[0074] Reference Example 1 : Preparation of Serenoa repens Capsules

[0075] Table-1

[0076] Process for Preparation:

[0077] 1 . Serenoa repens hexane extract was loaded to tank and heated to 50-60 °C,

[0078] 2. Polyethylene glycol (PEG) 10000 was added to the solution obtained in step (1 ) and mixed until dissolved,

[0079] 3. colloidal silicone dioxide was granulated with the granulation solution obtained in step (2),

[0080] 4. granules obtained in step (3) were sieved with a suitable sieving system,

[0081] 5. silicified microcrystalline cellulose was added to the granules obtained in step (4) and mixed,

[0082] 6. magnesium stearate was added to the granules obtained in step (5) and mixed,

[0083] 7. powder mixture obtained in step (6) was filled into the capsules. Observation: Clumps formation in powder composition was observed during capsule filling, which resulted into the weight variation of the capsules.

[0084] Example 2: Preparation of Serenoa repens Capsules

[0085] Table-2

[0086] Process for Preparation:

[0087] 1 . Serenoa repens hexane extract was loaded to tank and heated to 50-60 °C,

[0088] 2. Polyethylene glycol (PEG) 10000 was added to the solution obtained in step (1 ) and mixed until dissolved,

[0089] 3. colloidal silicone dioxide was granulated with the granulation solution obtained in step (2),

[0090] 4. granules obtained in step (3) were sieved with a suitable sieving system,

[0091] 5. silicified microcrystalline cellulose was added to the granules obtained in step (4) and mixed,

[0092] 6. magnesium stearate was added to the granules obtained in step (5) and mixed, and

[0093] 7. powder mixture obtained in step (6) was filled into the capsules.

[0094] Observation: No clumps formation was observed during the capsule filling and obtained capsules comply in content uniformity test.

[0095] Example 3: Disintegration time of Example 2 and reference product 6 samples of reference product (Permixon) and example 2 were analyzed in 0.1 N HCI medium at 37.0 ± 2 °C according to Ph. Eur. 2.9.1.

[0096] Table-3

[0097] *NMT: not more than

[0098] From the above disintegration time given in Table-3, it is evident that both Example-2 and reference product meet the acceptance criteria and Example-2 disintegrates fast comparatively.

[0099] Example 4: Stability Result of capsules prepared according to Example 2 at 30 °C & 40 °C.

[0100] The capsules prepared in Example-2, were placed in PVC / aluminum blisters, and stored for 3 months under conditions of 30°C / 65% RH & 40°C / 75% RH. 3 months stability result is presented herein below Table-4.

[0101] Table-4

Claims

CLAIMS1. A powder composition consisting essentially of:- 30 - 50 % by weight of Serenoa repens,- 1 .0 - 7.0 % by weight of polyethylene glycol,- 20 - 35 % by weight of colloidal silicone dioxide,- 27 - 45 % by weight of silicified microcrystalline cellulose, and- 0.5 - 5.0 % by weight of magnesium stearate by weight based on the total weight of the capsule.

2. A powder composition according to claim 1 is prepared by wet granulation method.

3. A process for the preparation of powder composition according to claim 1 comprises of steps: a. loading Serenoa repens extract to tank and heating to 50-60 °C b. adding polyethylene glycol to the solution obtained in step (a) and mixing until dissolved, c. granulating colloidal silicone dioxide with the granulation solution obtained in step (b), d. sieving the granules obtained in step (c) with a suitable sieving system, e. adding silicified microcrystalline cellulose to the granules obtained in step (d) and mixing, f. adding magnesium stearate to the granules obtained in step (e) and mixing, and g. filling the powder mixture obtained in step (f) into the capsules.

4. A powder composition according to claim 1 , wherein Polyethylene glycol has a molecular weight of 10000.

5. A powder composition according to claim 1 , wherein Serenoa repens extract is hexane extract.

6.

5. A powder composition according to any of preceding claims is useful for the treatment of benign prostatic hyperplasia in adult men.