WO2016199161A2 - A composition comprising pentosan polysulfate sodium for use in treatment of bladder outlet obstruction and/or lower urinary tract symptoms - Google Patents

A composition comprising pentosan polysulfate sodium for use in treatment of bladder outlet obstruction and/or lower urinary tract symptoms Download PDF

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WO2016199161A2
WO2016199161A2 PCT/IN2016/000148 IN2016000148W WO2016199161A2 WO 2016199161 A2 WO2016199161 A2 WO 2016199161A2 IN 2016000148 W IN2016000148 W IN 2016000148W WO 2016199161 A2 WO2016199161 A2 WO 2016199161A2
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composition
pentosan polysulfate
polysulfate sodium
tablet
capsule
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PCT/IN2016/000148
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French (fr)
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WO2016199161A3 (en
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Vishal Jajodia SWATI
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Swati Vishal Jajodia
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Priority to KR1020187000208A priority Critical patent/KR20180011840A/en
Priority to RU2017145064A priority patent/RU2680098C1/en
Publication of WO2016199161A2 publication Critical patent/WO2016199161A2/en
Publication of WO2016199161A3 publication Critical patent/WO2016199161A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
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    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A—HUMAN NECESSITIES
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
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    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • a composition comprising pentosan polysulfate sodium for use in treatment of bladder outlet obstruction and/or lower urinary tract symptoms
  • the present invention relates to a composition comprising pentosan polysulfate sodium.
  • This invention also relates to a composition further comprising alpha adrenergic blockers.
  • This invention further relates to use of the composition comprising pentosan polysulfate sodium for treatment of bladder outlet obstruction and/or lower urinary tract symptoms.
  • LUTS lower urinary tract symptoms
  • chronic retention that may be due to some anatomic obstructive lesion
  • symptoms due to some neurological disease can be labeled as cases of urethritis, cystitis, UTI, urethral syndrome and painful bladder syndrome.
  • local examination, ultrasonography, urine culture and cystourethroscopy can be of help in the diagnosis, but many times the cause of LUTS remains unexplained.
  • many of the female patients are wrongly diagnosed as UTI again and again even in the absence of evidence of infection, and given some antibiotics only.
  • Such chronic or recurrent LUTS e.g. frequency, urgency, dysuria, supra-pubic discomfort, difficulty in starting urination, slow stream, feeling of incomplete voiding etc. without the evidence of infection, are given the term urethral syndrome or urethral pain syndrome or painful bladder syndrome.
  • This is a group of LUTS commonly occurring in females during the reproductive years.
  • Female prostatitis is another concept which explains LUTS in females.
  • Availability of Specific immune-histochemical staining for prostate-specific antigen (PSA) has favored the view that female paraurethral glands are homologue to the male prostate.
  • Benign prostatic hyperplasia is a condition that affects the prostate gland in men.
  • BPH is a condition of aging. Most men over the age of 50 have an enlarged prostate. Prostrate growth is modulated by endocrine, neuroendocrine, paracrine, autocrine, intracrine and extracellular matrix factors and cell-cell interactions. There is currently no cure for BPH and once prostate growth starts, it often continues, unless medical therapy is started.
  • Pentosan polysulfate sodium is used worldwide in topical, oraj and parenteral forms of administration for different indications such as hemorrhoids, varicose veins, and research is being done on osteoarthitis, oncology, viral infections like HIV, Creutzfeld-Jacobs disease. It also has anti-viral and anti-histaminic properties and it also causes inhibition of elastase. It is also used to treat and prevent arteriosclerotic and thrombotic vascular diseases. PPS has a lipolytic effect and hence can be used to treat hyperlipidemia. Currently, 1 OOmg capsules of PPS are taken three times a day to treat interstitial cystitis.
  • Figure 1 Shows a MTT Assay curve for composition comprising pentosan polysulfate sodium and tamsulosin hydrochloride.
  • Figure 2 Shows dissolution profile for pentosan polysulfate sodium 100 mg capsules.
  • the present invention relates to a composition comprising pentosan polysulfate sodium and alpha adrenergic blocker for use in the treatment of BOO (bladder outlet obstruction) and/or LUTS (lower urinary tract symptoms).
  • BOO blade outlet obstruction
  • LUTS lower urinary tract symptoms
  • the BOO (bladder outlet obstruction) and/or LUTS (lower urinary tract symptoms) may optionally be associated with benign prostatic hyperplasia.
  • the alpha adrenergic blockers are selected from the group of tamsulosin hydrochloride, naftopidil, silodosin, alfuzosin, terazosin, prazosin, doxazosin, phenoxybenzamine, phentolamine, tolazoline, trazodone, atipamezole, idazoxan, mirtazapine, yohimbine.
  • composition comprises lOOmg of Pentosan polysulfate sodium in combination with , 0.2 or 0.4mg tamsulosin hydrochloride or 4mg or 8mg silodosin or 25mg naftopidil in admixture with pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients may include fillers/diluents which can be used include calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, magnesium stearate , cross carmellose sodium, powdered cellulose, dextrates, dextrin, dextrate, dextrose, fructose, kaolin, lacticol, lactose anhydrous, lactose monohydrate, maltodextrin, maltose, mannitol, sorbitol, starch, corn starch, potato starch, modified pregelatinised starch, tapioca starch, wheat starch, sucrose, compressible sugar and confectioner's sugar.
  • fillers/diluents which can be used include calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, magnesium stearate , cross carmellose sodium, powdered cellulose,
  • composition of pentosan polysulfate sodium and alpha adrenergic blocker having therapeutic activity against benign prostatic hyperplasia comprising 100 mg of Pentosan polysulfate sodium in combination with 0.5mg dutasterideor 5mg finasteride, 0.2 or 0.4mg tamsulosin, 4mg or 8mg silodosin or 25mg naftopidil or 10 mg alfuzosin and 10% w/w to 40% w/w of fillers/diluents based on the total weight of the formulation
  • composition can be in the form of a sustained release tablet in tablet or tablet in capsule comprising 200 to 300 mg of pentosan polysulfate sodium in combination with 0.2 or 0.4 mg tamsulosin hydrochloride or 8mg or 16mg silodosin or 75mg naftopidil in admixture with pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients also include retardents, lubricants and glidants which do not interfere with the desired activity of pentosan polysulfate sodium.
  • fillers such as calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, powdered cellulose, dextrates, dextrin, dextrate, dextrose, fructose, kaolin, lacticol, lactose anhydrous, lactose monohydrate, maltodextrin, maltose, mannitol, sorbitol, starch, corn starch, potato starch, modified pregelatinised starch, tapioca starch, wheat starch, sucrose, compressible sugar and confectioner's sugar.may be utilized if desired to adjust the size of the dosage form.
  • Further ingredients such as carriers may be necessary for solubilisation or enhanced drug delivery.
  • retardents are methycellulose, hydroxyethyl cellulose, hydroxypropylme hyl cellulose, sodium carboxymethyl cellulose, carboxypolymethylene, galactomannose and sodium alginate.
  • lubricants are stearic acid, stearic acid salts, stearic acid derivatives, talc, polyethylene glycols, surfactants and waxes.
  • the glidants and flow promoters which can be include silica derivatives, talc and corn starch.
  • colors which can be added include dyes and lakes commonly used in pharmaceutical compositions and optionally, natural and artificial sweeteners can also be added.
  • compositions having therapeutic activity against benign prostatic hyperplasia comprising 200 to 300mg of Pentosan polysulfate sodium in combination with 0.2 or 0.4 mg tamsulosin hydrochlorideor 8mg or 16mg silodosin or 75mg naftopidil or alfuzosin lOmg ,50%w/w to 80%w/w of retardents based on the total weight of the composition, 0.5%w/w to 3%w/w of lubricants based on the total weight of the composition and optionally l%w/w to 3%w/w of glidants and flow promoters and pharmaceutically acceptable carriers and other excipients based on the total weight of the composition.
  • the sustained release tablet/capsule of the invention comprising 200 to 300mg of pentosan polysulfate sodium releases the active ingredient i.e. pentosan polysulfate sodium steadily over the course of the day with the other drug in combination and maintains a steady level of the drug in the blood stream.
  • the pharmaceutical composition of the invention caused regression of scarring and regression of established and proliferative lesions of prostatic tissue.
  • Prostate gland growth is modulated by endocrine, neuroendocrine, paracrine, autocrine, intracrine and extracellular matrix factors and cell-cell interactions.
  • the composition affected mainly extracellular matrix regulation.
  • the composition also inhibited complement activation, antagonized growth factor binding and inhibited DNAse activity while simultaneously displaying a very low incidence of side effects.
  • Example 1 The mouse embryonic fibroblasts cell line (NIH3T3) was obtained from National Centre for Cell Science (NCCS), Pune and grown in Dulbecco's modified eagle's medium (DMEM) containing 10% fetal bovine serum (FBS). All cells were maintained at 370C, 5% C02, 95% air and 100% relative humidity. Maintenance cultures were passaged weekly and the culture medium was changed twice a week. Cell treatment procedure :-
  • the monolayer cells were detached with trypsin-ethylene diamine tetra acetic acid (EDTA) to make single cell suspensions and viable cells were counted using a hemocytometer and diluted with medium with 5% FBS to give final density of 1x105 cells/ml.
  • EDTA trypsin-ethylene diamine tetra acetic acid
  • ⁇ of cell suspension was seeded into each of the 96-well plates at plating density of 10,000 cells / well and incubated to allow for cell attachment at 370C, 5% C02, 95% air and 100% relative humidity. After 24 hours the cells were treated with serial concentrations of the extracts.
  • the extracts were initially dissolved in dimethylsulfoxide (DMSO) and further diluted in serum free medium to produce five concentrations.
  • DMSO dimethylsulfoxide
  • % cell Inhibition 100- [Asample/Acontrol] xlOOThe dilution of pentosan polysulfate sodium and tamsulosin hydrochloride were prepared in the ratio of 1 :250, 1 :500 and 1 : 1000 and results are given below in table 1
  • dilution 1 :250 has maximum amount of inhibition of 99% which further directs us to take the combination to preclinical and clinical trial.
  • Pentosan polysulfate sodium and tamsulosin hydrochloride do not inhibit the cell in terms of percentage as seen in the absorbance as compared to the combination of pentosan polysulfate sodium and tamsulosin hydrochloride in the ratio.
  • the invitro studies show that a combination of pentosan polysulfate sodium and tamsulosin hydrochloride in certain percentage shows the benefit on the fibroblastic growth cells which are also the major cause of the LUTS or Bladder outlet obstruction with or without BPH.
  • Tamsulosin hydrochloride is granulated with excipients and tablets are made after coating of tamsulosin hydrochloride to prepare a modified or sustained release tablet.
  • Pentosan Polysulfate sodium has been dry mixed in blender and tablet and pentosan polsyufalte sodium mixture are added simultaneously in the machine where tablet in capsule are added adjusting the weight of Pentosan Polysulfate mixture for the proposed dosage.
  • Each dose will comprise of a capsule in which, blend of Pentosan polysulfate sodium with excipient along with the tablet of either 0.2 mg or 0.4 mg tamsulosin hydrochloride will be made available (tablet in capsule form).

Abstract

The invention relates to a composition comprising pentosan polysulfate sodium and an alpha adrenergic blocker for use in treatment of bladder outlet obstruction and/or lower urinary tract symptoms. The invention also relates to the composition being formulated as a tablet in tablet or tablet in capsule.

Description

TITLE OF THE INVENTION
A composition comprising pentosan polysulfate sodium for use in treatment of bladder outlet obstruction and/or lower urinary tract symptoms
FIELD OF THE INVENTION
The present invention relates to a composition comprising pentosan polysulfate sodium. This invention also relates to a composition further comprising alpha adrenergic blockers. This invention further relates to use of the composition comprising pentosan polysulfate sodium for treatment of bladder outlet obstruction and/or lower urinary tract symptoms.
BACKGROUND AND PRIOR ART
Patients with LUTS (lower urinary tract symptoms) other than stress incontinence, chronic retention (that may be due to some anatomic obstructive lesion) and symptoms due to some neurological disease can be labeled as cases of urethritis, cystitis, UTI, urethral syndrome and painful bladder syndrome. In few cases, local examination, ultrasonography, urine culture and cystourethroscopy can be of help in the diagnosis, but many times the cause of LUTS remains unexplained. In view of frequent normal results of routinely done investigations such as USG, KUB X-ray, urine culture and routine microscopy etc., many of the female patients are wrongly diagnosed as UTI again and again even in the absence of evidence of infection, and given some antibiotics only. Such chronic or recurrent LUTS, e.g. frequency, urgency, dysuria, supra-pubic discomfort, difficulty in starting urination, slow stream, feeling of incomplete voiding etc. without the evidence of infection, are given the term urethral syndrome or urethral pain syndrome or painful bladder syndrome. This is a group of LUTS commonly occurring in females during the reproductive years. Female prostatitis is another concept which explains LUTS in females. Availability of Specific immune-histochemical staining for prostate-specific antigen (PSA) has favored the view that female paraurethral glands are homologue to the male prostate.
In some females with urethral syndrome, anterior vaginal wall tenderness and relief of symptoms by treatment with antibiotics against Chlamydia sp. (most common organi .sm retrieve 'Vd f"rom anterior urethra) suggest female prostatitis as the cause for LUTS. Instead of so many proposed etiologies, the definitive cause is yet to be proved.
Reference:- Epidemiology, perception and treatment of females presenting with lower urinary tract symptoms at a government hospital in central India; Dr. Gupta Shilpi et.al, the internet journal of surgery, Volume 21, Number l.LUTS (lower urinary tract symptoms) in Men Lower urinary tract symptoms (LUTS) are common in men affecting upto 78% of the elderly population. The most common LUTS are urinary frequency, urgency, hesitancy, weak stream and nocturia. Until recently, the constellation of obstructive and irritative symptoms, observed in aging men was termed prostatism. However, the preferred usage for these manifestations in recent years is LUTS, rather than to try and make a diagnosis on the basis of a mixture of symptoms. The pathophysiology of LUTS, being multifactorial, is not well characterized. Traditionally, lower urinary tract symptoms in men were attributed to bladder outlet obstruction, secondary to prostate enlargement mainly benign prostatic hyperplasia (BPH). However, recent studies have failed to reveal any significant correlation of LUTS with bladder outlet obstruction. Further, urinary symptoms can stem from other disease entities and have been shown to be present in women as wells. Thus, the term 'LUTS' or lower urinary tract dysfunction has been proposed for use when symptoms are not necessarily specific to the prostate. The severity of LUTS is best quantified by using quantitative symptoms indices, including the American Urological Association (AUA) symptom index and the International Prostate Symptom Score or IPSS. The prevalence of LUTS, mostly measured by IPSS has been reported from United States, United Kingdom, Canada, Australia and several other countries. Recently, the relationship of nocturia with international prostate symptom score in men with lower urinary tract symptoms due to BPH has been reported from Japan.
Reference :- Causes of lower urinary tract symptoms (LUTS) in adult Indian males; Year : 2004 I Volume : 20 | Issue : 2 | Page : 95-100, C Nagweshwar Rao et. Al .Indian Journal of Urology.
Benign prostatic hyperplasia (BPH) is a condition that affects the prostate gland in men. BPH is a condition of aging. Most men over the age of 50 have an enlarged prostate. Prostrate growth is modulated by endocrine, neuroendocrine, paracrine, autocrine, intracrine and extracellular matrix factors and cell-cell interactions. There is currently no cure for BPH and once prostate growth starts, it often continues, unless medical therapy is started.
Pentosan polysulfate sodium (PPS) is used worldwide in topical, oraj and parenteral forms of administration for different indications such as hemorrhoids, varicose veins, and research is being done on osteoarthitis, oncology, viral infections like HIV, Creutzfeld-Jacobs disease. It also has anti-viral and anti-histaminic properties and it also causes inhibition of elastase. It is also used to treat and prevent arteriosclerotic and thrombotic vascular diseases. PPS has a lipolytic effect and hence can be used to treat hyperlipidemia. Currently, 1 OOmg capsules of PPS are taken three times a day to treat interstitial cystitis. We have described, in our patent application No 521 /MUM/2010 filed on 26 August 2010, a pharmaceutical composition for the treatment of diabetes nephropathy, the composition comprising a pharmaceutically effective amount of Pentosan polysulfate sodium in admixture with pharmaceutically acceptable inert ingredients and also in our patent application No 1897/MUM/2010, filed on 29 December 2010, A sustained release composition having therapeutic activity against interstitial cystitis. Thus, there is a need for a pharmaceutical composition having therapeutic activity against treatment of BOO (bladder outlet obstruction) and LUTS (lower urinary tract symptoms) with or without benign prostatic hyperplasia.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1 : Shows a MTT Assay curve for composition comprising pentosan polysulfate sodium and tamsulosin hydrochloride.
Figure 2: Shows dissolution profile for pentosan polysulfate sodium 100 mg capsules.
DETAILED DESCRIPTION OF THE INVENTION
The description of the specific embodiments will so fully reveal the general nature of the embodiments herein that others can, by applying current knowledge, readily modify and/or adapt for various applications such specific embodiments without departing from the generic concept, and, therefore, such adaptations and modifications should and are intended to be comprehended within the meaning and range of equivalents of the disclosed embodiments. It is to be understood that the phraseology or terminology employed herein is. for the purpose of description and not of limitation. Therefore, while the embodiments herein have been described in terms of preferred embodiments, those skilled in the art will recognize that the embodiments herein can be practiced with modification within the spirit and scope of the embodiments as described herein. The present inventors have carried out detailed studies and found that pentosan polysulfate sodium is highly effective in treatment of BOO (bladder outlet obstruction) and LUTS (lower urinary tract symptoms) with or without benign prostatic hyperplasia.
The present invention relates to a composition comprising pentosan polysulfate sodium and alpha adrenergic blocker for use in the treatment of BOO (bladder outlet obstruction) and/or LUTS (lower urinary tract symptoms). The BOO (bladder outlet obstruction) and/or LUTS (lower urinary tract symptoms) may optionally be associated with benign prostatic hyperplasia.
The alpha adrenergic blockers are selected from the group of tamsulosin hydrochloride, naftopidil, silodosin, alfuzosin, terazosin, prazosin, doxazosin, phenoxybenzamine, phentolamine, tolazoline, trazodone, atipamezole, idazoxan, mirtazapine, yohimbine.
The composition comprises lOOmg of Pentosan polysulfate sodium in combination with , 0.2 or 0.4mg tamsulosin hydrochloride or 4mg or 8mg silodosin or 25mg naftopidil in admixture with pharmaceutically acceptable excipients.
The pharmaceutically acceptable excipients may include fillers/diluents which can be used include calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, magnesium stearate , cross carmellose sodium, powdered cellulose, dextrates, dextrin, dextrate, dextrose, fructose, kaolin, lacticol, lactose anhydrous, lactose monohydrate, maltodextrin, maltose, mannitol, sorbitol, starch, corn starch, potato starch, modified pregelatinised starch, tapioca starch, wheat starch, sucrose, compressible sugar and confectioner's sugar. The composition of pentosan polysulfate sodium and alpha adrenergic blocker having therapeutic activity against benign prostatic hyperplasia, the composition, comprising 100 mg of Pentosan polysulfate sodium in combination with 0.5mg dutasterideor 5mg finasteride, 0.2 or 0.4mg tamsulosin, 4mg or 8mg silodosin or 25mg naftopidil or 10 mg alfuzosin and 10% w/w to 40% w/w of fillers/diluents based on the total weight of the formulation
The composition can be in the form of a sustained release tablet in tablet or tablet in capsule comprising 200 to 300 mg of pentosan polysulfate sodium in combination with 0.2 or 0.4 mg tamsulosin hydrochloride or 8mg or 16mg silodosin or 75mg naftopidil in admixture with pharmaceutically acceptable excipients.
The pharmaceutically acceptable excipients also include retardents, lubricants and glidants which do not interfere with the desired activity of pentosan polysulfate sodium. Also, fillers such as calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, powdered cellulose, dextrates, dextrin, dextrate, dextrose, fructose, kaolin, lacticol, lactose anhydrous, lactose monohydrate, maltodextrin, maltose, mannitol, sorbitol, starch, corn starch, potato starch, modified pregelatinised starch, tapioca starch, wheat starch, sucrose, compressible sugar and confectioner's sugar.may be utilized if desired to adjust the size of the dosage form. Further ingredients such as carriers may be necessary for solubilisation or enhanced drug delivery. Examples of retardents are methycellulose, hydroxyethyl cellulose, hydroxypropylme hyl cellulose, sodium carboxymethyl cellulose, carboxypolymethylene, galactomannose and sodium alginate. Examples of the lubricants are stearic acid, stearic acid salts, stearic acid derivatives, talc, polyethylene glycols, surfactants and waxes. The glidants and flow promoters which can be include silica derivatives, talc and corn starch. Optionally colors which can be added include dyes and lakes commonly used in pharmaceutical compositions and optionally, natural and artificial sweeteners can also be added.
There is provided a composition having therapeutic activity against benign prostatic hyperplasia, the formulation being a sustained release tablet in tablet or tablet in capsule comprising 200 to 300mg of Pentosan polysulfate sodium in combination with 0.2 or 0.4 mg tamsulosin hydrochlorideor 8mg or 16mg silodosin or 75mg naftopidil or alfuzosin lOmg ,50%w/w to 80%w/w of retardents based on the total weight of the composition, 0.5%w/w to 3%w/w of lubricants based on the total weight of the composition and optionally l%w/w to 3%w/w of glidants and flow promoters and pharmaceutically acceptable carriers and other excipients based on the total weight of the composition.
The sustained release tablet/capsule of the invention comprising 200 to 300mg of pentosan polysulfate sodium releases the active ingredient i.e. pentosan polysulfate sodium steadily over the course of the day with the other drug in combination and maintains a steady level of the drug in the blood stream.
Based on its properties, as found out, the use of PPS in the treatment of benign prostatic hyperplasia is ideal. The pharmaceutical composition of the invention caused regression of scarring and regression of established and proliferative lesions of prostatic tissue. Prostate gland growth is modulated by endocrine, neuroendocrine, paracrine, autocrine, intracrine and extracellular matrix factors and cell-cell interactions. The composition affected mainly extracellular matrix regulation. The composition also inhibited complement activation, antagonized growth factor binding and inhibited DNAse activity while simultaneously displaying a very low incidence of side effects. EXAMPLES
The following examples are illustrative of the invention but not limitative of the scope thereof
Example 1 The mouse embryonic fibroblasts cell line (NIH3T3) was obtained from National Centre for Cell Science (NCCS), Pune and grown in Dulbecco's modified eagle's medium (DMEM) containing 10% fetal bovine serum (FBS). All cells were maintained at 370C, 5% C02, 95% air and 100% relative humidity. Maintenance cultures were passaged weekly and the culture medium was changed twice a week. Cell treatment procedure :-
The monolayer cells were detached with trypsin-ethylene diamine tetra acetic acid (EDTA) to make single cell suspensions and viable cells were counted using a hemocytometer and diluted with medium with 5% FBS to give final density of 1x105 cells/ml. ΙΟΟμΙ of cell suspension was seeded into each of the 96-well plates at plating density of 10,000 cells / well and incubated to allow for cell attachment at 370C, 5% C02, 95% air and 100% relative humidity. After 24 hours the cells were treated with serial concentrations of the extracts. The extracts were initially dissolved in dimethylsulfoxide (DMSO) and further diluted in serum free medium to produce five concentrations. ΙΟΟμΙ of each concentration was added to the plates to obtain final concentrations of 100 mg pentosan polysulfate sodium , 0.2 mg tamsulosin hydrochloride and 0.4 mg tamsulosin hydrochloride, 1:250, 1 :500, 1:1000. The final volume in each well was 200 μΐ and the plates were incubated at 370C, 5% C02, 95% air and 100% relative humidity for 48h. The medium containing no sample served as control. Triplicate was maintained for all concentrations was added. After 48 hours of incubation, 15μ1 of 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) (5mg/ml) in phosphate buffered saline (PBS) was added to each well and incubated at 370C for 4 hours. The medium with MTT was then flicked off and the formed formazan crystals were solubilized in ΙΟΟμΙ of DMSO and then the absorbance was measured at 570 nm using micro plate reader. The % cell inhibition was determined using the following formula:
% cell Inhibition = 100- [Asample/Acontrol] xlOOThe dilution of pentosan polysulfate sodium and tamsulosin hydrochloride were prepared in the ratio of 1 :250, 1 :500 and 1 : 1000 and results are given below in table 1
Table 1
Figure imgf000010_0001
From the results of Table 1 and Figure 1 it may be concluded that dilution 1 :250 has maximum amount of inhibition of 99% which further directs us to take the combination to preclinical and clinical trial. Pentosan polysulfate sodium and tamsulosin hydrochloride do not inhibit the cell in terms of percentage as seen in the absorbance as compared to the combination of pentosan polysulfate sodium and tamsulosin hydrochloride in the ratio. The invitro studies show that a combination of pentosan polysulfate sodium and tamsulosin hydrochloride in certain percentage shows the benefit on the fibroblastic growth cells which are also the major cause of the LUTS or Bladder outlet obstruction with or without BPH.
Table 2
Dissolution for Pentosan Polysulfate sodium 100 mg capsules
Figure imgf000011_0001
Method of capsule preparation
Tamsulosin hydrochloride is granulated with excipients and tablets are made after coating of tamsulosin hydrochloride to prepare a modified or sustained release tablet.
In next step Pentosan Polysulfate sodium has been dry mixed in blender and tablet and pentosan polsyufalte sodium mixture are added simultaneously in the machine where tablet in capsule are added adjusting the weight of Pentosan Polysulfate mixture for the proposed dosage. Each dose will comprise of a capsule in which, blend of Pentosan polysulfate sodium with excipient along with the tablet of either 0.2 mg or 0.4 mg tamsulosin hydrochloride will be made available (tablet in capsule form).

Claims

Claims:-
1. A composition for use in treatment of bladder outlet obstruction and/or lower urinary tract symptoms comprising pentosan polysulfate sodium and an alpha adrenergic blocker.
2. The composition as claimed in claim 1, wherein the alpha adrenergic blocker is selected from a group consisting of tamsulosin hydrochloride, silodosin, alfuzosin, terazosin, prazosin, doxazosin, phenoxybenzamine, phentolamine, tolazoline, trazodone, atipamezole, idazoxan, mirtazapine and/oryohimbine.
3. The composition as claimed in clajm 1, wherein 100 mg-300 mg of pentosan polysulfate sodium in combination with , 0.2 or 0.4mg tamsulosin and/or 4mg or 8mg silodosin and/or 25mg naftopidil in admixture with pharmaceutically acceptable excipients.
4. The composition as claimed in claim 1 wherein it is formulated as a tablet in capsule comprising a capsule containing blend of pentosan polysulfate sodium with excipients along with the tablet of 0.2mg or 0.4 mg tamsulosin hydrochloride.
5. The composition as claimed in claim 1 , wherein the pentosan polysulfate sodium and alpha adrenergic blocker are mixed in the ratio of 1 :250 to 1 : 1000 per dose.
6. The composition as claimed in claim 1, wherein it is administered as a lOOmg
capsule/tablet dosage of once a day, twice a day or thrice a day.
7. The composition as claimed in claim 1, administered as a 0.2 mg tablet/capsule or 0.4 mg tablet/capsule once a day, twice a day or thrice a day.
PCT/IN2016/000148 2015-06-12 2016-06-09 A composition comprising pentosan polysulfate sodium for use in treatment of bladder outlet obstruction and/or lower urinary tract symptoms WO2016199161A2 (en)

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WO2020001852A1 (en) 2018-06-27 2020-01-02 Nextraresearch S.R.L. Compositions for oral administration of pentosan polysulfate in form of nanoparticles with improved intestinal absorption

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