ZA200106888B - Effer vescent laxatives. - Google Patents
Effer vescent laxatives. Download PDFInfo
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- ZA200106888B ZA200106888B ZA200106888A ZA200106888A ZA200106888B ZA 200106888 B ZA200106888 B ZA 200106888B ZA 200106888 A ZA200106888 A ZA 200106888A ZA 200106888 A ZA200106888 A ZA 200106888A ZA 200106888 B ZA200106888 B ZA 200106888B
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- effervescent
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- 239000008141 laxative Substances 0.000 title description 26
- 229940125722 laxative agent Drugs 0.000 title description 8
- 229920001223 polyethylene glycol Polymers 0.000 claims description 35
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 34
- 239000000203 mixture Substances 0.000 claims description 34
- 239000002202 Polyethylene glycol Substances 0.000 claims description 32
- 238000009472 formulation Methods 0.000 claims description 27
- 235000015165 citric acid Nutrition 0.000 claims description 11
- 206010010774 Constipation Diseases 0.000 claims description 8
- 230000008878 coupling Effects 0.000 claims description 8
- 238000010168 coupling process Methods 0.000 claims description 8
- 238000005859 coupling reaction Methods 0.000 claims description 8
- 229920002562 Polyethylene Glycol 3350 Polymers 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- 230000003204 osmotic effect Effects 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- 206010056325 Faecaloma Diseases 0.000 claims description 3
- 208000008415 Fecal Impaction Diseases 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 239000000796 flavoring agent Substances 0.000 claims description 3
- 235000011090 malic acid Nutrition 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical class OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- 239000004150 EU approved colour Substances 0.000 claims description 2
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 claims description 2
- 235000011037 adipic acid Nutrition 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Chemical class OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 2
- RRPFCKLVOUENJB-UHFFFAOYSA-L disodium;2-aminoacetic acid;carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O.NCC(O)=O RRPFCKLVOUENJB-UHFFFAOYSA-L 0.000 claims description 2
- 239000001630 malic acid Chemical class 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims 1
- 239000001361 adipic acid Substances 0.000 claims 1
- 238000004040 coloring Methods 0.000 claims 1
- 238000005056 compaction Methods 0.000 claims 1
- 230000002550 fecal effect Effects 0.000 claims 1
- 235000003599 food sweetener Nutrition 0.000 claims 1
- 239000001530 fumaric acid Substances 0.000 claims 1
- 239000003765 sweetening agent Substances 0.000 claims 1
- 239000011975 tartaric acid Substances 0.000 claims 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 26
- 230000002475 laxative effect Effects 0.000 description 18
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- 235000017557 sodium bicarbonate Nutrition 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 230000002378 acidificating effect Effects 0.000 description 7
- 239000003792 electrolyte Substances 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 6
- KJFMBFZCATUALV-UHFFFAOYSA-N phenolphthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2C(=O)O1 KJFMBFZCATUALV-UHFFFAOYSA-N 0.000 description 6
- 239000000835 fiber Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000008143 stimulant laxative Substances 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 239000000799 cathartic agent Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000000112 colonic effect Effects 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- 239000011736 potassium bicarbonate Substances 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- KHOITXIGCFIULA-UHFFFAOYSA-N Alophen Chemical compound C1=CC(OC(=O)C)=CC=C1C(C=1N=CC=CC=1)C1=CC=C(OC(C)=O)C=C1 KHOITXIGCFIULA-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 206010007269 Carcinogenicity Diseases 0.000 description 2
- 235000006693 Cassia laevigata Nutrition 0.000 description 2
- 241000522641 Senna Species 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 229960000503 bisacodyl Drugs 0.000 description 2
- 231100000260 carcinogenicity Toxicity 0.000 description 2
- 230000007670 carcinogenicity Effects 0.000 description 2
- QBPFLULOKWLNNW-UHFFFAOYSA-N chrysazin Chemical compound O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O QBPFLULOKWLNNW-UHFFFAOYSA-N 0.000 description 2
- CEYULKASIQJZGP-UHFFFAOYSA-L disodium;2-(carboxymethyl)-2-hydroxybutanedioate Chemical compound [Na+].[Na+].[O-]C(=O)CC(O)(C(=O)O)CC([O-])=O CEYULKASIQJZGP-UHFFFAOYSA-L 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 2
- 231100000025 genetic toxicology Toxicity 0.000 description 2
- 230000001738 genotoxic effect Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229940124513 senna glycoside Drugs 0.000 description 2
- 239000000021 stimulant Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 206010000060 Abdominal distension Diseases 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 241001116389 Aloe Species 0.000 description 1
- 239000010369 Cascara Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 208000012258 Diverticular disease Diseases 0.000 description 1
- 206010013554 Diverticulum Diseases 0.000 description 1
- 241000556215 Frangula purshiana Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- -1 alkaline earth metal carbonate Chemical class 0.000 description 1
- 235000011399 aloe vera Nutrition 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 208000024330 bloating Diseases 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 229940058505 cascara Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940081970 citrucel Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 229940105597 colyte Drugs 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 229960001577 dantron Drugs 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 239000008151 electrolyte solution Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229940056944 golytely Drugs 0.000 description 1
- 208000024798 heartburn Diseases 0.000 description 1
- 208000014617 hemorrhoid Diseases 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000002262 irrigation Effects 0.000 description 1
- 238000003973 irrigation Methods 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229940042003 metamucil Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 229940060946 miralax Drugs 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229940118092 nulytely Drugs 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940050929 polyethylene glycol 3350 Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000007686 potassium Nutrition 0.000 description 1
- 230000001543 purgative effect Effects 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
Classifications
-
- 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
- A61K31/74—Synthetic polymeric materials
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/10—Laxatives
Description
EFFERVESCENT LAXATIVES
The present invention is directed to a novel over-the-counter (OTC) laxative as an improved, replacement therapy to current stimulant laxatives.
Background of the Invention. I iy
Within the next 2 to 3 years, the Food and Drug Administration (FDA) appears likely to discontinue OTC approval of several current stimulant laxatives. Over the last decade, positive carcinogenicity and/or genotoxicity results have resulted in FDA banning danthron (mid-1980’s) and in 1997, the FDA delisted phenolphthalein as an
OTC laxative due to safety issues.
Specifically, in June 1998, the FDA has continued to pressure the OTC stimulant laxative category, reclassifying remaining approved stimulants: senna, cascara, aloe, bisacodyl, from Category I (safe and effective) to Category III (more data needed), and : requiring manufacturers to provide updated carcinogenicity and genotoxicity evaluations for these laxative actives. Failure to meet this mandate, and/or prove safety will result in further delisting of laxative actives from the tentative final monographs (TFM), (Fed. Reg. 63: 33592-33595, June 19, 1998). Indeed, in a recent review of scientific literature, van Gorkom et al., concluded that anthranoid laxatives, which include the active moieties in senna extracts, and the chemical laxatives phenolphthalein bisacodyl, can have a potential role in both promotion and initiation of tumorgenesis, and may be associated with increased risk for colorectal cancer (van
Gorkom, B.A.P.; de Vries, E.G.E.; Karrenbeld, A.; Kleibeuker, J.H. Anthranoid laxatives and their potential carcinogenic effects. Alimentary Pharmacology &
Therapeutics, Vol. 13: pp. 443-452, 1999. Hence the potential for further delistings are strong. -
Hence, there is a strong potential for dramatic change to this segment of the OTC laxative market over the next several years. If the events which followed the FDA action to ban phenolphthalein recur, any FDA action will be followed by similar delisting in other countries.
While bulk fiber products, such as Metamucil® and Citrucel®, are presently available, a large number of individuals have found that these products have unacceptable product aesthetics (e.g., taste, viscosity, volume etc). Therefore new alternative therapies to these bulk fiber laxatives based on ease of use and aesthetic properties are desired.
One group of the newer alternative therapies for bowel cleansing prior to colonoscopic exam or GI surgery are the prescription isosmotic bowel evacuant solutions, such as
Golytely® and Nulytely® (Braintree Labs, Braintree, MA, USA). Similar prescription products are marketed in the US by Colyte® by Schwarz Pharma, and in Europe an osmotic laxative by Movicol® (Norgine, Lmtd., Middlesex, UK). Recently, a new laxative containing only polyethylene glycol 3350 NF, has also been introduced in the
US (Miralax®, Braintree Labs, Braintree, MA, USA), where it is available only by prescription.
All of these products contain polyethylene glycol (PEG) as the active ingredient. In most products, the PEG is mixed with various salts to provide a laxative action with osmotic balance. This is required when the products are used in the high volumes (2-4
L) required for colonic purgation and cleansing. In high volume these PEG-containing agents provide excellent colonic cleansing prior to GI surgical or colonoscopic procedures. They neither stimulate water and electrolyte secretion into the GI tract, nor do the products result in significant water and electrolyte absorption; essentially, the volume of ingested liquid simply passes through the GI tract. For this indicated usage as a bowel evacuant, patients are instructed to drink 2 to 4 liters over several hours.
US Patent 5,710,183, Halow, G., discloses a PEG composition with a fiber bulking agent for clinical treatment of constipation and/or diarrhea.
US 5,124,144, Castagnola et al., discloses what is a PEG/electrolyte product for use as a cathartic laxative.
WO 87/00754, Fordtran, J., discloses a low-sodium laxative and lavage solution containing PEG with various electrolytes added such as sodium, potassium, chloride and bicarbonate.
DE 3807712, Deyhle et al., discloses a laxative formulation also containing electrolytes, PEG, alkali hydrogen carbonate and citric acid.
RU 2111741, Chumak et al. discloses use of a reduced lavage volume, 2 liters, of PEG with an electrolyte solution. The electrolyte mixture contains sodium bicarbonate and citric acid which may be in an amount sufficient to provide effervescence.
WO 98/43654, Jacob et al., is directed towards a non-aqueous colonic purgative _ __ containing magnesium salts and potentially polyethylene glycol.
JP 4198126 OTSUKA PHARM CO LTD discloses a liquid preparation of PEG and electrolytes along with o~aminoacid. for colon irrigation. The ot-amino acids are used as antioxidants to stabilize PEG and prevent formation of formaldehyde. This was an attributed problem of PEG-based laxatives early in their product life. Use of the highly purified PEG's today overcome these issues. The levels of product 0.01 % range (0.1 g/L) are also too low to provide any appreciable effervescence.
The present invention is directed to a pharmaceutical formulation comprising polyethylene glycol (PEG) 3350, and a pharmaceutically acceptable effervescent coupling system: : - Another aspect of the present invention is a method of administering to a mammal, an effective amount of the above noted pharmaceutical formulation for the treatment of constipation, or for the treatment of fecal impaction, in a mammal in need thereof.
The present invention is directed towards an effervescent formulation of an osmotic bowel evacuant solution, such as a polyethylene glycol based product. These formulations provide for an acceptable level of laxative efficacy, with superior safety advantages over current stimulants, which are under FDA review for safety concerns.
Further, these formulations should be safe and appropriate for use in pediatric constipation. )
The effervescent/PEG osmotic formulation offers an alternative that provides for a new, and safe, product as a replacement to the current technologies. The PEG based osmotic formulations have proven to be both safe and highly physician recommended.
However, an effervescent/PEG based formulation, for use as an OTC laxative would require consumption of a much smaller volume, such as one or two 4-8 oz doses over a 24 hour period. Several published studies have shown utility of the PEG-based technology for use as a laxative with low-volume dosage. E. Corazziari, D. Badiali,
F.L. Habib, G. Reboa, G. Pitto, G. Mazzacca, F. Sabbatini, R. Galeazzi, Te, Cilluffo, I.
Vantini, E. Bardelli, F. Baldi. Small volume isosmotic polyethylene glycol electrolyte balanced solution (PMF-100) in treatment of chronic nonorganic constipation.
Digestive Diseases & Sciences, Vol. 41: 1636-1642, 1996.
J.A. DiPalma, P.H. deRidder, R.C. Orlando, B. E. Kolts, M.v.B. Cleveland. A randomized placebo-controlled, multicenter study of the safety and efficacy of
Braintree 851 laxative. Gastroenterology, Vol. 112: A722, 1997. P. Culbert, H. Gillett, A. Ferguson. Highly effective oral therapy (polyethylene glycol/electrolyte solution) for faecal impaction and severe constipation. Clinical
Drug Investigation, Vol. 16: 355-360, 1998.
A. Attar, M. Lemann, A. Ferguson, M. Halphen, M.-C. Boutron, B. Flourie, E. Alix,
M. Salmeron, F. Guillemot, S. Chaussade, A.-M. Menard, J. Moreau, G. Naudin, M.
Barthet. Comparison of a low dose polyethylene glycol electrolyte solution with lactulose for treatment of chronic constipation. Gut, Vol. 44: 226-230, 1999.
Therefore, one aspect of the present invention is the use of an osmotic acting composition containing polyethylene-glycol based systems, ( preferably, PEG 3350
NF, or PEG 4000 NF, in combination with an effervescent coupling system, which is diluted with a suitable volume of a liquid, such as water, or juice.
The effervescent couple comprises a basic ingredient and an acidic ingredient, the basic ingredient liberating carbon dioxide when it and the acidic ingredient are - contacted with added water.
The amount of the effervescent couple is selected at a level sufficient to cause a "fizzy reaction” without itself causing discomfort in the patients mouth.
The effervescent couple typically comprises citric acid or sodium hydrogen citrate and sodium bicarbonate, but other physiologically acceptable acid/alkaline or alkaline earth metal carbonate mixtures may be used, for example tartaric, adipic, fumaric or malic acids, and sodium, potassium or calcium (bi)carbonates or sodium glycine carbonate.
In general it has been found that preferred taste characteristics are exhibited when the relative proportions of the components of the effervescent couple on a chemical molecular equivalent basis are in the range of 3:1 to 3:4, more preferably about 1410 1.9:1, expressed as the ratio of molecular equivalents of the basic component to the © acidic component. where the basic and acid components are sodium bicarbonate (NaHCO3) and citric acid, respectively. However, it is possible to utilize much less bicarbonate and acid than a number of well known effervescent systems. The examples herein will demonstrate usefulness of high and low levels of effervescent ~ coupling reagents. In terms of a preferred combination of sodium bicarbonate and citric acid, these values represent on a weight basis, a range from 3:1 to 0.6-0.8:1, preferably approximately 1:1 expressed as the ratio of basic to acidic component.
However, in some formulations, the choice of flavouring agents may result in optimization of taste characteristics when there is an excess of acidic component, for example, on a chemical molecular equivalent basis of from about 11:3 to 4:3 : expressed as the ratio of acidic to basic component. For the combination of citric acid and sodium bicarbonate this may represent 5:1 to 1:1 on a weight basis. }
The weight of the acidic component in the formulation may be in the range 7% to . 31%, preferably 9% to 18%, by weight.
The weight of the basic component in the formulation may be in the range 7% to 32%, preferably 9% to 18%, by weight.
Preferred combinations comprise sodium bicarbonate with citric acid (or sodium hydrogen citrate) or malic acid in a weight ratio of 2: 1 to 1:1.
Other preferred combinations may substitute potassium bicarbonate for part or all of the sodium bicarbonate as the basic component of the effervescent couple. To maintain molecular equivalence, substitution of potassium bicarbonate for sodium bicarbonate is at a ratio of approximately 1.2:1. Potassium bicarbonate can be used with any of the above acid components.
The preferred level of the coupling agents, preferably bicarbonate and citrate for an effervescence mixture, is about 2.3 gram NaHCO3 (sodium bicarbonate) and 2.2 gram citric acid. This dose provides very significant ANC (acid neutralizing capacity) approximately 20 mEq. However, the levels can be reduced by a factor of 4-5 and still provide some degree of effervescence (e.g., 0.5 g NaHCO3 and 0.4 g citric acid).
It is recognized that additional excipients may be added to the formulation, such as flavouring agents, colouring agents, sweetning agents, antioxidants, and other well known agents for stability and packaging considerations.
A preferred PEG for use herein is PEG 3350, a nonabsorbable and inert polymer of about 3,000 molecular weight. Generally, the range of PEG 3350 for a 125 to 240 ml reconstitution in liquid will be from a about 5 grams to about 30 gms, preferably from about 10 to about 20 gms, more preferably 13 to 17 grams. Treatment may be : once or more daily, up to 4 times daily, but preferably once daily.
In contrast to bulk-fibers, the resulting effervescent/PEG-based formulations when made into a liquid dosage, are non-viscous and are optimally be provided to consumers as either bulk powder, or preferably as single dose powder sachets, for dissolution in a suitable liquid, such as water or juice. The product would dissolve rapidly (within seconds) and completely, and does not thicken on standing.
Based on volume consumed (e.g., one or two 4-8 oz doses), performance attributes would be consistent with those presently desired by stimulant laxative users (rapid action, clean-out), but without the negative side-effects of cramping and gas, and without systemic exposure potentially harmful agents.
The required dosage for use as a laxative may be one which is equivalent to the “minimally effective dose”, i.e., one that requires 2 to 3 days treatment before significant effect, having a similar onset and action to the bulk fiber based laxatives.
Or the dosage could be increased to be equivalent in action to the current stimulant based products, having an earlier onset of action (a few hours to overnight).
The present invention is useful as primary treatment for both occasional and chronic constipation, and for the treatment of fecal impaction (at a higher dose). Another aspect of the present invention is the treatment of upper GI symptoms associated with such constipation, such as heartburn or bloating. Suitably, the composition herein may also be used for other constipation related disorders, such as irritable bowel syndrome, diverticular disease, and hemorrhoids.
METHODS OF PREPARATION
The following examples illustrates the invention but is not intended to limit the scope thereof. All parts and percentages are by weight unless otherwise indicated. _ . EXAMPLE 1 So Co
A preferred example provides as sachet for reconstitution in 240 ml water for use as laxative.
PEG System: 17.0 g polyethylene glycol (PEG) 3350 NF
Effervescent Coupling Reagents: 1.50 g NaHCO3 1.00 g Citric Acid
The PEG solution is combined with effervescent coupling system and packaged as a sachet to be added to a 8 ounce glass of water.
EXAMPLE 2
Another preferred examples provides as sachet for reconstitution in 240 ml water for use as laxative.
PEG System: 17.0 g polyethylene glycol (PEG) 3350 NF
Effervescent Coupling Reagents: 2.32 g NaHCO3 2.18 g Citric Acid -
The PEG solution is combined with effervescent coupling system and packaged as a sachet to be added to a 8 ounce glass of water.
EXAMPLE 3
Another preferred examples provides as sachet for reconstitution in 125 - 180 ml water for use as laxative.
Claims (16)
1. ~ A pharmaceutical formulation comprising an osmotic amount of polyethylene glycol (PEG) 3350, or PEG 4000, and a pharmaceutically acceptable effervescent coupling system.
2. The formulation according to Claim 1 wherein the effervescent couple comprises about 10 to about 30% of the total weight of the formulation.
3. The formulation according to Claim 1 wherein the effervescent couple comprises an acid component selected from citric acid, tartaric acid, adipic acid. fumaric acid, malic acid, or acid salts thereof, or mixtures thereof.
4. The formulation according to Claim 1 wherein the effervescent couple comprises an alkaline component selected from sodium, potassium or calcium (bi) carbonates or sodium glycine carbonate.
S.
The formulation according to any one of Claims 1 to 4 which further comprises one or more flavoring, colouring or sweetening agents.
7. The formulation according to Claim 1 wherein the PEG is present in an amount of 7.5 to 30 grams per unit dose.
8. The formulation according to Claim 1 wherein the PEG is present in an amount of 10 to 20 grams per unit dose.
9. A formulation according to any of claims 1 to 8, for use in treating constipation in a mammal.
10. A formulation according to any of claims 1 to 8, for use in treating fecal impaction in a mammal.
11. A formulation according to any one of claims I to 6 wherein the formulation is in a unit dose sachet. : -11- AMENDED SHEET
12. Use of a formulation according to any of claims 1 to 8 for treating constipation.
13. Use of a formulation according to any of claims 1 to 8 for treating fecal } compaction.
14. A formulation according to claim 1, substantially as herein described and exemplified.
15. A formulation according to claim 9 or 10, substantially as herein described and exemplified.
16. A use according to claim 12 or 13, substantially as herein described and exemplified. AMENDED SHEET -11A-
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US12108999P | 1999-02-22 | 1999-02-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200106888B true ZA200106888B (en) | 2002-09-27 |
Family
ID=22394460
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200106888A ZA200106888B (en) | 1999-02-22 | 2001-08-21 | Effer vescent laxatives. |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP1154765A4 (en) |
| JP (1) | JP2002537248A (en) |
| KR (1) | KR20010102323A (en) |
| CN (1) | CN1341016A (en) |
| AU (1) | AU3604600A (en) |
| BR (1) | BR0008385A (en) |
| CA (1) | CA2362355A1 (en) |
| CZ (1) | CZ20013043A3 (en) |
| EA (1) | EA003064B1 (en) |
| HK (1) | HK1043046A1 (en) |
| HU (1) | HUP0105351A3 (en) |
| PL (1) | PL349360A1 (en) |
| WO (1) | WO2000048585A1 (en) |
| ZA (1) | ZA200106888B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6048901A (en) * | 1999-04-20 | 2000-04-11 | Braintree Laboratories, Inc. | Method of reducing intestinal gas, cramping and anorectal irritation |
| DE102004023288A1 (en) * | 2004-05-11 | 2005-12-15 | Stefan Spiess | Macrogol preparation |
| JP5020096B2 (en) * | 2004-12-30 | 2012-09-05 | ギブン イメージング リミテッド | Kit for in vivo testing |
| CN101002832B (en) * | 2006-09-02 | 2011-01-05 | 江西农业大学 | Granulated quickly dissolving medicine for relaxing bowel |
| CN102573499B (en) * | 2009-04-21 | 2016-03-30 | 戴尔·R·巴赫威茨 | Colonic irrigation system |
| MX346936B (en) | 2011-01-28 | 2017-04-05 | A Shaver William | Method, composition and package for bowel cleansing. |
| JP2014532725A (en) * | 2011-11-06 | 2014-12-08 | エスエスブイ セラピューテクス，リミティド ライアビリティ カンパニー | Concentrated prunes and prebiotic formulations as laxatives and food supplements |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB942743A (en) * | 1959-05-22 | 1963-11-27 | Welloome Foundation Ltd | Oestrogen preparations and the manufacture thereof |
| GB1518364A (en) * | 1976-05-05 | 1978-07-19 | Beecham Group Ltd | Pharmaceutical composition |
| US4093710A (en) * | 1976-07-07 | 1978-06-06 | Sandoz, Inc. | Rapid dissolving effervescent granules |
| JPH01283222A (en) * | 1988-05-10 | 1989-11-14 | Tokai Kapuseru Kk | Soft capsule agent of sodium picosulfate |
| IT1229568B (en) * | 1989-04-17 | 1991-09-04 | Giuliani Spa | PHARMACEUTICAL COMPOSITION FOR ORAL USE SUITABLE FOR USE IN GASTRO-INTESTINAL WASHING, IN PARTICULAR FOR DIAGNOSTIC USE, OR AS A CATHARTIC LAXATIVE. |
| US4946939A (en) * | 1989-05-30 | 1990-08-07 | The Dow Chemical Company | High purity polyether polyols |
| US5710183A (en) * | 1995-07-14 | 1998-01-20 | Halow; George M. | Laxative/antidiarrheal composition comprising polyethylene glycol and fiber bulking agent |
| US6048901A (en) * | 1999-04-20 | 2000-04-11 | Braintree Laboratories, Inc. | Method of reducing intestinal gas, cramping and anorectal irritation |
-
2000
- 2000-02-22 AU AU36046/00A patent/AU3604600A/en not_active Abandoned
- 2000-02-22 WO PCT/US2000/004701 patent/WO2000048585A1/en not_active Application Discontinuation
- 2000-02-22 PL PL00349360A patent/PL349360A1/en not_active Application Discontinuation
- 2000-02-22 EP EP00914689A patent/EP1154765A4/en not_active Withdrawn
- 2000-02-22 HU HU0105351A patent/HUP0105351A3/en unknown
- 2000-02-22 CN CN00804156A patent/CN1341016A/en active Pending
- 2000-02-22 CA CA002362355A patent/CA2362355A1/en not_active Abandoned
- 2000-02-22 BR BR0008385-2A patent/BR0008385A/en not_active IP Right Cessation
- 2000-02-22 EA EA200100785A patent/EA003064B1/en not_active IP Right Cessation
- 2000-02-22 JP JP2000599377A patent/JP2002537248A/en not_active Withdrawn
- 2000-02-22 CZ CZ20013043A patent/CZ20013043A3/en unknown
- 2000-02-22 KR KR1020017010689A patent/KR20010102323A/en not_active Application Discontinuation
-
2001
- 2001-08-21 ZA ZA200106888A patent/ZA200106888B/en unknown
-
2002
- 2002-04-12 HK HK02102792.4A patent/HK1043046A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EA003064B1 (en) | 2002-12-26 |
| EP1154765A1 (en) | 2001-11-21 |
| CA2362355A1 (en) | 2000-08-24 |
| BR0008385A (en) | 2002-01-29 |
| PL349360A1 (en) | 2002-07-15 |
| KR20010102323A (en) | 2001-11-15 |
| WO2000048585A1 (en) | 2000-08-24 |
| AU3604600A (en) | 2000-09-04 |
| CN1341016A (en) | 2002-03-20 |
| HUP0105351A3 (en) | 2004-06-28 |
| HK1043046A1 (en) | 2002-09-06 |
| EA200100785A1 (en) | 2002-04-25 |
| EP1154765A4 (en) | 2004-12-01 |
| HUP0105351A2 (en) | 2002-05-29 |
| CZ20013043A3 (en) | 2001-11-14 |
| JP2002537248A (en) | 2002-11-05 |
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