IES86031Y1 - A solid formulation for oral administration comprising polyethylene glycol and mannitol - Google Patents
A solid formulation for oral administration comprising polyethylene glycol and mannitolInfo
- Publication number
- IES86031Y1 IES86031Y1 IE2011/0480A IE20110480A IES86031Y1 IE S86031 Y1 IES86031 Y1 IE S86031Y1 IE 2011/0480 A IE2011/0480 A IE 2011/0480A IE 20110480 A IE20110480 A IE 20110480A IE S86031 Y1 IES86031 Y1 IE S86031Y1
- Authority
- IE
- Ireland
- Prior art keywords
- peg
- solid
- solid formulation
- subject
- mannitol
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 54
- 239000007787 solid Substances 0.000 title claims abstract description 45
- 239000002202 Polyethylene glycol Substances 0.000 title claims abstract description 41
- 229920001223 polyethylene glycol Polymers 0.000 title claims abstract description 41
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 title claims abstract description 12
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 title claims abstract description 12
- 239000000594 mannitol Substances 0.000 title claims abstract description 12
- 235000010355 mannitol Nutrition 0.000 title claims abstract description 12
- 238000009472 formulation Methods 0.000 title claims description 29
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 14
- 208000008665 Gastrointestinal Disease Diseases 0.000 claims abstract description 8
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 7
- 230000002496 gastric Effects 0.000 claims abstract description 4
- 230000036541 health Effects 0.000 claims abstract description 3
- 239000003814 drug Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 229960001855 mannitol Drugs 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 7
- 206010010774 Constipation Diseases 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000003792 electrolyte Substances 0.000 description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000007909 solid dosage form Substances 0.000 description 4
- 206010056325 Faecaloma Diseases 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- 230000037406 food intake Effects 0.000 description 3
- 201000002146 gastrointestinal system disease Diseases 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 239000001103 potassium chloride Substances 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000010030 laminating Methods 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 210000001072 Colon Anatomy 0.000 description 1
- 235000014755 Eruca sativa Nutrition 0.000 description 1
- 244000024675 Eruca sativa Species 0.000 description 1
- 206010016766 Flatulence Diseases 0.000 description 1
- 206010017367 Frequent bowel movements Diseases 0.000 description 1
- 235000016257 Mentha pulegium Nutrition 0.000 description 1
- 240000006217 Mentha pulegium Species 0.000 description 1
- 229920002562 Polyethylene Glycol 3350 Polymers 0.000 description 1
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000000112 colonic Effects 0.000 description 1
- 238000007723 die pressing method Methods 0.000 description 1
- 230000001079 digestive Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 230000036449 good health Effects 0.000 description 1
- 235000001050 hortel pimenta Nutrition 0.000 description 1
- 230000000968 intestinal Effects 0.000 description 1
- 239000008141 laxative Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 235000006678 peppermint Nutrition 0.000 description 1
- 235000015132 peppermint Nutrition 0.000 description 1
- 235000007735 peppermint Nutrition 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 230000001543 purgative Effects 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 235000019615 sensations Nutrition 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000009475 tablet pressing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
Abstract
ABSTRACT The invention relates to solid formulations for oral administration comprising polyethylene glycol, mannitol, magnesium stearate and flavouring, and to use of the formulations for treating or preventing gastrointestinal disorders or maintaining gastrointestinal health in a subject.
Description
A SOLID FORMULATION FOR ORAL ADMINSTRATION COMPRISING POLYETHYLENE GLYCOL AND MAN NITOL The present invention relates to solid formulations, particularly to chewable or suckable solid formulations (for example tablets), comprising polyethylene glycol and mannitol.
Polyethylene glycol (PEG) has been shown to have beneficial effects in healthy subjects in low doses. For example, Hudziak et al. (Hudziak, H. et al., Gastroenterol. Clin. Biol., 1996, 20, 418-423) showed that healthy subjects taking 20g of PEG 4000 per day (without accompanying electrolytes) had a significantly increased stool frequency. Mean stool weight was also shown to be increased. In a similar study, Flourie et al. (F lourie, B et al., Gastroenterol. Clin. Biol, 1994, 18, A108) showed that stool weight and stool frequency was significantly increased in healthy subjects taking low doses of PEG with electrolytes (sodium chloride, sodium bicarbonate and potassium chloride). Bernier and Donazzolo (Bernier, J-J., and Donazzolo, Y., Gastroenterol. Clin. Biol, 1997, 21, 7-11) reported that low doses of PEG 3350 in the presence of electrolytes (5.9g PEG per day with 146mg sodium chloride, 568mg sodium sulphate, 75mg potassium chloride and mg sodium bicarbonate) led to stool softening in healthy subjects.
In the vast majority of published work regarding PEG-based products for oral ingestion, the PEG is taken as a solution/suspension in water. Taking compositions as solutions or suspensions is in many cases less convenient than taking a solid composition, as solutions and suspensions require the subject to carry a larger quantity of composition with them, or else require the subject to make use of a vessel and a source of liquid. Particularly for compositions that may be taken several times per day and/or at a time of the subject’s choosing, solid compositions offer many advantages to a subject.
Solid PEG products for ingestion in solid form have been described in some patent specifications. For example, in WO2005/ 102364, there is described a solid pharmaceutical composition comprising PEG and electrolytes for treating constipation, faecal impaction, faecal retention, intestinal gas and cramping, flatulence, or for cleansing the colon, wherein the PEG makes up from 80 to 99.5% by weight of the composition. In WO2006/122104, there are described possible ingredient ranges for a solid colonic purgative composition comprising PEG and various other ingredients.
To date, no PEG-based products for ingestion in solid form have reached the market.
There may be several reasons for this. Preparation of solid dosage forms that simultaneously have good structural integrity (ie sufficient hardness to hold together), but yet are comfortably chewable by a subject (ie a hardness that is not so high as to affect the subject’s ease of taking the dosage) is not straightforward. It is known to add excipients to solid dosage forms to assist in achieving satisfactory overall properties. In order for good compliance to be maintained, the subject must not experience discomfort or inconvenience when taking the dosage form. Accordingly, each tablet should be of a size that can be chewed, sucked or swallowed without any discomfort, and it should not be necessary to take more than three tablets per day. Therefore, if an active component is to be taken in quantities of over 500mg per day, for example over lg or over 2g per day (as is the case with PEG), then the total amount of excipients that can be included is limited by the overall size of a tablet, and the number of tablets that might be needed to accommodate the total amount of actives and excipients. In addition, a solid dosage form must have good manufacturing properties (minimal capping or laminating of tablets, or sticking to tableting machinery) and excipients must not impart an unpleasant taste or mouthfeel to the formulation. Fonnulation of a PEG solid dosage form that has good manufacturing properties and good subject compliance is thus difficult.
The present invention provides a solid formulation for oral administration as a solid, comprising: (a) about 82 to 84% w/w (for example 2273.7mg) polyethylene glycol (PEG) having an average molecular weight within the range 3,000 to 4,000 Da; (b) about 14 to 17% w/w (for example 420.75 mg) mannitol; (c) about 0.5% w/W (for example 13.75mg) magnesium stearate; and (d) flavouring.
“% W/w” of a component is understood herein to mean the proportion, as a percentage, that the weight of the component makes up of the total weight of the solid formulation.
Preferably, the solid formulation is chewable and/or suckable. It may be a solid tablet, for example a chewable and/or suckable tablet.
It has surprisingly been found that a solid formulation of the invention is pleasantly chewable or suckable, has good taste, structural integrity and beneficial manufacturing properties. By chewable or suckable is meant herein that the formulation is for oral administration and not to be swallowed whole but chewed or sucked in the mouth so that the first step in the digestive process starts in the buccal cavity. Herein, a powder formulation is not considered suitable for administration as a solid. A formulation of the invention is preferably not effervescent in contact with water.
Formulations of the invention are preferably substantially fi'ee from electrolytes. For example, they are preferably substantially fi'ee from sodium chloride, potassium chloride and sodium bicarbonate. They are preferably substantially fiee from sulphates or phosphates, for example, they are preferably from free sodium sulphate. Formulations of the invention are preferably substantially free fi'om carbonates or bicarbonates. In many instances, flavourings, lubricants and sweeteners may contain small amounts of electrolytes. Such amounts are not considered herein to be “substantial”. Formulations of the invention are preferably substantially free ficm alginates.
It has been found by the present inventors that a solid formulation of the invention is morepalatable than a solid fonnulation comprising PEG and no mannitol, even if flavouring is added. In particular, it has been found that a tablet of the invention has a low requirement for lubricant or lubrication during tablet manufacture. A high level of a lubricant in a tablet generally makes the tablet have an unacceptable taste.
The polyethylene glycol (PEG) for use in solid formulations of the invention has an average molecular weight (for example a weight average molecular weight), in Daltons, within the range 3,000 to 4,000. For example, the PEG may be, or comprise PEG 3,350, PEG 4,000 as defined in national pharmacopoeias. Further examples of suitable PEGS recognized in some national pharmacopoeias include Macrogols, for example Macrogol ,000. Optionally, the PEG used in compositions of the invention may comprise two or more different PEG components. PEG of the relevant molecular weights in a form suitable for use in humans is available commercially.
Typically, solid formulations of dry ingredients are manufactured using dry granulation followed by punching with punch and die equipment. In a punch and die machine, dry ingredients are compressed together. It has surprisingly been found that a solid formulation of the invention has good structural integrity and is convenient to manufacture. Solid formulations of the invention are not susceptible to capping and laminating during punch and die manufacture. Solid formulations that become capped or laminated during die pressing are not suitable for use and they become waste. It has been found by the current inventors that a solid formulation of the invention has good tablet pressing characteristics. Mannitol is commercially available from several suppliers, including Merck, SPI Polyols Inc and Roquette.
It has also surprisingly been found that a solid formulation of the invention is not prone to sticking to punch and die equipment A solid formulation of the invention can be of any convenient size. A tablet should be sufficiently large to provide the desired quantity of PEG to the subject, but not be so large as to be uncomfortable in the mouth, difficult to chew or suck, or difficult to package.
In one embodiment, a tablet of the invention has a mass of 2.75g.
For example, a solid formulation of the invention comprises: (a) 82.7% w/w (for example 2273.7mg) polyethylene glycol (PEG) having an average molecular weight within the range 3,000 to 4,000 Da; (b) 15.3% w/w (for example 420.75 mg) mannitol; (c) 0.5% w/w (for example 13.75mg) magnesium stearate; and (d) 1.5% w/w (for example 41 .8mg) llavouring.
For example, a solid formulation of the invention comprises; (a) 82.9%w/w (for example 2284mg) polyethylene glycol (PEG) having an average molecular weight within the range 3,000 to 4,000 Da; (b) 16.2% w/w (for example 446 mg) mannitol; (c) 0.5% w/w (for example l3.75mg) magnesium stearate; and (d) 0.4% w/w (for example 1 lmg) flavouring.
The solid formulations of the invention can be taken on their own as presented and chewed or sucked by a subject. It is not necessary for a subject to take water or another drink with the solid formulation. Some subjects may wish to drink water or another fluid with or soon after taking a solid formulation of the invention so as to facilitate the intake.
The convenient packaging and the lack of a need to take water or another drink greatly increases the convenience of the solid formulations to subjects in comparison with other ' forms of PEG-based products currently on the market.
The number of solid formulations (and thus the total mass of PEG) that a subject takes depends on the subject’s perceived needs.
In one embodiment, a solid formulation of the invention may be used as a PEG-based composition to prevent gastrointestinal disorders. The composition may be particularly beneficial for maintenance of good health, in particular maintenance of good gastrointestinal health. It may, for example, prevent dehydration of the stool, soften the stool for ease of defaecation, prevent constipation and allow regular gastrointestinal transit. The solid formulation of the invention may be used to promote stool sofiening, increase stool weight and/or increase stool frequency in healthy subjects. Improvement of those features may lead to an increased sensation of well-being.
The invention thus provides a method of preventing gastrointestinal disorders in a healthy subject, for example sofiening the stool, increasing stool weight and/or increasing stool frequency, preventing dehydration of the stool, softening the stool for ease of defaecation or preventing constipation in a healthy subject, comprising administering a solid formulation according to the invention. In particular, it provides a method of non- therapeutically preventing gastrointestinal disorders in a healthy subject, for example sofiening the stool, increasing stool weight and/or increasing stool frequency, preventing dehydration of the stool, softening the stool for ease of defaecation or preventing constipation in a healthy subject. For example may be subject of more than 50 years of age, for example more than 60, 65 or 70 years of age.
In an alternative embodiment, a solid formulation of the invention is for use as a medicament. For example, the medicament may be for the treatment of a gastrointestinal disorder, for example constipation, faecal impaction, faecal retention or other gastrointestinal disorder. The medicament may be for therapeutically softening the stool, therapeutically increasing stool weight and/or therapeutically increasing stool frequency in a subject in need thereof. Accordingly, the invention provides a method of therapeutically sofienin g the stool, therapeutically increasing stool weight, therapeutically increasing stool fiequency, or treating constipation, faecal impaction, faecal retention or another gastrointestinal disorder in a subject in need thereof comprising administering a solid formulation of the invention to the subject.
Examples Example: Tablets of the invention The tablets described in Table 1 were prepared by combining the dry ingredients and compressing in a punch and die machine. The machine was a Manesty 16 punch D machine with a standard stainless steel punch and die with flat 22mm diameter and beveled edge with PTFE and vulcalon inserts from I Holland Ltd.
Table 1- Composition of Tablets of the Invention Component Tablets of the invention Unit formula A 5kg bag Unit formula B Skg bag blend blend PEG av, MW 3000- 2284mg (82.9%) 4.155kg 2273.7mg (82.7%) 4.144kg 4000 Mannitol 446mg (16.2%) 0.8lOkg 420.75 mg (15.3%) O.765kg Magnesium 13.75mg (0.5%) 0.025kg l3.75mg (0.5%) 0.025kg Stearate A Flavouring Ilmg (0.4%) 0.020kg 41 .8mg (1.5%) 0.075kg (peppermint) (raspberry-lemon) Total wt 2754.75mg 2749.3mg Table 2 —— Properties of Tablet of the Invention Unit Formula A Unit Formula B Ease of No sticking or capping; good Good weights and hardness Manufacture weight and hardness control; throughout batch good appearance Taste Acceptable taste Acceptable taste Hardness 6.34-9.19kg 8.95—14.29kg
Claims (5)
1. A solid formulation for oral aciministration as a solid, comprising: (a) about 82 to 84% w/w polyethylene glycol (PEG) having an average molecular weight within the range 3,000 to 4,000 Da; (b) about 14 to 17% w/w mannzitol; (c) about 0.5% w/w magnesium stearate; and (d) flavouring.
2. A solid formulation as claimed in claim 1 comprising; (a) about 228-4mg of PEG; (b) about 446mg mannitol; (c) about l3.75.mg magnesium stearate; ((1) about llmg flavou-ring or (a) about 2273.7mg of PEG; (b) about 420.75 mg of mannitol; (c) about l3.'75m.g of magnesium stearate; (<1) about 41 .8:rng flavouring.
3. A solid formulation as claimed in claim 1 or claim 2 in the form of a tablet, preferably in the form of a chewable or suelcable tablet.
4. A solid formulation as claimed in any ofclaims l to 3 for use as a medicament, preferably for use in the treatment or prevention of gastrointestinal disorders in a subject.
5. Use of a solid formulation as claimed in -any of claims ‘l to 3 for non- therapeuticaily maintaining gastrointestinal health in a subject. ANNE RYAN & CO. AGENTS FOR THE APPLICANT
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBUNITEDKINGDOM04/11/20101018648.4 |
Publications (2)
Publication Number | Publication Date |
---|---|
IES86031Y1 true IES86031Y1 (en) | 2012-07-18 |
IE20110480U1 IE20110480U1 (en) | 2012-07-18 |
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