Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-03-19
2001-06-26
Peselev, Elli (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S023000
Reexamination Certificate
active
06251875
ABSTRACT:
The present invention relates to an aqueous laxative syrup which possesses a balance of characteristics including taste and viscosity which makes it palatable to a wide range of individuals.
The disaccharide lactulose (4-&bgr;-D-galatosyl-D-fructose) is known to be pharmacologically active as a laxative. It is 0.5-0.6 times as sweet as sucrose. Lactulose is generally marketed as a syrup because its crystallisation and drying are difficult and costly. When used to treat constipation, it is normally administered in the form of such a syrup.
Lactulose syrups which are presently marketed for the treatment of constipation or portal systemic encephalopathy (PSE) contain 620-740 g/l of lactulose. These syrups also contain about 50 g/l and 100 g/l respectively of lactose and galactose. These two sugars are by-products of the usual synthetic pathway used to produce lactulose. These sugars increase the viscosity of the syrup. Constipation is usually treated by taking 15 ml of lactulose syrup twice daily at the beginning of the treatment. This dosage is reduced according to the patient's needs. For the treatment of PSE, initially, 30-50 ml are taken three times daily, the dosage being subsequently adjusted to produce 2-3 soft stools daily.
It has been noted that patient compliance with lactulose syrups is unsatisfactory. This is firstly because such syrups are very sweet and many patients find it difficult to take a dose of three teaspoons (5 ml each) without feeling nauseous. This effect is greatly aggravated when using lactulose syrups to treat PSE, where a dose of 6-10 teaspoons has to be taken at the beginning of the treatment. In addition, lactulose syrup is relatively viscous. For instance, commercially available lactulose syrups comprising about 670 g/l have a viscosity of 230 mPa.s at 20° C. Both young and elderly patients can find such viscous syrups difficult to swallow. If the concentration of lactulose in the lactulose syrup is reduced to 500 g/l by dilution with water, then the syrup's viscosity in turn reduces to about 75 mPa.s. However, syrups of this concentration are not marketed because their dilution results in patients needing to take large-volume doses. Whilst it has been suggested to mix lactulose syrup with food or drink, medical advice is for patients to take this medicament on its own prior to a meal in order to ensure that its absorption and efficacy are not affected by food ingredients.
In summary, commercially available solutions of lactulose are highly viscous and very sweet and these factors reduce their palatability. The use of more dilute preparations, whilst solving these problems, is not satisfactory because of the need to take large volumes of the diluted solutions to obtain efficacy.
It is also known to treat constipation and PSE with lactitol. This polyol belongs to the same group of laxatives as lactulose. Lactitol (4-&bgr;-D-galactosyl-D-sorbitol) is a disaccharide sugar alcohol produced commercially by the catalytic hydrogenation of lactose. Lactitol crystallises in several anhydrous and hydrous crystalline forms, but it is usually marketed as a powder of its most stable monohydrate form.
The British National Formulary, No. 27 (March 1994) indicates that for the treatment of constipation, 20 g of lactitol should be taken initally as a daily single dose, and that this amount should be subsequently adjusted so that one stool is produced daily. This amount is increased to 50-70 g daily for the treatment of PSE. Lactitol may be administered by mixing its powder directly into a meal. It may also be taken as a solution by dissolving in water. A solution formed from 670 g of lactitol per liter of water has a viscosity of 23 mPa.s at 20° C. Accordingly, lactitol solutions have a significantly lower viscosity than lactulose syrups comprising an equivalent concentration of lactulose. In addition, lactitol is not as sweet as lactulose, being around 0.35 times as sweet as sucrose. Thus, lactitol does not suffer from the main disadvantages of lactulose when used as a laxative.
Some patients however find lactitol solutions to have imperfect palatability as they perceive them to have a somewhat acidic, bitter and medicinal taste. Accordingly, the problem remains to formulate a solution for treating constipation and/or PSE which has a balance of properties such as viscosity and taste which the vast majority of patients find acceptable.
It has also been reported that the polyol maltitol has a laxative effect. However, there is no commercial use at present of this polyol as a laxative.
EP-A-0 464 362 describes an animal feed comprising a mixture of lactitol and lactulose which promotes growth and good intestinal function. The lactulose and lactitol are present in a combined total concentration of 6.6 g/l. There is no teaching of any human application nor that the feeds have any laxative effect.
FR-A-2 215 206 describes a laxative composition comprising crystalline lactulose and crystalline sorbitol in a ratio of 1:3 to 3:1. The mixture is provided in a sachet containing 8 grams of lactulose and 8 grams of sorbitol. This mixture is dissolved in a glass of water and taken as a medicament. The resulting solution would have a combined concentration of about 150 g of lactulose and sorbitol per liter.
An object of the present invention is to provide an aqueous laxative syrup having a balance of properties providing greater palatability than presently available laxative syrups comprising either lactulose or lactitol.
According to one aspect, the present invention provides an aqueous laxative syrup having a viscosity of 5-70 mPa.s at 20° C. comprising one part by weight of lactulose and 0.6-1.5 parts by weight of a polyol selected from lactitol and/or maltitol.
Such a syrup has a lower viscosity than commercially available lactulose syrups comprising 620 g/l of lactulose or more. Such prior art syrups have a viscosity of about 185 mPa.s or more at 20° C. Further, the present syrups have a balance of flavours which renders them more palatable than laxative syrups comprising only one of lactulose and lactitol.
The syrups of the present invention may be prepared by mixing commercially available lactulose syrups with a solution formed by dissolving lactitol in water, so that the resulting syrup has appropriate relative concentrations of both lactulose and lactitol. The resulting syrup has a lower viscosity than a correspondingly concentrated solution of lactulose and a slightly greater viscosity than a correspondingly concentrated solution of lactitol.
It is preferred that the syrup should comprise 1 part by weight of lactulose and 0.8-1.2 parts by weight of the polyol. More preferably, the syrup should comprise 1 part by weight of lactulose and about 1 part by weight of the polyol.
The above aqueous laxative syrup may be prepared in a form suitable for immediate oral administration, or in a form suitable for administration after dilution with water. An aqueous syrup for immediate oral administration as a laxative preferably comprises a total of 500-800 g, more preferably 600-700 g, and most preferably about 666 g, of both lactulose and the polyol per liter.
It is preferred that the solvent in which the lactulose and polyol are dissolved is water. This may however contain other pharmacologically acceptable solvent components such as a small amount of ethanol.
In all of the above embodiments, it is preferred that the polyol is lactitol only.
According to a further aspect of the invention, the use is provided of water, lactulose and a polyol selected from lactitol and/or maltitol for the manufacture of an aqueous laxative syrup comprising 1 part by weight of lactulose and 0.66-1.5 parts by weight of the polyol.
In such a use, it is preferred that the resulting laxative syrup should have a viscosity of 5-70 mPa.s at 20° C. The resulting laxative syrup also preferably has all of the preferred features previously described.
It will be evident that viscosity is an important characteristic of the aqueous laxative syrup provided by the present invention. Such viscosity can b
Pearson Julita
Saunders David
Fitch Even Tabin & Flannery
Peselev Elli
Xyrofin Oy
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