CA1213219A - Pharmaceutical composition for the treatment of diabetes - Google Patents
Pharmaceutical composition for the treatment of diabetesInfo
- Publication number
- CA1213219A CA1213219A CA000456752A CA456752A CA1213219A CA 1213219 A CA1213219 A CA 1213219A CA 000456752 A CA000456752 A CA 000456752A CA 456752 A CA456752 A CA 456752A CA 1213219 A CA1213219 A CA 1213219A
- Authority
- CA
- Canada
- Prior art keywords
- pharmaceutical composition
- weight
- locust bean
- bean gum
- glucose
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
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
- A61K31/70—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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
- A61K36/483—Gleditsia (locust)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Abstract
ABSTRACT
Pharmaceutical Compositions Pharmaceutical compositions comprising mixtures of xanthan gum and locust bean gum in a specified range of ratios have been found to exhibit synergistic effects in an in vitro test model. Pharmaceutical compositions adapted for oral administration comprising mixtures of xanthan gum and locust bean gum in the range of ratios are described for use in the treatment of diabetes or of satiety.
Pharmaceutical Compositions Pharmaceutical compositions comprising mixtures of xanthan gum and locust bean gum in a specified range of ratios have been found to exhibit synergistic effects in an in vitro test model. Pharmaceutical compositions adapted for oral administration comprising mixtures of xanthan gum and locust bean gum in the range of ratios are described for use in the treatment of diabetes or of satiety.
Description
I
PHARMACEUTICAL COMPOSITIONS
This invention relates to pharmaceutical compositions and in particular to compositions for use in the treatment of diabetes or of satiety.
It is well known that certain unabsorbable plant polysaccharides such as guard gum and pectin, when administered in substantial quantities t can cause a reduction in the levels of glucose and cholesterol in healthy volunteers and in diabetic patients. Unfortunately in order to obtain the desired effects patients have to take large quantities of unpalatable gum. Thus in a study reported by Jenkins JOY et at (Lance 1976, 7994, 1086) patients received daily doses of 16.5 or 25.0g guard gum.
During an investigation with other polysaccharides to evaluate their inhibitory effects on -the diffusion of glucose across a membrane we found a synergistic effect when xanthan gum and locust bean gum were mixed in certain proportions. Our investigations of the mixtures were extended to include in viva studies in the rat and in human volunteers which confirmed the blood glucose lowering properties.
I According to this invention there is provided a pharmaceutical composition in dry powder or granular farm adapted for oral administration which comprises xanthan gum and locust bean gum in a weight weight ratio of between 1:9 and Sol and 2.5 to 10% by weight of the composition of an alcohol soluble binding agent.
.
.
I
- lo -In a preferred composition the ratio of xanthan gum to locust bean gum is between 1:3 and 3:1 and conveniently in the ratio of 1~1.
I
The compositions are useful in the treatment of diabetes where in mild cases they may be used as sole treatment or where in more severe cases, where hypoglycemic agents and/or insulin administration is required, their use can lead to lower or less frequent dosing of these agents.
The compositions are also useful in the treatment of satiety where they afford a feeling in patients of fullness leading to a reduction in food intake.
The invention also includes the use of xanthan gum and locust bean gum in a weight weight ratio of between 1:9 and 9:1 in the treatment of diabetes and of satiety.
Xanthan gum and locust bean gum have been used separately as thickeners and emulsifiers in the cosmetic food and pharmaceutical industries. Locust bean gum is available in a hot-water soluble form and in a cold-water soluble form, a commercial form of the latter being Meyprodyn 200 (Registered Trade Mark Molly Chemical AGO., Kreuzlinga, Switzerland).
The effective oral dose in the treatment of diabetes depends upon the severity of the diabetes and as to whether the compositions comprise the sole therapy or are a part of a multi-drug regime. Generally the dosage Norm employed will contain 2 to 69 of the mixed gums with dosing 3 times a day taken before or during meals. In the treatment of satiety a similar dosage regime is employed.
The compositions will normally be in the form of dry powders or granules which are to be added to water or added to a drink such as tomato juice or orange juice. With hot water dispersible locust bean gums it is necessary to add .
the compositions Jo ho liquid (50-75C), but the mixture can then be cooled before administration. Where the compositions do not contain a hot water dispersible locust bean gum they may alternatively be sprinkled onto food.
For the ease of dosing the compositions in the form of powders or granules are conveniently packaged into sachets.
A convenient unit dose of the composition in a sachet in the form of powder or granules will comprise from to 6g of the mixed gums.
The compositions in the form of a fine granular free flowing powder or coarser more discrete granules may include
PHARMACEUTICAL COMPOSITIONS
This invention relates to pharmaceutical compositions and in particular to compositions for use in the treatment of diabetes or of satiety.
It is well known that certain unabsorbable plant polysaccharides such as guard gum and pectin, when administered in substantial quantities t can cause a reduction in the levels of glucose and cholesterol in healthy volunteers and in diabetic patients. Unfortunately in order to obtain the desired effects patients have to take large quantities of unpalatable gum. Thus in a study reported by Jenkins JOY et at (Lance 1976, 7994, 1086) patients received daily doses of 16.5 or 25.0g guard gum.
During an investigation with other polysaccharides to evaluate their inhibitory effects on -the diffusion of glucose across a membrane we found a synergistic effect when xanthan gum and locust bean gum were mixed in certain proportions. Our investigations of the mixtures were extended to include in viva studies in the rat and in human volunteers which confirmed the blood glucose lowering properties.
I According to this invention there is provided a pharmaceutical composition in dry powder or granular farm adapted for oral administration which comprises xanthan gum and locust bean gum in a weight weight ratio of between 1:9 and Sol and 2.5 to 10% by weight of the composition of an alcohol soluble binding agent.
.
.
I
- lo -In a preferred composition the ratio of xanthan gum to locust bean gum is between 1:3 and 3:1 and conveniently in the ratio of 1~1.
I
The compositions are useful in the treatment of diabetes where in mild cases they may be used as sole treatment or where in more severe cases, where hypoglycemic agents and/or insulin administration is required, their use can lead to lower or less frequent dosing of these agents.
The compositions are also useful in the treatment of satiety where they afford a feeling in patients of fullness leading to a reduction in food intake.
The invention also includes the use of xanthan gum and locust bean gum in a weight weight ratio of between 1:9 and 9:1 in the treatment of diabetes and of satiety.
Xanthan gum and locust bean gum have been used separately as thickeners and emulsifiers in the cosmetic food and pharmaceutical industries. Locust bean gum is available in a hot-water soluble form and in a cold-water soluble form, a commercial form of the latter being Meyprodyn 200 (Registered Trade Mark Molly Chemical AGO., Kreuzlinga, Switzerland).
The effective oral dose in the treatment of diabetes depends upon the severity of the diabetes and as to whether the compositions comprise the sole therapy or are a part of a multi-drug regime. Generally the dosage Norm employed will contain 2 to 69 of the mixed gums with dosing 3 times a day taken before or during meals. In the treatment of satiety a similar dosage regime is employed.
The compositions will normally be in the form of dry powders or granules which are to be added to water or added to a drink such as tomato juice or orange juice. With hot water dispersible locust bean gums it is necessary to add .
the compositions Jo ho liquid (50-75C), but the mixture can then be cooled before administration. Where the compositions do not contain a hot water dispersible locust bean gum they may alternatively be sprinkled onto food.
For the ease of dosing the compositions in the form of powders or granules are conveniently packaged into sachets.
A convenient unit dose of the composition in a sachet in the form of powder or granules will comprise from to 6g of the mixed gums.
The compositions in the form of a fine granular free flowing powder or coarser more discrete granules may include
2.5 to 10%, preferably 5% by weight of the composition of an alcohol soluble binding agent such as polyvinylpyrrolidone.
other binding agents that may be used include ethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose and hydroxyethyl solely Oslo When the compositions are added to water gelatin of the gums takes place. It is desirable therefore that the resultant mixtures are consumed by a patient soon after adding to water otherwise if they are allowed to stand for too long they become too viscous to drink. We have found that the rate of gelatin is dependent upon the pi with a lower pi giving slower gelatin. Desirably therefore the composition may include US to 10% by weight of the 25 composition of an organic acid such as citric acid or tartaric acid.
The compositions may also include one or more of a sweetening agent (e.g. saccharin or aspartame), a flavoring agent and/or a coloring agent.
The invention is illustrated by the following Examples.
A preparation in the form of granules was prepared from .
the lot 1 owl no formula ail on:
xanthan gum 1500g cold water do spurs bye locus bean gum (Meyprodyn 200) 15009 sodium saccharin n 259 got our, if Avery no 2059 I.
lo 10 polyvinylpyrrolidone (Kollidon K30BASF) 1759 The dry powders were screened through a 5001,m sieve before briny thoroughly blended. They were then wet granulated using isopropanol and the mass then dried at 50-60C. After drying the mass was passed through an I appropriate sized sieve to give the required granule size proofer I 250-750~m). The granules were packaged into unit dose sachets each containing approximately 2.0, 3.~1 4-0, 5.0, or 6.0g ox the mixed gums.
The formulation of Example 1 was varied by adding citric acid (2509) to the mixed powders.
EXAMPLES 3 to 6 , The formulations of Examples 1 and 2 were varied by employing differing amounts of xanthan gum, Meyprodyn 200 and citric acid whilst using the same quantities of sodium saccharin, color, if averring and polyvinylpyrrolidone r Jo rude Jo ~.2~32~
other binding agents that may be used include ethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose and hydroxyethyl solely Oslo When the compositions are added to water gelatin of the gums takes place. It is desirable therefore that the resultant mixtures are consumed by a patient soon after adding to water otherwise if they are allowed to stand for too long they become too viscous to drink. We have found that the rate of gelatin is dependent upon the pi with a lower pi giving slower gelatin. Desirably therefore the composition may include US to 10% by weight of the 25 composition of an organic acid such as citric acid or tartaric acid.
The compositions may also include one or more of a sweetening agent (e.g. saccharin or aspartame), a flavoring agent and/or a coloring agent.
The invention is illustrated by the following Examples.
A preparation in the form of granules was prepared from .
the lot 1 owl no formula ail on:
xanthan gum 1500g cold water do spurs bye locus bean gum (Meyprodyn 200) 15009 sodium saccharin n 259 got our, if Avery no 2059 I.
lo 10 polyvinylpyrrolidone (Kollidon K30BASF) 1759 The dry powders were screened through a 5001,m sieve before briny thoroughly blended. They were then wet granulated using isopropanol and the mass then dried at 50-60C. After drying the mass was passed through an I appropriate sized sieve to give the required granule size proofer I 250-750~m). The granules were packaged into unit dose sachets each containing approximately 2.0, 3.~1 4-0, 5.0, or 6.0g ox the mixed gums.
The formulation of Example 1 was varied by adding citric acid (2509) to the mixed powders.
EXAMPLES 3 to 6 , The formulations of Examples 1 and 2 were varied by employing differing amounts of xanthan gum, Meyprodyn 200 and citric acid whilst using the same quantities of sodium saccharin, color, if averring and polyvinylpyrrolidone r Jo rude Jo ~.2~32~
3 4 5 6 xanthan yam 750 750 2250 2250 g Meyprodyn 200Z250 2250 750 750 9 citric acid - 250 250 9 The formulations of Examples 1 to 6 can be varied by replacing the cold water dispersible locust bean gum by an equal weight of a hot water dispersible locust bean gum (TAM. Douche & Sons (UK) lid).
The formulations of Examples 1 to 7 can be varied by omitting the binding agent polyvinyl purl i done and effecting thy wet granulation by using 50% v/v aqueous isopropanol. The gums act as their own binding agents and the use of an isopropanol/water mix enables an even distribution of granulating fluid to be imparted onto the mixed powders.
Diabetic patients often experience problems maintaining a healthy weight there being a tendency for overweight. In thy trials with healthy volunteers, discussed below, the compositions when taken before a meal provided a feeling of fullness. The compositions therefore find utility for these persons, whether or not they are diabetics, who have an overweight problem.
The in vitro and in viva properties of the compositions of the invention have been studied according to the following procedures:
1. In vitro Studies .
In the preliminary studies to determine the relative ~32~
effects of different polymers on passive glucose diffusion a conventional two compartment dialysis cell as described by Brewster and Muir, Clinical Pharmacology and Therapeutics 27, No. I 76 82 (19803 was employed (Figure 1), solutions of polymer in citric acid:phospha~e buffer at pi = 5.4 containing 10% w/v 14C glucose were prepared and dialyzed across a presoaked cellulose acetate membrane (Spectraphor 25 Registered Trade Mark MUSE Ltd., Rowley, England) into buffer only solution. The dialysis cell was rotated on power driven rollers a 37C. Dialysis was stopped after one hour, allocates from the two cells taken, counted by liquid scintillation in the presence of emulsifier scintillation fluid ESSAY (Cam lab, Cambridge, England) and thy amount of 14C glucose to diffuse calculated.
In further studies, a novel three compartment dialysis cell was used in which the test polymer solution in the middle compartment was separated by cellulose acetate membranes from a 14C glucose solution on one side and solvent only on the other (Figure 2), Experiments were tarried out using either Ringer Knobs pi - 7.4 buffer or water only as the solvent for the polymer and dialysis was terminated after 1.25 hours. The amount of 14C glucose to diffuse through the test polymer solution into the solvent only reference cell was calculated.
The effect of various polymers and polymeric mixtures on in vitro diffusion using the two compartment dialysis cell is illustrated in Table 1. In the Table On = xanthan gum, LUG = hot water dispersible locust bean gum and percentages are weight volume (w/v).
Table 1 Polymer % 14C Released*
after one hour Control 96 1% Guard 45 1% Sodium allegiant 99 1% Ispaghula, Noah soluble fraction 100 0.5% Hydroxyethylcellulose 250tl 88 0.5% On (unheated) 68 1% LUG unheated) 89 0.05% Xn:0.5% LUG:
(i) Unheated I
(ii) Heated 49 * Amount of 14C in the reference cell 9 expressed as a Z of maximum possible at equilibrium The relatively non-viscous polymers such as sodium allegiant, hydroxyethylcellulose, Ispaghula and locust bean gum, (which is cold water insoluble) have negligible glucose retaining properties compared to the more viscous guar.
Xanthan gum although less viscous than guard has an ability in its own right to retain glucose, but this can be further enhanced by addition of locust bean gum. The aqueous Xn:LBG
mixture when unheated is relatively non-viscous, but when heated to approximately 75C, to render the LUG soluble, an interaction between the two gums occur and when subsequently cooled to ambient temperature, a gel is formed.
The results in the three rompar~ment cell are shown in Table II where My = cold water soluble Meyprodyn 200.
I
Table II
Polymer % 14C Released (0.1% wlv) into reference cell On 29 My 25 Xn:LBG (1:1) (heated) 3 Xn:Mn (1:1) (unheated) The effect of varying the relative proportions of Xanthan gum and locust bean gum (hot water soluble or the cold water soluble Meyprodyn 250~ on glucose diffusion in the three compartment cell is shown in Figures 3 and 4. At concentrations of 0.1~ the individual gums have negligible effect over control on glucose diffusion in the three compartment dialysis model but 0.1% Xn:LBG over the range ~1:9) to (9:1~ and 0,1~ Xn:Meyprodyn 2G0 from (1:9) to (7:3) exert a clear synergistic effect over the individual gums.
2. In viva studies in the rat The effect of gums in viva using a tied intestinal loop rat model Chased on the method described by Chinook et at, Naunyn-Schmiedeberg's Arch Pharmacol 321, 223-225 (1982)]
has been investigated; male Waster rats (250-280g) were anesthetized with barbiturate (it), the small intestine exposed and a length of jejunum (approximately 20 ems) from the duodenal-Jejunal flexor isolated. This segment was cannulated at both ends, flushed with Knobs - bicarbonate Ringer solution and divided into four loops each approximately 5 cm long. Each loop was cannulated at one end and tied at the other. To each loop 1~5 ml of the :`
I
g appropriate 501 union containing OH glucose and 14C
carboxylic acid insulin and Knobs bicarbonate Ringer buffer was added and left for twenty minutes, after which time the loop contents were resample, 14C and OH concentrations determined by liquid scintillation and glucose uptake calculated.
In order to minimize loop effects or, glucose uptake the regimen was repeated six times and a total of 24 rats were used. The control solution was Knobs bicarbonate Ringer containing OH glucose and 14C arboxylic acid insulin.
14C Car~oxylic acid insulin was added to make allowance for any fluid volume change. Statistical analysis of the results was carried out using unpaired k test The effect of the gums on glucose absorption in viva from the rat small intestine tied loop is shown in Figure 5;
the rate of absorption is inhibited by xanthan gum alone at concentrations ~0.2~ and by Xn:LBG (1:1) at a concentration ~0.1X. LUG has been tested at concentrations of up to 0.3 and been found to have no statistically significant effect over control.
3, In viva studies in man .
The effect of gums in man using the oral glucose tolerance test Catkins, BMJ, 284, 1690, (1982)~ has been investigated; in crossover studies up to nine healthy I volunteers were given meals consisting of 200 ml distilled water, 50 ml diabetic orange squash and 50 grams glucose with or without 2.5 grams of test material.
The Xn:LBG (1:1~ test meal was heated Jo 75C and subsequently cooled before administration to allow the gel ~3L3~
1 o to form. For consistency, all other test meals except Xn:Meyprodyn 200 were treated in the same way Blood samples were drawn from a cannulated forearm vein immediately prior to and a Zen minute intervals throughout the study and assayed for brood glucose (Yellow Springs Institute Corporation Glucose Analyzer Model AMY) and insulin ARIA test kit, Washington, NOAH lop) content.
The On, LUG and Xn:LBG studies were carried out in the same group of volunteers. A different group was used in the Xn:Meyprodyn 200 study Statistical analysis of results was carried out using the pared t test. Areas under the curve were compared using Simpson or the Trapezoidal rule.
The effect of 2.5 grams Xn:LBG (1:1) on the change in blood glucose levels over basal in healthy volunteers after the 50 gram glucose challenge is illustrated in Figure 6:
the mixture is seen to have a significant effect over control at 30, 40~ 50 and 60 minutes indicating that it may be useful in the treatment of hyperglycemia, particularly if administered at a slightly higher dose. 2.5 Grams On was significantly different from control at 50 and 60 minutes (Figure 73 whereas a similar dose of LUG has no effect at any time point (Figure 8). No test treatment had any effect on areas under curve after two hours indicating no malabsorption of glucose to have occurred. A limited study (n-3) with 1.25 grams Xn~LBG (1:1) showed no effect at any time point Neither was any observed with unheated Xn:Meyprodyn 200 ( 1: 1 ), no (Figure 9).
I
..
Plasma insulin data was found to be a more sensitive indicator of the action of the polysaccharides than was the glucose data (Figure 10). Insulin levels after 2.5 grams Xn:LBG (1:1) are significantly different from control at 309 5 60 and 90 minutes respectively, and after 2.5 grams On only treatment at 30 and 90 minutes. 2.5 Grams LUG and 1.25 grams Xn:LBG ~1:1) had no significant effect at any time point. After treatment with 2.5 grams Xn:Mn 200 the plasma i nsul i n 1 evil at on my nuts and the area under the curve up to two hours after dosing (p<0.05) are significantly different from control. figure 11).
The formulations of Examples 1 to 7 can be varied by omitting the binding agent polyvinyl purl i done and effecting thy wet granulation by using 50% v/v aqueous isopropanol. The gums act as their own binding agents and the use of an isopropanol/water mix enables an even distribution of granulating fluid to be imparted onto the mixed powders.
Diabetic patients often experience problems maintaining a healthy weight there being a tendency for overweight. In thy trials with healthy volunteers, discussed below, the compositions when taken before a meal provided a feeling of fullness. The compositions therefore find utility for these persons, whether or not they are diabetics, who have an overweight problem.
The in vitro and in viva properties of the compositions of the invention have been studied according to the following procedures:
1. In vitro Studies .
In the preliminary studies to determine the relative ~32~
effects of different polymers on passive glucose diffusion a conventional two compartment dialysis cell as described by Brewster and Muir, Clinical Pharmacology and Therapeutics 27, No. I 76 82 (19803 was employed (Figure 1), solutions of polymer in citric acid:phospha~e buffer at pi = 5.4 containing 10% w/v 14C glucose were prepared and dialyzed across a presoaked cellulose acetate membrane (Spectraphor 25 Registered Trade Mark MUSE Ltd., Rowley, England) into buffer only solution. The dialysis cell was rotated on power driven rollers a 37C. Dialysis was stopped after one hour, allocates from the two cells taken, counted by liquid scintillation in the presence of emulsifier scintillation fluid ESSAY (Cam lab, Cambridge, England) and thy amount of 14C glucose to diffuse calculated.
In further studies, a novel three compartment dialysis cell was used in which the test polymer solution in the middle compartment was separated by cellulose acetate membranes from a 14C glucose solution on one side and solvent only on the other (Figure 2), Experiments were tarried out using either Ringer Knobs pi - 7.4 buffer or water only as the solvent for the polymer and dialysis was terminated after 1.25 hours. The amount of 14C glucose to diffuse through the test polymer solution into the solvent only reference cell was calculated.
The effect of various polymers and polymeric mixtures on in vitro diffusion using the two compartment dialysis cell is illustrated in Table 1. In the Table On = xanthan gum, LUG = hot water dispersible locust bean gum and percentages are weight volume (w/v).
Table 1 Polymer % 14C Released*
after one hour Control 96 1% Guard 45 1% Sodium allegiant 99 1% Ispaghula, Noah soluble fraction 100 0.5% Hydroxyethylcellulose 250tl 88 0.5% On (unheated) 68 1% LUG unheated) 89 0.05% Xn:0.5% LUG:
(i) Unheated I
(ii) Heated 49 * Amount of 14C in the reference cell 9 expressed as a Z of maximum possible at equilibrium The relatively non-viscous polymers such as sodium allegiant, hydroxyethylcellulose, Ispaghula and locust bean gum, (which is cold water insoluble) have negligible glucose retaining properties compared to the more viscous guar.
Xanthan gum although less viscous than guard has an ability in its own right to retain glucose, but this can be further enhanced by addition of locust bean gum. The aqueous Xn:LBG
mixture when unheated is relatively non-viscous, but when heated to approximately 75C, to render the LUG soluble, an interaction between the two gums occur and when subsequently cooled to ambient temperature, a gel is formed.
The results in the three rompar~ment cell are shown in Table II where My = cold water soluble Meyprodyn 200.
I
Table II
Polymer % 14C Released (0.1% wlv) into reference cell On 29 My 25 Xn:LBG (1:1) (heated) 3 Xn:Mn (1:1) (unheated) The effect of varying the relative proportions of Xanthan gum and locust bean gum (hot water soluble or the cold water soluble Meyprodyn 250~ on glucose diffusion in the three compartment cell is shown in Figures 3 and 4. At concentrations of 0.1~ the individual gums have negligible effect over control on glucose diffusion in the three compartment dialysis model but 0.1% Xn:LBG over the range ~1:9) to (9:1~ and 0,1~ Xn:Meyprodyn 2G0 from (1:9) to (7:3) exert a clear synergistic effect over the individual gums.
2. In viva studies in the rat The effect of gums in viva using a tied intestinal loop rat model Chased on the method described by Chinook et at, Naunyn-Schmiedeberg's Arch Pharmacol 321, 223-225 (1982)]
has been investigated; male Waster rats (250-280g) were anesthetized with barbiturate (it), the small intestine exposed and a length of jejunum (approximately 20 ems) from the duodenal-Jejunal flexor isolated. This segment was cannulated at both ends, flushed with Knobs - bicarbonate Ringer solution and divided into four loops each approximately 5 cm long. Each loop was cannulated at one end and tied at the other. To each loop 1~5 ml of the :`
I
g appropriate 501 union containing OH glucose and 14C
carboxylic acid insulin and Knobs bicarbonate Ringer buffer was added and left for twenty minutes, after which time the loop contents were resample, 14C and OH concentrations determined by liquid scintillation and glucose uptake calculated.
In order to minimize loop effects or, glucose uptake the regimen was repeated six times and a total of 24 rats were used. The control solution was Knobs bicarbonate Ringer containing OH glucose and 14C arboxylic acid insulin.
14C Car~oxylic acid insulin was added to make allowance for any fluid volume change. Statistical analysis of the results was carried out using unpaired k test The effect of the gums on glucose absorption in viva from the rat small intestine tied loop is shown in Figure 5;
the rate of absorption is inhibited by xanthan gum alone at concentrations ~0.2~ and by Xn:LBG (1:1) at a concentration ~0.1X. LUG has been tested at concentrations of up to 0.3 and been found to have no statistically significant effect over control.
3, In viva studies in man .
The effect of gums in man using the oral glucose tolerance test Catkins, BMJ, 284, 1690, (1982)~ has been investigated; in crossover studies up to nine healthy I volunteers were given meals consisting of 200 ml distilled water, 50 ml diabetic orange squash and 50 grams glucose with or without 2.5 grams of test material.
The Xn:LBG (1:1~ test meal was heated Jo 75C and subsequently cooled before administration to allow the gel ~3L3~
1 o to form. For consistency, all other test meals except Xn:Meyprodyn 200 were treated in the same way Blood samples were drawn from a cannulated forearm vein immediately prior to and a Zen minute intervals throughout the study and assayed for brood glucose (Yellow Springs Institute Corporation Glucose Analyzer Model AMY) and insulin ARIA test kit, Washington, NOAH lop) content.
The On, LUG and Xn:LBG studies were carried out in the same group of volunteers. A different group was used in the Xn:Meyprodyn 200 study Statistical analysis of results was carried out using the pared t test. Areas under the curve were compared using Simpson or the Trapezoidal rule.
The effect of 2.5 grams Xn:LBG (1:1) on the change in blood glucose levels over basal in healthy volunteers after the 50 gram glucose challenge is illustrated in Figure 6:
the mixture is seen to have a significant effect over control at 30, 40~ 50 and 60 minutes indicating that it may be useful in the treatment of hyperglycemia, particularly if administered at a slightly higher dose. 2.5 Grams On was significantly different from control at 50 and 60 minutes (Figure 73 whereas a similar dose of LUG has no effect at any time point (Figure 8). No test treatment had any effect on areas under curve after two hours indicating no malabsorption of glucose to have occurred. A limited study (n-3) with 1.25 grams Xn~LBG (1:1) showed no effect at any time point Neither was any observed with unheated Xn:Meyprodyn 200 ( 1: 1 ), no (Figure 9).
I
..
Plasma insulin data was found to be a more sensitive indicator of the action of the polysaccharides than was the glucose data (Figure 10). Insulin levels after 2.5 grams Xn:LBG (1:1) are significantly different from control at 309 5 60 and 90 minutes respectively, and after 2.5 grams On only treatment at 30 and 90 minutes. 2.5 Grams LUG and 1.25 grams Xn:LBG ~1:1) had no significant effect at any time point. After treatment with 2.5 grams Xn:Mn 200 the plasma i nsul i n 1 evil at on my nuts and the area under the curve up to two hours after dosing (p<0.05) are significantly different from control. figure 11).
Claims (10)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A pharmaceutical composition in dry powder or granular form adapted for oral administration which comprises xanthan gum and locust bean gum in a weight:weight ratio of between 1:9 and 9:1 and 2.5 to 10% by weight of the composition of an alcohol soluble binding agent.
2. A pharmaceutical composition as claimed in claim 1 wherein the ratio is between 1:3 and 3:1.
3. A pharmaceutical composition as claimed in claim 2 wherein the ratio is 1:1.
4. A pharmaceutical composition as claimed in claim 1, 2 or 3 wherein the locust bean gum is a cold water dispersible locust bean gum.
5. A pharmaceutical composition as claimed in claim 1, 2 or 3 wherein the alcohol soluble binding agent is present at 5%
by weight.
by weight.
6, A pharmaceutical composition as claimed in claim 1, 2 or 3 wherein the alcohol soluble binding agent is polyvinyl-pyrrolidone.
7. A pharmaceutical composition as claimed in claim 1, 2 or 3 which further includes 2.5 to 10% by weight of the composition of an organic acid.
8. A pharmaceutical composition as claimed in claim 1, 2 or 3 which further includes 2.5 to 10% by weight of the composition of citric acid or tartaric acid.
9. A pharmaceutical composition as claimed in claim 1, 2 or 3 in unit dose form.
10. A pharmaceutical composition as claimed in claim 1, 2 or 3 in unit dose form wherein the weight of the mixed gums is between 2 and 6 g.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8317595 | 1983-06-29 | ||
| GB838317595A GB8317595D0 (en) | 1983-06-29 | 1983-06-29 | Pharmaceutical compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1213219A true CA1213219A (en) | 1986-10-28 |
Family
ID=10544954
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000456752A Expired CA1213219A (en) | 1983-06-29 | 1984-06-15 | Pharmaceutical composition for the treatment of diabetes |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US4689219A (en) |
| EP (1) | EP0130771A3 (en) |
| JP (1) | JPS6023323A (en) |
| AU (1) | AU564982B2 (en) |
| CA (1) | CA1213219A (en) |
| DK (1) | DK315484A (en) |
| GB (2) | GB8317595D0 (en) |
| GR (1) | GR81447B (en) |
| NZ (1) | NZ208403A (en) |
| PT (1) | PT78813B (en) |
| ZA (1) | ZA844352B (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5122362A (en) * | 1989-12-04 | 1992-06-16 | Board Of Regents, The University Of Texas System | Methods and compositions for the measurement of glucose tolerance |
| US6726930B1 (en) * | 1993-09-09 | 2004-04-27 | Penwest Pharmaceuticals Co. | Sustained release heterodisperse hydrogel systems for insoluble drugs |
| AU2068797A (en) * | 1996-01-29 | 1997-08-20 | Edward Mendell Co. Inc. | Sustained release excipient |
| GB9720061D0 (en) | 1997-09-19 | 1997-11-19 | Crosfield Joseph & Sons | Metal compounds as phosphate binders |
| US7638150B2 (en) * | 2002-08-02 | 2009-12-29 | Simply Thick Llp | Process for preparing concentrate thickener compositions |
| US20060100171A1 (en) * | 2002-09-09 | 2006-05-11 | Ekhart Peter F | Branched alpha-glucans for weight management |
| US20060233900A1 (en) * | 2002-12-19 | 2006-10-19 | Beisel Guenther | Preparation for reducing the appetite, producing a satiated feeling and/or for weight loss in children |
| AU2003296628A1 (en) * | 2002-12-19 | 2004-07-14 | Gunther Beisel | Agent with a retarded release of substances |
| JP2006516995A (en) | 2003-01-31 | 2006-07-13 | シンプリー スィック，リミティド ライアビリティー カンパニー | Improved thickening beverage for dysphagia |
| WO2005021038A2 (en) * | 2003-08-27 | 2005-03-10 | Beisel Guenther | Agent for treating metabolic syndrome |
| MY157620A (en) | 2006-01-31 | 2016-06-30 | Cytochroma Dev Inc | A granular material of a solid water-soluble mixed metal compound capable of binding phosphate |
| WO2008137181A1 (en) * | 2007-05-07 | 2008-11-13 | Clearly Superior, Inc | Food thickening agent, method for producing food thickening agent |
| GB0714670D0 (en) * | 2007-07-27 | 2007-09-05 | Ineos Healthcare Ltd | Use |
| GB0720220D0 (en) * | 2007-10-16 | 2007-11-28 | Ineos Healthcare Ltd | Compound |
| GB0913525D0 (en) | 2009-08-03 | 2009-09-16 | Ineos Healthcare Ltd | Method |
| GB201001779D0 (en) | 2010-02-04 | 2010-03-24 | Ineos Healthcare Ltd | Composition |
| US9101156B2 (en) | 2013-03-15 | 2015-08-11 | Kent Precision Foods Group, Inc. | Thickener composition, thickened nutritive products, methods for preparing thickened nutritive products, and methods for providing nutrition |
| US11751594B2 (en) | 2020-10-22 | 2023-09-12 | Grain Processing Corporation | Food thickener composition and method |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3557016A (en) * | 1965-10-22 | 1971-01-19 | Kelco Co | Heat reversible gel and method for preparing same |
| US3700451A (en) * | 1970-04-06 | 1972-10-24 | Itek Corp | Gelable and gelled compositions |
| US3944427A (en) * | 1970-04-06 | 1976-03-16 | Itek Corporation | Gelable and gelled compositions |
| US3900569A (en) * | 1971-09-30 | 1975-08-19 | Sucrest Corp | Direct compression vehicle |
| US4038206A (en) * | 1976-01-15 | 1977-07-26 | General Mills Chemicals, Inc. | Hydroxyalkyl locust bean/xanthomonas hydrophilic colloid blends |
| US4136173A (en) * | 1977-01-31 | 1979-01-23 | American Home Products Corp. | Mixed xanthan gum and locust beam gum therapeutic compositions |
-
1983
- 1983-06-29 GB GB838317595A patent/GB8317595D0/en active Pending
-
1984
- 1984-06-06 GB GB08414458A patent/GB2142821B/en not_active Expired
- 1984-06-06 NZ NZ208403A patent/NZ208403A/en unknown
- 1984-06-07 US US06/618,239 patent/US4689219A/en not_active Expired - Fee Related
- 1984-06-08 ZA ZA844352A patent/ZA844352B/en unknown
- 1984-06-14 GR GR75011A patent/GR81447B/el unknown
- 1984-06-15 CA CA000456752A patent/CA1213219A/en not_active Expired
- 1984-06-25 EP EP84304294A patent/EP0130771A3/en not_active Withdrawn
- 1984-06-27 JP JP59132816A patent/JPS6023323A/en active Pending
- 1984-06-27 AU AU29922/84A patent/AU564982B2/en not_active Ceased
- 1984-06-28 DK DK315484A patent/DK315484A/en not_active Application Discontinuation
- 1984-06-28 PT PT78813A patent/PT78813B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU564982B2 (en) | 1987-09-03 |
| EP0130771A3 (en) | 1987-11-25 |
| PT78813A (en) | 1984-07-01 |
| GB2142821A (en) | 1985-01-30 |
| NZ208403A (en) | 1987-02-20 |
| EP0130771A2 (en) | 1985-01-09 |
| GR81447B (en) | 1984-12-11 |
| US4689219A (en) | 1987-08-25 |
| GB8317595D0 (en) | 1983-08-03 |
| PT78813B (en) | 1986-06-05 |
| DK315484D0 (en) | 1984-06-28 |
| AU2992284A (en) | 1985-01-03 |
| JPS6023323A (en) | 1985-02-05 |
| GB2142821B (en) | 1987-06-24 |
| DK315484A (en) | 1984-12-30 |
| ZA844352B (en) | 1985-02-27 |
| GB8414458D0 (en) | 1984-07-11 |
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Legal Events
| Date | Code | Title | Description |
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| MKEX | Expiry |