WO2002026104A2 - A combination of appetite controlling agents which create a synergy and produce a satiating result - Google Patents
A combination of appetite controlling agents which create a synergy and produce a satiating result Download PDFInfo
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- WO2002026104A2 WO2002026104A2 PCT/US2001/020420 US0120420W WO0226104A2 WO 2002026104 A2 WO2002026104 A2 WO 2002026104A2 US 0120420 W US0120420 W US 0120420W WO 0226104 A2 WO0226104 A2 WO 0226104A2
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- satiety
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- pharmaceutical composition
- appetite
- lipase inhibitor
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/74—Synthetic polymeric materials
- A61K31/765—Polymers containing oxygen
- A61K31/77—Polymers containing oxygen of oxiranes
Definitions
- This invention relates to a composition and method for controlling carbohydrate craving and reducing absorption of fats in the food of humans. More particularly, the invention concerns the reduction in caloric absorption, in a mammal, by a two-prong approach: reducing satiety response for carbohydrates while reducing the absorption of fats using a known lipase inhibitor.
- a major class of weight control agents are drugs which act on the central nervous system (CNS) to suppress appetite.
- CNS appetite suppressant drugs interacts with cathecolaminergic receptors in the brainstem. These include controlled drugs such as amphetamine, phenmetrazine, and diethylproprion, and over-the-counter drags such as phenylpropanolamine.
- Manizidol is another CNS active drag which, although not a catecholamine, activates the central nervous system.
- Each of these agents have potential for addiction and, at doses which effectively reduce appetite, i.e., suppress food intake by 20- 30%, they induce significant CNS side effects, such as nervousness, loss of concentration, and insomnia.
- D-fenfluramine for example, releases and depletes brain serotonin, but it causes sedation at appetite suppressant levels, and it may precipitate depression upon its withdrawal.
- Fluoxetine is an inhibitor of serotonin reuptake in the brainstem. However, at effective appetite control doses, Fluoxetine often causes nausea asthenia, i.e., weakness, lassitude.
- Amantadine is another drug, that also acts on the central nervous system, by affecting the extracellular levels of dopamine and norepinephrine in the brain and in the periphery and decreases the levels of prolactin. Prolatin works to promote adiposity and weight gain. Consequently, this satiety agent, works as an anorectic drag in that it acts on the lateral hypothalamus and reduced the intake of food, while also enhancing the bodies metabolism rate when levels of prolactin are decreased.
- Another major class of weight control agents is drugs, which promote malabsorption of nutrients through suppression of digestive enzymes.
- One agent in this category is Acarbose, a bacterial inhibitor of amylase and brushborder glycosidases.
- Another is tetrahydrolipostatin, a fungal inhibitor of Upases.
- Another category of compounds is that of polyols, particularly Pluronic L-101 or 81, which specifically inhibit pancreatic lipase enzyme and thus reduce breakdown of triglycerides and other fat forms of an absorbable form. Included in this category is orlistat (Xenical) that interferes in the absorption of dietary fat.
- Acarbose was shown to be ineffective in humans, and tetrahydrolipostatin was shown to reduce human absorption of fat by only 30%.
- a second major drawback to this approach is that subjects taking these agents develop hyperphagia for other foodstuffs. For example, subjects taking tetrahydrolipostatin will consume more carbohydrate to compensate, thus increasing the intake of food, especially of foodstuffs of a different class.
- a third class of weight control agents are noncaloric, non-nutritive dietary substitutes, like saccharin or Nutrasweet, sugar substitutes, and sucrose polyester, a fat substitute. These agents, while not absorbed, provide a taste and/or texture like the nutrient for which they are substituted.
- the disadvantage of these substitutes is that persons develop a hyperphagia to compensate for the reduction of calories by the substitution.
- sucrose polyester a nondigestible lipid, fat soluble, enterohepatically circulated vitamins partition into the unabsorbed polyester and are lost from the body, a potential problem that can also occur with tetrahydrolipostatin.
- Thermogenic drugs are also sometimes used.
- the catecholamine drugs discussed above have some thermogenic activity, in addition to their suppression of appetite.
- Thyroid hormone is also commonly used.
- Semi-starvation diets are universally effective in short term weight loss, but regain of weight after resumption of less restricted diets is the rale. Long-term use of semi starvation diets is nutritionally unsound because of the development of multiple deficiencies of essential nutrients.
- Intragastric balloons have been placed endoscopically according to the theory that they increase the amount of gastric distension and thus augment satiety responses.
- they have been discontinued because, while they were not shown to be any better than restricted diets in promoting weight loss, their long term use was associated with severe side effects such as gastric ulceration and migration of the balloons into the small intestine resulting in intestinal obstructions.
- the potential benefit is to reduce the side effects of each drug given at higher doses and to provide a synergy of therapy.
- the present invention is based on known compounds and offers such novel combination as a modality of new therapy for weight loss.
- composition comprising: a pharmaceutically acceptable satiety agent such as an appetite suppressant that acts by central mechanism including amantadine, phenylpropanolamine and other such compounds that curtail appetite or satiety response for specific food groups or food in general.
- a pharmaceutically acceptable satiety agent such as an appetite suppressant that acts by central mechanism including amantadine, phenylpropanolamine and other such compounds that curtail appetite or satiety response for specific food groups or food in general.
- a pharmaceutically acceptable satiety agent such as an appetite suppressant that acts by central mechanism including amantadine, phenylpropanolamine and other such compounds that curtail appetite or satiety response for specific food groups or food in general.
- a pancreatic lipase inhibitor such as orlistat or polyols (Pluronic L 101 or 81) in quantities sufficient to produce a partial or total reversible block of lipase enzyme.
- This invention is based on a combination of satiety or appetite controlling agents which each individually, mechanistically effect and control food intake differently, while together create a synergy and produce a high satiating result without the side-effects of which each satiety or appetite controlling agent individually may cause.
- the novel combination allows for different food intake control agents to perform better in the combination, with a result of lower side-effects and allow for lower dose intake.
- the synergy between the pharmaceutical appetite controlling agents produces the novel and unobvious results of a safer and more effective satiety effect.
- the satiety combination comprises a dopaminergic agent and a lipase inhibitor.
- the satiety combination comprises a dopaminergic agent and a pancreatic lipase inhibitor or an inhibitor of intestinal transport of fat.
- the satiety combination comprises a dopaminergic agent with orilistat a pharmaceutical composition manufactured by Hoffman-LaRoche (Roche Laboratories) under the commercial name Xenical.
- Orlistat is a molecule having an empirical formula of C29H53O5, with a molecular weigh of 495.75, comprising of the following derivatives: (1) (S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)-3-hexyl-4-oxo- 2-oxetanyl] methylj-dodecyl ester; (2) L-Leucine, N-formyl-, l-[(3-hexyl-4-oxo-2- oxentanyl)methyl]dodecyl ester, [2S-2((R*),3(]]-; (3) N-formyl-L-leucine, ester with (3S,4S0-3-hexyl-4-[2S]-2-hydroxytridecyl]-2-oxetanone, and has the following structural formula:
- Another combination of the satiety combination comprises a dopaminergic agent and a polyol, otherwise defined as a block polymer.
- the block polymer which is a polyoxyethylene-polyoxypropylene block polymer or poloxamer that conforms generally to the formula:
- the dopaminergic agent is an amine of tricyclo-decane, and more specifically is tricyclo[3,3,l,l]decan-l-amine;l-adama ⁇ tanamine; 1-aminoadamantane; 1- aminodiamantane, l-aminotricyclo[3,3,l,l]decane.
- the dopaminergic agent is a molecule having an empirical formula of C10H17N with a molecular weight of 151.26, and conforms generally to the following formula:
- the dopaminergic agent is amantadine, a molecule commercially manufactured under the name Symmetrol by DuPont.
- the doses given may vary based on body surface area per kilogram, however typical therapeutic dosage of amantadine is 200 mg/day.
- Dopaminergic agents such as amines of tricylco- decanes mimic the actions of dopamine and show a biochemical effect in the brain to reduce appetite; specifically this pharmaceutical agent, amantadine, a widely used drug, which acts as an anti-viral agent, causes an increase in dopamine synthesis, release and the inhibition of re-uptake of noradrenaline and dopamine in central and periperal catecholminergic neurons. The toxicity of this drag is well suited for routme human use. In an experiment conducted on rats it was found that amantadine at a small dose level (1 mg) in rats had significant (statistically) effect on body weight gain.
- Lipase inhibitors function by decreasing the breakdown of triglycerides and other fats of an absorbable form.
- the activity of forming a covalent bond with the active serine residue site of gastric and pancreatic lipases occurs in the lumen of the stomach and small intestine.
- the inactivated enzymes are thus unavailable to hydrolyze dietary fat in the form of triglycerides into absorbable free fatty acids and nomoglycerides. These undigested unabsorbable triglycerides allow for a caloric deficit which in turn results in weight loss. Systemic absorption of the drug is therefore not needed for activity.
- the body By inhibiting the pancreatic lipase enzymes from interacting with the triglycerides and other absorbable fats the body is prevented from digesting the carbohydrates that it takes in, and thus, creates an effective reduction in caloric absorption, despite continued consumption.
- the lipase inhibitors include orlistat, pluronic L-81 or pluronic L-101.
- the doses given may vary based on body surface area per kilogram, however a typical therapeutic dosage of the pancreatic lipase inhibitor, such as orlistat, alone is 120 mg three times a day, and results in an inhibition of dietary fat absorption of approximately 30%.
- each satiety agent, dopaminergic agent and a pancreatic lipase inhibitor affect the amount of body weight gained in a subject; however, in combination the synergy between the two results in a unique and enhanced reduction in body weight that demonstrates an enhanced activity of the satiety agents, without the noted side effects.
- pancreatic lipase inhibitor has a reversible effect on the amount of lipase enzyme available in the intestine to digest fat.
- the lipase inhibitor can only inhibit so much, and thus can not complete withdraw or maintain an inhibition throughout, resulting in a less effective satiety agent.
- a central nervous system appetite suppressor at a lower dose than if taken alone, allows for the subject to reduce body weight effectively by inl ibiting fat absorbing enzymes and also controlling brain receptors to suppress the further food intake that is the side-effect of the lipase inhibitor alone.
- Each rat was weighed in the morning and then administered a dose of treatment described above.
- the table below summarized the body weight data of these animals.
- Orlistat is a white to off-white crystalline powder. Orlistat is practically insoluble in water, freely soluble in chloroform, and very soluble in methanol and ethanol. Orlistat has no p K a within the physiological pH range.
- XENICAL is available for oral administration in dark-blue, hard-gelatin capsules, with light-blue imprinting.
- Each capsule contains 120 mg of the active ingredient, orlistat.
- the capsules also contain the inactive ingredients microcrystalline cellulose, sodium starell glycolate, sodium lauryl sulfate, povidone, and talc.
- Each capsule shell contains gelatin, titanium dioxide, and FD&C Blue No. 1, with printing of pharmaceutical glaze NF, titanium dioxide, and FD&C Blue No. I aluminum lake.
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Abstract
This invention includes a combination of satiety or appetite controlling agents which create a synergy and produce a high satiating result without the side-effects of which each satiety or appetite controlling agent individually may cause. The novel combination allows for different food intake control agents to perform better in the combination, with a result of lower side-effects and allow for lower dose intake. The synergy between the pharmaceutical appetite controlling agents produces the novel and unobvious results of a safer and more effective satiety effect.
Description
A COMBINATION OF APPETITE CONTROLLING AGENTS WHICH CREATE A SYNERGY AND PRODUCE A SATIATING RESULT
Field of the Invention
This invention relates to a composition and method for controlling carbohydrate craving and reducing absorption of fats in the food of humans. More particularly, the invention concerns the reduction in caloric absorption, in a mammal, by a two-prong approach: reducing satiety response for carbohydrates while reducing the absorption of fats using a known lipase inhibitor.
Background of the Invention
A major class of weight control agents are drugs which act on the central nervous system (CNS) to suppress appetite. One major subclass of CNS appetite suppressant drugs interacts with cathecolaminergic receptors in the brainstem. These include controlled drugs such as amphetamine, phenmetrazine, and diethylproprion, and over-the-counter drags such as phenylpropanolamine. Manizidol is another CNS active drag which, although not a catecholamine, activates the central nervous system. Each of these agents have potential for addiction and, at doses which effectively reduce appetite, i.e., suppress food intake by 20- 30%, they induce significant CNS side effects, such as nervousness, loss of concentration, and insomnia. Another class of CNS active appetite control drugs interferences with serotonergic systems. D-fenfluramine, for example, releases and depletes brain serotonin, but it causes sedation at appetite suppressant levels, and it may precipitate depression upon its withdrawal. Fluoxetine is an inhibitor of serotonin reuptake in the brainstem. However, at effective appetite control doses, Fluoxetine often causes nausea asthenia, i.e., weakness, lassitude. Amantadine, is another drug, that also acts on the central nervous system, by affecting the extracellular levels of dopamine and norepinephrine in the brain and in the periphery and decreases the levels of prolactin. Prolatin works to promote adiposity and weight gain. Consequently, this satiety agent, works as an anorectic drag in that it acts on the
lateral hypothalamus and reduced the intake of food, while also enhancing the bodies metabolism rate when levels of prolactin are decreased.
Another major class of weight control agents is drugs, which promote malabsorption of nutrients through suppression of digestive enzymes. One agent in this category is Acarbose, a bacterial inhibitor of amylase and brushborder glycosidases. Another is tetrahydrolipostatin, a fungal inhibitor of Upases. Another category of compounds is that of polyols, particularly Pluronic L-101 or 81, which specifically inhibit pancreatic lipase enzyme and thus reduce breakdown of triglycerides and other fat forms of an absorbable form. Included in this category is orlistat (Xenical) that interferes in the absorption of dietary fat. These agents work by preventing digestion of carbohydrates and/or fats, thus creating an effective reduction in the number of calories absorbed, despite continued consumption. One drawback is that virtually complete inhibition of the respective enzymes must be maintained throughout the digestive period, a situation that can be rarely achieved. Thus, Acarbose was shown to be ineffective in humans, and tetrahydrolipostatin was shown to reduce human absorption of fat by only 30%. A second major drawback to this approach is that subjects taking these agents develop hyperphagia for other foodstuffs. For example, subjects taking tetrahydrolipostatin will consume more carbohydrate to compensate, thus increasing the intake of food, especially of foodstuffs of a different class.
A third class of weight control agents are noncaloric, non-nutritive dietary substitutes, like saccharin or Nutrasweet, sugar substitutes, and sucrose polyester, a fat substitute. These agents, while not absorbed, provide a taste and/or texture like the nutrient for which they are substituted. The disadvantage of these substitutes is that persons develop a hyperphagia to compensate for the reduction of calories by the substitution. With sucrose polyester, a nondigestible lipid, fat soluble, enterohepatically circulated vitamins partition into the
unabsorbed polyester and are lost from the body, a potential problem that can also occur with tetrahydrolipostatin.
Thermogenic drugs are also sometimes used. The catecholamine drugs discussed above have some thermogenic activity, in addition to their suppression of appetite. Thyroid hormone is also commonly used.
Semi-starvation diets are universally effective in short term weight loss, but regain of weight after resumption of less restricted diets is the rale. Long-term use of semi starvation diets is nutritionally unsound because of the development of multiple deficiencies of essential nutrients.
Surgical devices have also been employed to control appetite. Intragastric balloons have been placed endoscopically according to the theory that they increase the amount of gastric distension and thus augment satiety responses. However, they have been discontinued because, while they were not shown to be any better than restricted diets in promoting weight loss, their long term use was associated with severe side effects such as gastric ulceration and migration of the balloons into the small intestine resulting in intestinal obstructions.
Patients with morbid obesity (about 3% of the overweight population) are often encouraged to undergo bariatic surgery because, as a class, they suffer from more than four times the incidence of diabetes, cardiovascular disease, uterine and breast cancer, degenerative joint disease, and social stigmatization. Ileojejunal bypass, the first such surgery undertaken 30 years ago, has now been abandoned because of severe side effects such as poor subsequent malnutrition, fatal cirrhosis or renal failure. Biliopancreatic by-pass, gastric by-pass, and gastric partitioning (stapling) are the current procedures, but the long- term side effects have not yet been determined.
Summary Of The Invention
It is an object of the present invention to provide a composition and method for reducing weight by a combination approach whereby two drugs each acting on a different mechanism that controls food intake and food absorption are combined. The potential benefit is to reduce the side effects of each drug given at higher doses and to provide a synergy of therapy. The present invention is based on known compounds and offers such novel combination as a modality of new therapy for weight loss.
Accordingly, there is provided a composition comprising: a pharmaceutically acceptable satiety agent such as an appetite suppressant that acts by central mechanism including amantadine, phenylpropanolamine and other such compounds that curtail appetite or satiety response for specific food groups or food in general. Mixed with satiety or appetite controlling agents is a pancreatic lipase inhibitor such as orlistat or polyols (Pluronic L 101 or 81) in quantities sufficient to produce a partial or total reversible block of lipase enzyme.
Detailed Description Of The Invention
This invention is based on a combination of satiety or appetite controlling agents which each individually, mechanistically effect and control food intake differently, while together create a synergy and produce a high satiating result without the side-effects of which each satiety or appetite controlling agent individually may cause. The novel combination allows for different food intake control agents to perform better in the combination, with a result of lower side-effects and allow for lower dose intake. The synergy between the pharmaceutical appetite controlling agents produces the novel and unobvious results of a safer and more effective satiety effect.
The satiety combination comprises a dopaminergic agent and a lipase inhibitor. Particularly, the satiety combination comprises a dopaminergic agent and a pancreatic lipase inhibitor or an inhibitor of intestinal transport of fat.
Specifically, the satiety combination comprises a dopaminergic agent with orilistat a pharmaceutical composition manufactured by Hoffman-LaRoche (Roche Laboratories) under the commercial name Xenical. Orlistat is a molecule having an empirical formula of C29H53O5, with a molecular weigh of 495.75, comprising of the following derivatives: (1) (S)-2-formylamino-4-methyl-pentanoic acid (S)-1-[[(2S, 3S)-3-hexyl-4-oxo- 2-oxetanyl] methylj-dodecyl ester; (2) L-Leucine, N-formyl-, l-[(3-hexyl-4-oxo-2- oxentanyl)methyl]dodecyl ester, [2S-2((R*),3(]]-; (3) N-formyl-L-leucine, ester with (3S,4S0-3-hexyl-4-[2S]-2-hydroxytridecyl]-2-oxetanone, and has the following structural formula:
Another combination of the satiety combination comprises a dopaminergic agent and a polyol, otherwise defined as a block polymer. Specifically, the block polymer, which is a polyoxyethylene-polyoxypropylene block polymer or poloxamer that conforms generally to the formula:
HO (CH2CH2O)x y (CEfeCKfeoyi
CH,
The average values of x, y and z can vary as follows: x, z = 2-128 and y = 16-67; preferably x, y and z may be 6, 29 and 6, known as poloxamer 231 or commercially known as Pluronic L-81, or the average values of x, y, and z are respectively 7, 54 and 7, recognized as poloxamer 331, and commercially known as Pluronic L-101. Both Pluronic L-81 and L-101 are manufactured by BASF.
The dopaminergic agent is an amine of tricyclo-decane, and more specifically is tricyclo[3,3,l,l]decan-l-amine;l-adamaιιtanamine; 1-aminoadamantane; 1- aminodiamantane, l-aminotricyclo[3,3,l,l]decane. The dopaminergic agent is a molecule having an empirical formula of C10H17N with a molecular weight of 151.26, and conforms generally to the following formula:
More specifically, the dopaminergic agent is amantadine, a molecule commercially manufactured under the name Symmetrol by DuPont. Furthermore, in humans, the doses given may vary based on body surface area per kilogram, however typical therapeutic dosage of amantadine is 200 mg/day.
Pharmaceutical agents that act on the central nervous system and increase the amount of dopamine synthesis, in essence directly affect the neural feeding mechanism, effectively decrease food intake. Because of the interrelationship between dopamine and reward,
domapaminergic agents are useful for the treatment of substance abuse and other addictive behavior disorders such as eating disorders. Dopaminergic agents such as amines of tricylco- decanes mimic the actions of dopamine and show a biochemical effect in the brain to reduce appetite; specifically this pharmaceutical agent, amantadine, a widely used drug, which acts as an anti-viral agent, causes an increase in dopamine synthesis, release and the inhibition of re-uptake of noradrenaline and dopamine in central and periperal catecholminergic neurons. The toxicity of this drag is well suited for routme human use. In an experiment conducted on rats it was found that amantadine at a small dose level (1 mg) in rats had significant (statistically) effect on body weight gain.
Lipase inhibitors, specifically pancreatic lipase enzyme inhibitors, function by decreasing the breakdown of triglycerides and other fats of an absorbable form. Typically, the activity of forming a covalent bond with the active serine residue site of gastric and pancreatic lipases occurs in the lumen of the stomach and small intestine. The inactivated enzymes are thus unavailable to hydrolyze dietary fat in the form of triglycerides into absorbable free fatty acids and nomoglycerides. These undigested unabsorbable triglycerides allow for a caloric deficit which in turn results in weight loss. Systemic absorption of the drug is therefore not needed for activity. By inhibiting the pancreatic lipase enzymes from interacting with the triglycerides and other absorbable fats the body is prevented from digesting the carbohydrates that it takes in, and thus, creates an effective reduction in caloric absorption, despite continued consumption. Specifically, the lipase inhibitors include orlistat, pluronic L-81 or pluronic L-101. Furthermore, in humans, the doses given may vary based on body surface area per kilogram, however a typical therapeutic dosage of the pancreatic lipase inhibitor, such as orlistat, alone is 120 mg three times a day, and results in an inhibition of dietary fat absorption of approximately 30%.
Alone each satiety agent, dopaminergic agent and a pancreatic lipase inhibitor, affect the amount of body weight gained in a subject; however, in combination the synergy between the two results in a unique and enhanced reduction in body weight that demonstrates an enhanced activity of the satiety agents, without the noted side effects.
Although the inventor does not wish to be bound by any particular theory of the invention, it is believed that alone the pancreatic lipase inhibitor has a reversible effect on the amount of lipase enzyme available in the intestine to digest fat. Typically, the lipase inhibitor can only inhibit so much, and thus can not complete withdraw or maintain an inhibition throughout, resulting in a less effective satiety agent. Additionally, subjects that ingest lipase inhibitors alone, as an appetite suppressant, develop hyperphagia for other foodstuffs, hi essence, subjects that ingest lipase inhibitors alone tend to consume more carbohydrates to compensate for the loss of fat absorption, and result in an increased consumption of different class foodstuffs. Therefore, the addition of a central nervous system appetite suppressor, at a lower dose than if taken alone, allows for the subject to reduce body weight effectively by inl ibiting fat absorbing enzymes and also controlling brain receptors to suppress the further food intake that is the side-effect of the lipase inhibitor alone.
Working Example One hundred forty male Sprague-Dawley rats weighing about 100 gm (and thus in fast body growth phase) were individually caged and allowed to acclimatize to their environment. High calorie diet and water were given ad libitum-fed and the animals were stored at ambient temperature in a diurnal light arrangement. Upon 6 days of stabilization, the animals were randomly divided into: a. control receiving water b. amantadine solution at a dose of 10 mg/kg
c. amantadine 10 mg/kg and orlistate 10 mg kg d. amantadine 10 mg/kg and pluronic LI 01 20 mg/kg e. orlistat 10 mg/kg and pluronic L101 20 mg/kg f. orlistat 10 mg/kg g. Pluronic LI 01 20 mg/kg
Each rat was weighed in the morning and then administered a dose of treatment described above. The table below summarized the body weight data of these animals.
Percentage Change in Body Weight over Control
*: Statistically insignificant compared to control (p > 0.05)
At the start of the study, the groups of rats assigned to different treatment groups were identical weights. By day 7 significant changes were observed between the control (group given water alone) and the treatment group receiving drugs or their combinations. Pluronic L 101 given alone had a greater observed effect than orlistat; given in combination there was a synergy indicating that perhaps the two lipase inhibotrs act through a different mechanism enhancing the total effect; use of amantadine alone resulted in a weight loss somewhat less but comparable to the loss of weight from the use of orlistat alone. However combination of amantadine with orlistat or Pluronic L 101 provided the most significant change in weight loss.
Since the studies were conducted on male rats the theory about prolactin role in the effect of amantadine is ruled out.
Orlistat is a white to off-white crystalline powder. Orlistat is practically insoluble in water, freely soluble in chloroform, and very soluble in methanol and ethanol. Orlistat has no p K a within the physiological pH range.
XENICAL is available for oral administration in dark-blue, hard-gelatin capsules, with light-blue imprinting. Each capsule contains 120 mg of the active ingredient, orlistat. The capsules also contain the inactive ingredients microcrystalline cellulose, sodium starell glycolate, sodium lauryl sulfate, povidone, and talc. Each capsule shell contains gelatin, titanium dioxide, and FD&C Blue No. 1, with printing of pharmaceutical glaze NF, titanium dioxide, and FD&C Blue No. I aluminum lake.
While the invention will be further described in connection with certain preferred embodiments, it is not intended to limit the invention to those embodiments. On the contrary, it is intended to cover all alternatives, modifications and equivalents as may be included within the spirit and scope of the invention.
Claims
1. A method for controlling appetite comprising: selecting a pharmaceutically acceptable dopaminergic agent; selecting a pharmaceutically acceptable lipase inhibitor; formulating said dopaminergic agent and said lipase inhibitor in a dosage form in a therapeutically effective amount.
2. A pharmaceutical composition for controlling appetite comprising: a selected satiety agent controlling the amount of dopamine synthesis, said selected satiety agent combined with a selected lipase inhibitor reducing the absorption of fats, wherein said combination comprising satiety agent with a selected lipase inhibitor is orally administered to a subject.
3. A method of controlling appetite according to claim 1, wherein said dopaminergic agent is an amine of tricyclo-decane.
4. A method of controlling appetite according to claim 1, wherein said dopaminergic agent is tricyclo[3,3,l,l]decane-l-amine.
5. A method of controlling appetite according to claim 1, wherein said lipase inhibitor is a pancreatic lipase inhibitor.
6. A method of controlling appetite according to claim 1 , wherein said lipase inhibitor is orlistat.
7. A method of controlling appetite according to claim 1, wherein said lipase inhibitor is block polymer.
8. A method of controlling appetite according to claiml, wherein said lipase inhibitor is a poloxamer.
9. A method of controlling appetite according to claim 1 , wherein said lipase inhibitor is a polyxyethylene-polyoxypropylene block polymer.
10. A method of controlling appetite according to claim 1, wherein said lipase inhibitor is poloxamer 331.
11. A method of controlling appetite according to claim 1, wherein said lipase inhibitor is poloxamer 231.
12. A method of controlling appetite according to claim 1, wherein said effective amount is orally administered to a subject in an effective dosage.
13. A pharmaceutical composition according to claim 2, wherein said satiety agent controlling the amount of dopamine synthesis is an amine of tricyclo-decane.
14. A pharmaceutical composition according to claim 2, wherein said satiety agent controlling the amount of dopamine synthesis is tricyclo[3,3,l,l]decane-l-amine.
15. A pharmaceutical composition according to claim 2, wherein said lipase inhibitor is a pancreatic lipase inhibitor.
16. A pharmaceutical composition according to claim 2, wherein said lipase inhibitor is orlistat.
17. A pharmaceutical composition according to claim 2, wherein said lipase inhibitor is a block polymer.
18. A pharmaceutical composition according to claim 2, wherein said lipase inhibitor is a polyethylene-polyoxypropylene block polymer.
19. A pharmaceutical composition according to claim 2, wherein said lipase inhibitor is poloxamer 231.
20. A pharmaceutical composition according to claim 2, wherein said lipase inhibitor is poloxamer 331.
21. A method of controlling appetite comprising: combining an appetite controlling pharmaceutically effective amount of amantidine, with an appetite controlling pharmaceutically effective amount of orlistat, and orally administering to a subject.
22. A method of controlling appetite comprising: combining an appetite controlling pharmaceutically effective amount of amantidine, with an appetite controlling pharmaceutically effective amount of polyoxyethylene- polyoxypropylene block polymer, and orally administering to a subject.
23. A pharmaceutical composition for controlling appetite comprising: an effective, pharmaceutically acceptable amount of amantadine, said amantadine combined with an effective, pharmaceutically acceptable amount of orlistat, wherein said combination comprising amantadine and said orlistat is ingested by a subject.
24. A pharmaceutical composition for controlling appetite comprising: an effective, pharmaceutically acceptable amount of amantadine, said amantadine combined with an effective, pharmaceutically acceptable amount of polyoxyethylene-polyoxypropylene block copolymer, wherein said combination comprising amantadine and said polyoxyethlene-polyoxypropylene block copolymer is ingested by a subject.
25. A method according to claim 21, wherein said satiety formulation orally administered reduced a subject's body weight by 15% to 40%.
26. A method according to claim 21, wherein said satiety formulation orally administered reduced a subject's body weight by 20% to 35%.
27. A method according to claim 21, wherein said satiety formulation orally administered reduced a subject's body weight by 32.7%.
28. A method according to claim 22, wherein said satiety formulation orally administered reduced a subject's body weight by 15% to 30%.
29. A method according to claim 22, wherein said satiety formulation orally administered reduced a subject's body weight by 18% to 28%.
30. A method according to claim 1, wherein said satiety formulation orally administered reduced a subject's body weight by 24.7%.
31. A pharmaceutical composition according to claim 23, wherein said satiety formulation reduces a subject's body weight by 15% to 40%.
32. A pharmaceutical composition according to claim 23, wherein said satiety formulation reduces a subject's body weight by 20% to 35%.
33. A pharmaceutical composition according to claim 23, wherein said satiety formulation reduces a subject's body weight by 32.7%.
34. A pharmaceutical composition according to claim 24, wherein said satiety formulation reduces a subject's body weight by 15% to 30%.
35. A pharmaceutical composition according to claim 24, wherein said satiety formulation reduces a subject's body weight by 18% to 28%.
36. A pharmaceutical composition according to claim 23, wherein said satiety formulation reduces a subj ect's body weight by 15% to 40%.
37. A pharmaceutical composition according to claim 24, wherein said satiety formulation reduces a subject's body weight by 24.7%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU2001268731A AU2001268731A1 (en) | 2000-09-27 | 2001-06-27 | A combination of appetite controlling agents which create a synergy and produce a satiating result |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US67184700A | 2000-09-27 | 2000-09-27 | |
| US09/671,847 | 2000-09-27 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2002026104A2 true WO2002026104A2 (en) | 2002-04-04 |
| WO2002026104A3 WO2002026104A3 (en) | 2009-06-04 |
Family
ID=24696103
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2001/020420 WO2002026104A2 (en) | 2000-09-27 | 2001-06-27 | A combination of appetite controlling agents which create a synergy and produce a satiating result |
Country Status (2)
| Country | Link |
|---|---|
| AU (1) | AU2001268731A1 (en) |
| WO (1) | WO2002026104A2 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3592426A4 (en) * | 2017-03-09 | 2020-11-04 | Yeditepe Üniversitesi | A product for obesity treatment |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5244915A (en) * | 1990-08-31 | 1993-09-14 | Warner-Lambert Company | Amico acid derivatives cyclized at the c-terminal |
| US6235305B1 (en) * | 1999-10-29 | 2001-05-22 | 2Pro Chemical | Essentially nonabsorbable lipase inhibitor derivatives, pharmaceutical compositions and methods of use therefor |
| US6258836B1 (en) * | 1988-02-26 | 2001-07-10 | Protarga, Inc. | Dopamine analog amide |
-
2001
- 2001-06-27 WO PCT/US2001/020420 patent/WO2002026104A2/en active Application Filing
- 2001-06-27 AU AU2001268731A patent/AU2001268731A1/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6258836B1 (en) * | 1988-02-26 | 2001-07-10 | Protarga, Inc. | Dopamine analog amide |
| US5244915A (en) * | 1990-08-31 | 1993-09-14 | Warner-Lambert Company | Amico acid derivatives cyclized at the c-terminal |
| US6235305B1 (en) * | 1999-10-29 | 2001-05-22 | 2Pro Chemical | Essentially nonabsorbable lipase inhibitor derivatives, pharmaceutical compositions and methods of use therefor |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3592426A4 (en) * | 2017-03-09 | 2020-11-04 | Yeditepe Üniversitesi | A product for obesity treatment |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2002026104A3 (en) | 2009-06-04 |
| AU2001268731A8 (en) | 2009-07-16 |
| AU2001268731A1 (en) | 2002-04-08 |
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