AU2002216085A1 - Self Emulsifying Lipid Matrix (SELM) - Google Patents
Self Emulsifying Lipid Matrix (SELM)Info
- Publication number
- AU2002216085A1 AU2002216085A1 AU2002216085A AU2002216085A AU2002216085A1 AU 2002216085 A1 AU2002216085 A1 AU 2002216085A1 AU 2002216085 A AU2002216085 A AU 2002216085A AU 2002216085 A AU2002216085 A AU 2002216085A AU 2002216085 A1 AU2002216085 A1 AU 2002216085A1
- Authority
- AU
- Australia
- Prior art keywords
- pharmaceutical composition
- composition according
- active compound
- phenyl
- emulsifier
- 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.)
- Granted
Links
Description
Self Emulsifying Lipid Matrix ( SEL )
The present invention relates to novel galenic compositions and, in particular, to compositions for oral administration of medicaments.
Oral dosage forms are designed to enable sufficient availability of the active compound on its site of action. The bioavailability of a drug depends on several parameters, such as the physicochemical nature of the active compound, the dosage form, as well as physiological factors.
Many substances obtained from modern drug discovery are problematic in view of a sufficient bioavailability. Furthermore, such molecules often exhibit a very low aqueous solubility and also show a limited solubility in oils, so that a problem arises if high drug loads must be obtained. This is often the case with compositions in form of soft or hart gelatin capsules, wherein not only the solubility of the drug in the medium is very low, but also the filling volume of the capsules is limited.
In order to enhance the bioavailability of orally administered drugs, Self-Emulsifying Drug Delivery Systems (SEDDS) ma be used. SEDDS are mixtures of oils and surfactants, ideally isotropic, sometimes including cosolvents, which emulsify under conditions of gentle agitation, similar to those which would be encountered in the gastro intestinal tract. When such a composition is released into the lumen of the gut, it disperses to form a fine emulsion, so that the drug remains in solution in the gut, avoiding the dissolution step which frequently limits the rate of absorption of hydrophobic drugs from the crystalline state. This usually leads to improved bioavailability and/or a more consistent temporal profile of absorption from the gut. A description of compositions of SEDDS can be found for instance in C. W. Pouton, Advanced Drug Delivery Reviews, 25, (1997), 47-58.
While SEEDS increase the bioavailability, the solubility of the drugs in such systems is not always considerably increased. Additionally, it must be considered that SEEDS compositions are usually administered by means of capsules, whose volume cannot be arbitrarily increased without negatively affecting the patient's compliance. In the case of elevated daily therapeutic amounts, a patient is therefore obliged to swallow several capsules to provide his body with the necessary amount of drug.
The problem at the root of the present invention is therefore to provide a galenic composition for oral administration of medicaments which show low bioavailability and poor solubility in polar and/or apolar media.
According to the present invention, this problem is solved by providing a pharmaceutical composition for oral administration of an active compound showing a bioavailability of 20% or less, characterized in that it comprises, based on the total weight of the composition, from 0.01% to about 15% (w/w) of said active compound molecularly dissolved in the composition, from 30 to 80% (w/w) of an edible lipid matrix and from 1 to 20% (w/w) of an edible emulsifier, the ratio between the dose weight (mg) of the active compound and its solubility (mg/ml) in the composition being equal to or greater than 0.6 ml.
The definition of the bioavailability is given in the examples and the above value of 20% or less is determined on the basis of a simple oral formulation (e.g. a hard gelatin capsule) without additional exipients and wherein the active compound is in the crystalline form.
The dissolution of solid pharmaceutical active compounds in polar and apolar media is dealt for instance in A. Martin, Physical Pharmacy. 4th ed., Lea Febiger London, (1993), 221-237.
The composition according to the present invention can be defined as Self- Emulsifying Lipid Matrix (SELM) since, as the SEEDS compositions, it emulsifies at 37°C under condition of gentle agitation. The high percentage of fat (30-80%) enables to considerably increase the amount of drug molecularly dispersed in the dosage form. SELM formulations are applicable in the cases where the volume available for the molecular dispersion of the drug must be equal to or greater than 0.6 ml. The volume available for the molecular dispersion of the drug is defined as ratio between the dose weight of the active compound in the single dose (mg) and its solubility (mg/ml) in the composition.
This enables to significantly reduce the number of unit doses which must be taken daily by patients, thus increasing the overall acceptance of a given medicament. In fact, it has been often demonstrated, in particular in the case of children and aged people, that the positive result of a therapy also depends on the patient's compliance which, on its turn, is negatively affected by a complex posology.
Furthermore, the relative high amount of emulsifier confers to the present composition the self-emulsifying character which, as stated above, enables to considerably increase the bioavailability of the active compound in the body.
The pharmaceutical compositions according to the present invention can be administered in form of chewing tablets having a visual aspect similar to that of chocolate bars of different forms and sizes, or that of normal chocolates (pralines).
This enables to have a single dose volume, and therefore a drug load, which is sensibly higher than those of conventional SEEDS compositions which, on their turn, have to be administered by swallowing capsules.
Preferably, the composition of the invention has a visual aspect similar to that of normal chocolates (pralines).
According to a preferred embodiment, the ratio between the dose weight of the active compound and its solubility in the composition is equal to or greater than 1.2 ml, more preferably it varies between 0.6 and 10 ml and, still more preferably, between 3 and 7 ml.
According to a further preferred embodiment of the present invention, the edible lipid matrix is present in a concentration varying from 50 to 75% (w/w) of the total weight of the composition, and can be chosen among the natural and semi-synthetic vegetable triglycerides, such as coconut butter and cocoa butter, and hard fat (hydrogenated vegetable glycerides) respectively. Most preferably, cocoa butter is used as lipid matrix.
The edible emulsifier is preferably chosen among those which do not show substantial side effects. Advantageously, it is present in a concentration varying from 1 to 10% (w/w) and, still more advantageously, in a concentration varying from 2 to 8% (w/w) of the total weight of the composition. It is preferably selected from the group consisting of lecithins, such as natural lecithin, synthetic lecithin, soyalecithin, egglecithin, synthetic dipalmitinlecithin, partially or fully hydrogenated lecithin and mixtures thereof, polyglycolized triglycerides, such as Cremophor EL and Cremophor RH and polyethylenglycol sorbitane fatty esters, such as Polysorbate 20, 40, 65, 80 and 85.
Most preferably lecithin, and in particular soyalecithin, is used as emulsifier in the present compositions.
To obtain a better acceptance, the composition according to the present invention may contain further additives in usual concentrations. These include sweeteners, such as sucrose and aspartame, as well as flavors such as vanillin, honey and nut flavor.
As stated above, the present invention is suitable for the oral administration of active compounds which show a low bioavailability. Active compounds having a bioavailability of 20% or less, preferably of 10% or less, can be suitably administered by means of the composition according to the present invention. Examples of these active compounds can
be found among the sulfonamides, dihydropiridines, isoquinoline derivatives, 4- phenylpyridin derivatives and phenylamino-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)- phenyl] derivatives.
According to a preferred embodiment, the present composition is used for active compounds selected among the group of the 4-phenylpyridin derivatives such as
2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl- pyridin-3 -yl) -isobutyramide;
2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-l-yl)-4-o- tolyl-pyridin-3-yl] -isobutyramide; and
2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl- isobutyramide.
The above three compounds, whose synthesis maybe found in EP-A-1035115, are characterized by valuable therapeutic properties. They are highly selective antagonists of the Neurokinin 1 (NK-1, substance P) receptor. Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being so-named because of their prompt contractile action on extravascular smooth muscle tissue.
The neuropeptide receptor for substance P (NK-1) is widely distributed throughout the mammalian nervous system (especially brain and spinal ganglia), the circulatory system and peripheral tissues (especially the duodenum and jejunum) and are involved in regulating a number of diverse biological processes.
The central and peripheral actions of the mammalian tachykinin substance P have been associated with numerous inflammatory conditions including migraine, rheumatoid arthritis, asthma, and inflammatory bowel disease as well as mediation of the emetic reflex and the modulation of central nervous system (CNS) disorders such as Parkinson's disease (Neurosci. Res., 1996, 7, 187-214), anxiety (Can. J. Phys., 1997, 75, 612-621) and depression (Science, 1998, 281, 1640-1645).
Evidence for the usefulness of tachykinin receptor antagonists in pain, headache, especially migraine, Alzheimer's disease, multiple sclerosis, attenuation of morphine withdrawal, cardiovascular changes, oedema, such as oedema caused by thermal injury, chronic inflammatory diseases such as rheumatoid arthritis, asthma/bronchial hyperreactivity and other respiratory diseases including allergic rhinitis, inflammatory diseases of the gut including ulcerative colitis and Crohn's disease, ocular injury and ocular
inflammatory diseases has been reviewed in "Tachykinin Receptor and Tachykinin Receptor Antagonists", J. Auton. Pharmacol., 13, 23-93, 1993.
Furthermore, Neurokinin 1 receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinin, in particular substance P. Examples of conditions in which substance P has been implicated include disorders of the central nervous system such as anxiety, depression and psychosis (WO 95/16679, WO 95/18124 and WO 95/23798).
The neurokinin- 1 receptor antagonists are further useful for the treatment of motion sickness and for treatment induced vomiting.
In addition, the reduction of cisplatin-induced emesis by a selective neurokinin- 1- receptor antagonist has been described in The New England Journal of Medicine, Vol. 340, No. 3, 190-195, 1999.
The usefulness of neurokinin 1 receptor antagonists for the treatment of certain forms of urinary incontinence is further described in Neuropeptides, 32(1), 1-49, (1998) and Eur. J. Pharmacol., 383(3), 297-303, (1999).
An object of the present invention is also to provide a process for preparing a pharmaceutical composition as described above, which process comprises mixing, based on the total weight of the composition, from 0.01% to about 15% (w/w) of an active compound showing a bioavailability of 20% or less, from 30 to 80% (w/w) of an edible lipid matrix and from 1 to 20% (w/w) of an edible emulsifier, the ratio between the dose weight of the active compound and its solubility in the composition being equal to or greater than 0.6 ml. Preferably the entire manufacture process is carried out in a conventional industrial mixer with a build-in homogenizer. The dosing is preferably done with molds or by direct filling of suitably designed blisters.
The invention will be now illustrated in details by the following examples.
Examples 1-4 relate to four compositions according to the present invention, while comparative Example 5 is directed to a SEEDS composition.
The solubility of 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4- yl-4-o-tolyl-pyridin-3-yl)-isobutyramide in cocoa butter/lecithin mixtures has been measured and found to be less than 15 mg/ml.
A. PREPARATION OF THE COMPOSITIONS
Example 1
8 g Cremophor RH 40 were dispersed in 70.08 g of cocoa butter, previously warmed to 70-80°C. The temperature of the resulting mixture was then reduced to about 50-60°C and 1.4 g of 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl- pyridin-3-yl)-isobutyramide were dissolved together with 0.02 g vanillin. The temperature of the resulting mixture was further reduced to 40°C and 0.5 g aspartame were added. Finally, 20 g of milk powder were added at about 35°C (upper limit of the melting interval of cocoa butter). The resulting homogeneous mixture was then dosed in moulds whereby SELM tablets of 5 g each (corresponding to a volume of about 5 ml), and showing a ratio between the dose weight of the active compound and its solubility in the composition of at least 4.67" ml, were obtained.
Example 2
The procedure of Example 1 was repeated with the following composition: 1.4 g 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o- tolyl-ρyridin-3-yl)-isobutyramide
70.08 g Cocoa butter
8.0 g Lipoid S 100
20.0 g Whole milk powder
0.5 g Aspartame
0.02 g Vanillin
Example 3 The procedure of Example 1 was repeated with the following composition: 1.4 g 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o- tolyl-ρyridin-3-yl) -isobutyramide
77.08 g Cocoa butter
1.0 g Cremophor RH 40
20.0 g Whole milk powder
0.5 g Aspartame
0.02 g Vanillin
Example 4 The procedure of Example 1 was repeated with the following composition:
1.4 g 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o- tolyl-pyridin-3-yl)-isobutyramide
74.08 g Cocoa butter
4.0 g Lipoid S 40
20.0 g Skimmed milk powder
0.5 g Aspartame 0.02 g Vanillin
Example 5 (comparative SEEDS composition)
0.21 g 2-(3,5-Bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl- pyridin-3-yl)-isobutyramide were weighted in a 20 ml glass vial. 11.79 g of SEDDS (obtained by mixing 4.95 g Tween 80 and 6.84 g Miglyol 812 under vigorous stirring and at 70°C) were added thereto and the active compound was brought into solution, always under stirring and at 70°C. A yellow clear solution was obtained as final product.
B. TEST OF ORAL BIOAVAILABILITY IN DOGS
Oral bioavailability tests were performed with beagle dogs. Each composition was orally administered to the different beagle dogs typically at a dose of 6 mg/kg body weigh. Blood samples were collected during 48 h and the drug concentration was determined using a HPLC method. The blood concentrations after oral and intravenous administration were plotted against time and the areas under the curve for the per oral (AUCp.o.) and intravenous (AUQ.V) drug administration were calculated individually and using the trapezoidal rule. The bioavailability (%) was obtained from the dose normalized AUCorai divided by the dose normalized AUQV..
As shown in Table 1, the compositions according to the present invention showed excellent bioavailabilities up to 68%, as well as excellent drug loads of 70 mg per unit dose.
Table 2 shows that classical solid compositions did not enable sufficient bioavailability of the drug 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin- 4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide. The use of SEEDS compositions enabled an increase of the bioavailability of 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6- morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide up to 27%. However the limitation of the capsule volume did not allow to dissolve more than 20 mg of 2-(3,5-bis-
trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)- isobutyramide per hard gelatin capsule (standard size 00).
Table 1
Bioavailability of 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o- tolyl-pyridin-3-yl)-isobutyramide from the new drug delivery system (SELM)
* calculated from AUC (0-8h) ** best result obtained
Table 2
Bioavailability of 2-(3, 5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o- tolyl-pyridin-3-yl) -isobutyramide from compositions with crystalline drug and SEDDS
The compositions according to the present invention enable to considerably increase the drug load of active compounds which are hardly soluble in water and/or oil. Since it can be administered in form of chewing tablets, the present compositions may have elevated single dose volumes. This enables to further improve the drug load and, simultaneously, to reduce the number of unit doses to be taken daily.
Furthermore, the relative high amount of emulsifier confers to the present composition the self- emulsifying character which enables to considerably increase the bioavailability of the active compound in the body.
Claims (1)
- Claims1. Pharmaceutical composition for oral administration of an active compound showing a bioavailability of 20% or less, characterized in that it comprises, based on the total weight of the composition, from 0.01% to about 15% (w/w) of said active compound molecularly dissolved in the composition, from 30 to 80% (w/w) of an edible lipid matrix and from 1 to 20% (w/w) of an edible emulsifier, the ratio between the dose weight of the active compound and its solubility in the composition being equal to or greater than 0.6 ml.2. Pharmaceutical composition according to claim 1, wherein the edible lipid matrix is present in a concentration varying from 50 to 75% (w/w) of the total weight of the composition.3. Pharmaceutical composition according to claim 1 or 2, wherein the emulsifier is present in a concentration varying from 1 to 10% (w/w) of the total weight of the composition.4. Pharmaceutical composition according to claim 3, wherein the emulsifier is present in a concentration varying from 2 to 8% (w/w) of the total weight of the composition.5. Pharmaceutical composition according to any one of the preceding claims, wherein the lipid matrix is selected from the group consisting of natural vegetable triglycerides, semi-synthetic vegetable triglycerides and hydrogenated vegetable glycerides.6. Pharmaceutical composition according to claim 5, wherein the lipid matrix is cocoa butter.7. Pharmaceutical composition according to any one of the preceding claims, wherein the emulsifier is selected from the group consisting of lecithins and polyglycolized triglycerides.8. Pharmaceutical composition according to claim 7, wherein the emulsifier is soyalecithin.9. Pharmaceutical composition according to any one of the preceding claims, further comprising sweeteners and/or flavors.10. Pharmaceutical composition according to any one of the preceding claims, wherein the ratio between the dose weight of the active compound and its solubility in the composition is equal to or greater than 1.2 ml.11. Pharmaceutical composition according to claim 10, wherein the ratio between the dose weight of the active compound and its solubility in the composition varies between1.2 and 10 ml.12. Pharmaceutical composition according to claim 11, wherein the ratio between the dose weight of the active compound and its solubility in the composition varies between 3 and 7 ml.13. Pharmaceutical composition according to any one of the preceding claims, wherein the active compound is selected from the group consisting of sulfonamides, dihydropiridines, isoquinoline derivatives, 4-phenylpyridin derivatives and phenylamino- [5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl] derivatives.14. Pharmaceutical composition according to claim 13, wherein the active compound is a 4-phenylpyridin derivative.15. Pharmaceutical composition according to claim 14, wherein the active compound is selected from the group consisting of 2-(3,5-bis-trifluoromethyl-phenyl)-N- methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide; 2-(3,5-bis- trifluoromethyl-phenyl)-N-methyl-N-[6-(4-methyl-piperazin-l-yl)-4-o-tolyl-pyridin-3- yl] -isobutyramide; and 2-(3,5-bis-trifluoromethyl-phenyl)-N- [4-(2-chloro-phenyl)- pyridin-3-yl]-N-methyl-isobutyramide.16. Process for preparing a pharmaceutical composition according to any one of claims 1 to 15, comprising mixing, based on the total weight of the composition, from 0.01% to about 15% (w/w) of an active compound showing a bioavailability of 20% or less, from 30 to 80% (w/w) of an edible lipid matrix and from 1 to 20% (w/w) of an edible emulsifier, the ratio between the dose weight of the active compound and its solubility in the composition being equal to or greater than 0.6 ml.17. The invention as herein before described.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP00127414.1 | 2000-12-14 | ||
| EP00127414 | 2000-12-14 | ||
| PCT/EP2001/014437 WO2002047663A1 (en) | 2000-12-14 | 2001-12-08 | Self emulsifying lipid matrix (selm) |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| AU2002216085A1 true AU2002216085A1 (en) | 2002-08-29 |
| AU2002216085B2 AU2002216085B2 (en) | 2005-11-03 |
| AU2002216085B8 AU2002216085B8 (en) | 2006-03-02 |
Family
ID=8170664
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2002216085A Expired AU2002216085B8 (en) | 2000-12-14 | 2001-12-08 | Self Emulsifying Lipid Matrix (SELM) |
| AU1608502A Pending AU1608502A (en) | 2000-12-14 | 2001-12-08 | Self emulsifying lipid matrix (selm) |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU1608502A Pending AU1608502A (en) | 2000-12-14 | 2001-12-08 | Self emulsifying lipid matrix (selm) |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US6719996B2 (en) |
| EP (1) | EP1349541B1 (en) |
| JP (1) | JP4116436B2 (en) |
| KR (1) | KR100602299B1 (en) |
| CN (1) | CN1263446C (en) |
| AR (1) | AR032783A1 (en) |
| AT (1) | ATE341311T1 (en) |
| AU (2) | AU2002216085B8 (en) |
| BR (1) | BRPI0116121B8 (en) |
| CA (1) | CA2431397C (en) |
| DE (1) | DE60123661T2 (en) |
| DK (1) | DK1349541T3 (en) |
| ES (1) | ES2272408T3 (en) |
| MX (1) | MXPA03005169A (en) |
| PT (1) | PT1349541E (en) |
| WO (1) | WO2002047663A1 (en) |
| ZA (1) | ZA200304263B (en) |
Families Citing this family (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2001279284A1 (en) * | 2000-07-05 | 2002-01-14 | Capricorn Pharma, Inc | Rapid-melt semi-solid compositions, methods of making same and methods of using same |
| SE0200475D0 (en) * | 2002-02-15 | 2002-02-15 | Ltp Lipid Technologies Provide | Oral pharmaceutical preparation |
| SE0201922D0 (en) * | 2002-06-20 | 2002-06-20 | Ltp Lipid Technologies Provide | Anticoagulant Composition |
| DE602005026669D1 (en) | 2004-07-06 | 2011-04-14 | Hoffmann La Roche | METHOD OF PREPARING CARBOXAMIDE PYRIDINE DERIVATIVES AS INTERMEDIATE PRODUCTS IN THE SYNTHESIS OF NK-1 RECEPTOR ANTAGONISTS |
| UA90708C2 (en) | 2005-02-25 | 2010-05-25 | Ф. Хоффманн-Ля Рош Аг | Tablets with improved drug substance dispersibility |
| US20070104780A1 (en) * | 2005-10-25 | 2007-05-10 | Lipari John M | Formulation comprising a drug of low water solubility and method of use thereof |
| US7767248B2 (en) * | 2007-02-02 | 2010-08-03 | Overly Iii Harry J | Soft chew confectionary with high fiber and sugar content and method for making same |
| US20090011079A1 (en) * | 2007-07-02 | 2009-01-08 | Bestsweet, Inc. | Hard Coated Confectionary Having A Consumable Soft Chewing Core With An Active And Method For Making Same |
| EP2722045B1 (en) | 2009-11-18 | 2016-07-06 | Helsinn Healthcare SA | Compositions for treating centrally mediated nausea and vomiting |
| CN106512010A (en) | 2009-11-18 | 2017-03-22 | 赫尔辛医疗股份公司 | Compositions for treating centrally mediated nausea and vomiting |
| EP2744497B1 (en) | 2011-10-18 | 2016-04-06 | Helsinn Healthcare SA | Therapeutic combinations of netupitant and palonosetron |
| US8426450B1 (en) | 2011-11-29 | 2013-04-23 | Helsinn Healthcare Sa | Substituted 4-phenyl pyridines having anti-emetic effect |
| CN107404893B (en) * | 2015-02-26 | 2021-01-26 | 日清奥利友集团株式会社 | Powdered fat composition for chocolate |
| WO2017044693A1 (en) | 2015-09-11 | 2017-03-16 | Chase Pharmaceuticals Corporation | Muscarinic combination and its use for combating hypocholinergic disorders of the central nervous system |
| AU2018251604B2 (en) | 2017-04-10 | 2022-04-14 | Chase Therapeutics Corporation | NK1-antagonist combination and method for treating synucleinopathies |
| EP3645120A4 (en) | 2017-06-30 | 2021-03-24 | Chase Pharmaceuticals Corporation | Nk-1 antagonist compositions and methods for use in treating depression |
| CN109200018A (en) * | 2017-07-04 | 2019-01-15 | 南京诺瑞特医药科技有限公司 | Containing how the smooth microemulsion formulation of appropriate pyrrole |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL117773A (en) * | 1996-04-02 | 2000-10-31 | Pharmos Ltd | Solid lipid compositions of coenzyme Q10 for enhanced oral bioavailability |
| DK1394150T3 (en) * | 1999-02-24 | 2011-03-21 | Hoffmann La Roche | 4-phenylpyridine derivatives and their use as NK-1 receptor antagonists |
| US6375982B1 (en) * | 2000-07-05 | 2002-04-23 | Capricorn Pharma, Inc. | Rapid-melt semi-solid compositions, methods of making same and method of using same |
-
2001
- 2001-12-08 ES ES01270324T patent/ES2272408T3/en not_active Expired - Lifetime
- 2001-12-08 KR KR1020037007899A patent/KR100602299B1/en active IP Right Grant
- 2001-12-08 CA CA002431397A patent/CA2431397C/en not_active Expired - Lifetime
- 2001-12-08 DE DE60123661T patent/DE60123661T2/en not_active Expired - Lifetime
- 2001-12-08 AU AU2002216085A patent/AU2002216085B8/en not_active Expired
- 2001-12-08 PT PT01270324T patent/PT1349541E/en unknown
- 2001-12-08 DK DK01270324T patent/DK1349541T3/en active
- 2001-12-08 BR BRPI0116121A patent/BRPI0116121B8/en not_active IP Right Cessation
- 2001-12-08 AU AU1608502A patent/AU1608502A/en active Pending
- 2001-12-08 WO PCT/EP2001/014437 patent/WO2002047663A1/en active IP Right Grant
- 2001-12-08 AT AT01270324T patent/ATE341311T1/en active
- 2001-12-08 EP EP01270324A patent/EP1349541B1/en not_active Expired - Lifetime
- 2001-12-08 JP JP2002549237A patent/JP4116436B2/en not_active Expired - Lifetime
- 2001-12-08 MX MXPA03005169A patent/MXPA03005169A/en active IP Right Grant
- 2001-12-08 CN CNB018206085A patent/CN1263446C/en not_active Expired - Lifetime
- 2001-12-10 US US10/015,925 patent/US6719996B2/en not_active Expired - Lifetime
- 2001-12-12 AR ARP010105764A patent/AR032783A1/en not_active Application Discontinuation
-
2003
- 2003-05-30 ZA ZA200304263A patent/ZA200304263B/en unknown
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2431397C (en) | Self emulsifying lipid matrix (selm) | |
| AU2002216085A1 (en) | Self Emulsifying Lipid Matrix (SELM) | |
| CN105848646B (en) | The purposes of compressed tablets comprising cannabidiol, its manufacturing method and such tablet in oral medication mental illness or anxiety disorder | |
| US9737609B2 (en) | Natural suspending agent including a synergistic blend of xanthan gum and konjac powder for oral pharmaceutical suspensions | |
| WO2020016656A2 (en) | Extended release formulations of cannabinoids | |
| JP2009531305A (en) | Method of solubilizing, dispersing and stabilizing substances, products produced by the method and use thereof | |
| WO2019082171A1 (en) | Oral cannabinoid compositions with improved bioavailability | |
| US20220257772A1 (en) | Preparation of lipophilic active ingredients | |
| JP2003525893A (en) | Novel self-emulsifying drug delivery system | |
| PL189654B1 (en) | Solid pharmaceutical compositions containing miltefosine for oral administration in the treatment of leishmaniasis | |
| DE10392164T5 (en) | Oral pharmaceutical formulation | |
| JP3837062B2 (en) | Compound granular solid preparation containing poorly soluble drug | |
| US9421268B2 (en) | Pediatric oral liquid compositions containing nepadutant | |
| Mohammad et al. | Simultaneous Formulation, Evaluation and Estimation of Self Emulsifying Drug Delivery System (SEDDS) of Ibuprofen Tablet Dosage form using Varied quantities of Goat Fat as an Excipient and Tween-60 as a Surfactant | |
| WO2000054775A1 (en) | Stable pharmaceutical application form for paroxetin anhydrate | |
| GB2614129A (en) | Chewable semi-solid milk-based drug delivery platform and method for the preparation of milk-based drug compositions and its use |