WO2010039039A1 - Formulations orales de dérivés de gemcitabine - Google Patents
Formulations orales de dérivés de gemcitabine Download PDFInfo
- Publication number
- WO2010039039A1 WO2010039039A1 PCT/NO2009/000331 NO2009000331W WO2010039039A1 WO 2010039039 A1 WO2010039039 A1 WO 2010039039A1 NO 2009000331 W NO2009000331 W NO 2009000331W WO 2010039039 A1 WO2010039039 A1 WO 2010039039A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- composition according
- gemcitabine
- surfactant
- active ingredient
- Prior art date
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
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising certain long 5 chain saturated and monounsaturated fatty acid derivatives of 2',2'-difluorodeoxy- cytidine (Gemcitabine) as the active ingredient
- the present invention relates to a pharmaceutical composition and the method of preparation thereof, suitable for oral administration of therapeutically effective doses of the said derivatives in order to ameliorate compliance in treatment of cancer.
- Gemcitabine which is a well known cytostatic compound, marketed under the trade name Gemzar by Eli Lilly & Co., has the formula:
- Gemzar is administered intravenously (i.v.).
- the reason for choosing a parenteral administration route is due to the toxicity of gemcitabine.
- Oral administration is usually more acceptable for the patients compared to intravenous 20 administration.
- the active ingredients of the pharmaceutical composition of the present invention comprise gemcitabine derivatives of the formula I:
- R 1 , R 2 and R 3 are independently selected from hydrogen and Ci 8 - and C 2 o- saturated and monounsaturated acyl groups, with the proviso that R 1 , R 2 and R 3 cannot all be hydrogen.
- the gemcitabine derivatives of formula (I) have poor aqueous solubility and in silico modelling predicted that the oral absorption of these derivatives most probably would be limited by their solubility rather than their permeability through intestinal cells. This means that in order to increase the extent of absorption and bioavailability, the composition of the excipients in the oral dosage forms should be selected so that the said derivatives were better solubilized.
- solubilization strategy by using a careful selection of excipients means that the amount of the active substance, the gemcitabine derivatives of formula (I), in the final dosage will be reduced accordingly.
- a daily therapeutic dose of several grams, it is essential to find a formulation that can physically and technologically accommodate and solubilize a highest possible content of the active substance in order to reduce the number of the tablets or capsules or other dosage units that the patient needs to take.
- lipid-based formulations were investigated. These types of formulations have liquid or semi-solid character meaning that encapsulation of the final composition is necessary.
- the encapsulation technology based on filling and banding of two-piece hard shell capsules was selected. However, such formulations are also good candidates for filling in soft shell capsules.
- a pharmaceutical composition comprising a gemcitabine derivative of formula I:
- Ri, R 2 and R 3 are independently selected from hydrogen and C 18 - and C 20 - saturated and monounsaturated acyl groups, with the proviso that R 1 , R 2 and R 3 cannot all be hydrogen, or a pharmaceutically acceptable salt thereof as the active ingredient; wherein the active ingredient is dissolved or dispersed in a lipid-based formulation, comprising a lipophilic phase alone, or in combination with a surfactant and/or a co- surfactant, is provided.
- Genicitabine has three derivatisable functions, namely the 5'- and 3'-hydroxyl groups and the N 4" amino group.
- Each group can selectively be transformed into an ester or amide derivative, but di-adducts (di-esters or ester-amides) and tri-adducts may be formed as well.
- di- and tri-adducts the acyl substituent groups need 5 not necessarily be the same.
- the mono-acyl derivatives i.e. with two of Ri, R 2 and R 3 being hydrogen, are preferred for use as the active ingredient of the present pharmaceutical composition. It is especially preferred that the monosubstitution with the acyl group should be in the 3'-0 io and 5'-0 positions of the sugar moiety, with 5'-0 substitution being most preferred.
- the double bond of the mono-unsaturated acyl groups may be in either the cis or the trans configuration, although the therapeutic effect may differ depending on which configuration is used.
- the position of the double bond in the monounsaturated acyl groups also seem to affect the activity.
- esters or amides having their unsaturation in the ⁇ -9 position.
- the position ⁇ of the double bond of a monounsaturated fatty acid is counted from the terminal methyl group, so that, for0 example, eicosenoic acid (C 20 : 1 ⁇ -9) has 20 carbon atoms in the chain and a single double bond is formed between carbon 9 and 10 counting from the methyl end of the chain.
- Esters, ester-amides and amides of gemcitabine derived from stearic acid (Ci 8 :0) and eicosanoic acid (C 20 :0) are advantageously used in some cases.
- Elaidic acid (N 4 )-Gemcitabine amide, elaidic acid (5')-gemcitabine ester and elaidic0 acid (3')-gemcitabine ester are among the most preferred derivatives, and according to a preferred embodiment of the invention elaidic acid (5')-gemcitabine ester is the active ingredient of the pharmaceutical composition.
- the derivatives of formula (I) are prepared according to methods known in the prior art5 (see WO 98/32762 for further details).
- the lipophilic phase of the formulation may comprise the following excipients, which function as vehicles and/or bioavailability enhancers: medium chain or long chain triglycerides (e.g. Capmul MCM or Miglyol 812), mono- faty acid esters of glycerol such as glyceryl monolinoleate (e.g. Maisine 35:1) or glyceryl monooleate (e.g. Peceol), fatty acid esters of propylene glycol such as propylene glycol monocaprylate (e.g.
- medium chain or long chain triglycerides e.g. Capmul MCM or Miglyol 812
- mono- faty acid esters of glycerol such as glyceryl monolinoleate (e.g. Maisine 35:1) or glyceryl monooleate
- Capryol 90 or propylene glycol caprylate (e.g Capryol PGCM), polyglyceryl oleate (e.g. Plurol Oleique CC497) and polyglycolized glycerides (e.g. Labrasol, Gelucire 44/14 or Gelucire 50/13).
- propylene glycol caprylate e.g Capryol PGCM
- polyglyceryl oleate e.g. Plurol Oleique CC497
- polyglycolized glycerides e.g. Labrasol, Gelucire 44/14 or Gelucire 50/13.
- the lipophilic phase of the pharmaceutical composition is selected from the C8-C18 polyglycolized glycerides with high HLB value of 10-16, preferably lauroyl macro golglycerides or stearoyl macrogolglycerides , more preferably Gelucire 44/14 from Gattefosse.
- a surfactant with high HLB value of 10-16 is present in the pharmaceutical composition.
- the surfactant preferably comprises C8-C10 polyglycolized glycerides, more preferred Labrasol from Gattefosse.
- a co-surfactant is present in the pharmaceutical composition.
- the co-surfactant has a low HLB value of 3 - 6 and preferably consists of caprylic or lauric esters of propylene glycol, more preferably propylene glycol laurate with the trade name of Lauroglycol FCC from Gattefosse, and still more preferably propylene glycol monolaurate with the trade name Lauroglycol 90 from Gattefosse.
- the pharmaceutical composition comprises elaidic acid (5')-gemcitabine ester, Gelucire 44/14, Labrasol, and Lauroglycol 90.
- excipients of the pharmaceutical composition are selected to solubilize or to increase the solubility of the compounds of formula (I), or the rate of dispersion or dissolution of the compounds of formula (I) from the formulation in the gastrointestinal environment.
- the pharmaceutical composition according to the invention may be in solid, semisolid or liquid form, and may be presented in discrete units such as tablets, capsules or the like, or presented in multi-dosing units.
- the pharmaceutical form of the composition / may be powder, granules, solution, suspension, emulsion, (nano/micro) self- p emmnullsciiftfy ⁇ inng ⁇ , r*r or
- terapéuticaally effective amount refers to from about 0.001 to 10 grams per day of a gemcitabine derivative of formula (I) or a pharmaceutically acceptable salt thereof, more preferred from about 10 mg to 6 grams per day of a gemcitabine derivative of formula (I) or a pharmaceutically acceptable salt thereof, in a formulation containing 0.001 - 100% of the said derivative or salt thereof formulated for oral administration.
- the amount of the lipophilic phase may vary from about 1% to 99.99%, preferably 1 - 75%, and more preferably 10 - 60% of the pharmaceutical composition.
- the amount of the surfactant may vary from 0 to 90%, preferably 0.1 - 50%, more preferably 5 - 25% of the pharmaceutical composition.
- the amount of the co-surfactant may vary from 0 to 90%, preferably 0.1 - 50%, more preferably 1 - 25% of the pharmaceutical composition.
- the present invention also provides a process for the preparation of a pharmaceutical composition as mentioned above.
- the said process comprises the steps of melting all excipients before addition of the active substance in a suitable aliquot of the melt followed by addition of increasing portion of the melt and high shear stirring, or addition of the active substance to any of the melted excipients comprising the lipid- based formulation alone before further dilution of the concentrated mixture with the remainder of the excipients and high-shear stirring.
- a pharmaceutical wetting agent may initially be added to the active substance before mixing with the lipid excipients.
- the wetting agents are polymers, surfactants, carbohydrates, polysaccharides, mineral solids, oils, alcohols or acids, organic or inorganic.
- the final bulk product is kept at a defined temperature so that the molten mass has an optimum viscosity to be prosessed in the capsule- filling machine.
- the filled capsules are then banded appropriately and allowed to dry.
- These capsules may be coated with an acid-resistant polymer (enteric coating) to release the active substance in the upper intestine or with other polymers to release the active substance in lower parts of intestine.
- acid-resistant polymer enteric coating
- examples of such polymers are polymethacrylic acid copolymers or cellulose derivatives such as hydroxypropyl methylcellulose, hydroxyethylcellulose, cellulose acetate phthalate or the like.
- the molten mass may be used for preparation of solid formulations through granulation, pelletization, or the like, and encapsulation or tab letting of the final solid particles.
- excipients such as diluents, lubricants, glidants, disintegrants, and/or binding agents may be added.
- Formulations were prepared using lipids alone or in combination with other excipients in an attempt to prepare a suitable lipid-based formulation for manufacturing hard shell capsules of elaidic acid (5') gemcitabine ester with high concentration of the active substance.
- Gelucire 44/14 (75% w/w), Labrasol (20% w/w) and Lauroglycol 90 (5% w/w).
- the final mass ratio of elaidic acid (5') gemcitabine ester to the total mass was 1 :2 before capsule filling. This means that the final pharmaceutical composition was active substance 50%, Gelucire 44/14 37.5% , Labrasol 10%, Lauroglycol 90 2.5%.
- the method of manufacturing was by melting the excipients and (high-shear) stirring of the active material, which is suitable for large scale manufacturing.
- example 1 was investigated in the TEVI-I system simulating the average conditions in the stomach and small intestine of healthy adults during the fasting state (with intake of water on empty stomach) and fed state (with intake of high fat meal, according to the FDA requirements). These conditions include especially the dynamics of gastric emptying and small intestinal transit times, the gastric and the intestinal pH values, and the composition of the oral, gastric and duodenal secretion products (electrolytes, digestive enzymes, bile).
- the filtrate fraction in the jejunum and ileum segment was sampled throughout the study (5-6 hours) and is defined as the bioaccessible fraction of the initial dose (the fraction of the active compound that is potentially available for intestinal absorption in vivo). Also the Ileum effluent containing the non-bioaccessible fraction of the dose was sampled in the same time intervals. All samples were analysed for elaidic acid (5') gemcitabine ester and gemcitabine using HPLC. The capsules released their content within the first 4 minutes after the start of the experiment. During the five hours of the gastrointestinal passage under fasted condition, no precipitation was observed visually in any of the compartments of TIM-I. Under fed condition, this could not be investigated due to the presence of food resulting in opaque character of the fluids.
- Figure 1 shows the amount of the bioaccessible elaidic acid (5') gemcitabine ester (as percentage of the initial dose) recovered in the jejunum and ileum filtrate samples per time fraction. The results show that:
- elaidic acid (5') gemcitabine ester 3 male fasted Beagle dogs received one single dose of 15 mg/kg elaidic acid (5') gemcitabine ester. Plasma samples were collected at predefined time intervals. As expected, practically no prodrug (elaidic acid (5') gemcitabine ester) was detected, but a high amount of gemcitabine was observed in plasma.
- the geometric mean of AUC for 20 gemcitabine was 8160 ng/ml with a coefficient of variance (CV) of onlyl5.3% meaning that there was a low interdog variation in the absorption of gemcitabine.
- the geometric mean of Tmax was 0.87 h indicating a rapid absorption.
- the safety profile of the orally administered elaidic acid (5') gemcitabine ester is similar to that of the intravenousely administered product.
- doses up to 1600 mg/m2/day were administered.
- the dose limiting toxicity was fatigue grade 3.
- the most frequent toxicities included nausea, fatigue, vomiting and anorexia, the majority of mild intensity (CTCAE grade 1 and 2).
- the recommended dose (RD) for the intravenous administration in this treatment schedule is 1250 mg/m2 /d.
Abstract
L'invention concerne des formulations orales de certains dérivés d'acides gras saturés et monoinsaturés à longues chaînes de 2',2'-difluorodéoxycytidine (gemcitabine). En particulier, l'invention concerne une composition pharmaceutique et son procédé de préparation, afin d’adapter et d'améliorer l'absorption orale de doses thérapeutiquement efficaces desdits dérivés en améliorant leur conformité avec le traitement du cancer.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10243408P | 2008-10-03 | 2008-10-03 | |
US61/102,434 | 2008-10-03 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010039039A1 true WO2010039039A1 (fr) | 2010-04-08 |
Family
ID=42073684
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/NO2009/000331 WO2010039039A1 (fr) | 2008-10-03 | 2009-09-23 | Formulations orales de dérivés de gemcitabine |
Country Status (2)
Country | Link |
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TW (1) | TW201018470A (fr) |
WO (1) | WO2010039039A1 (fr) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011128629A3 (fr) * | 2010-04-14 | 2012-05-18 | Probio Asa | Compositions de médicament à vecteurs lipidiques |
EP2501364A1 (fr) * | 2009-11-20 | 2012-09-26 | Clavis Pharma ASA | Formulations parentérales de dérivés de gemcitabine |
US8497292B2 (en) | 2005-12-28 | 2013-07-30 | Translational Therapeutics, Inc. | Translational dysfunction based therapeutics |
US8956613B2 (en) | 2012-11-13 | 2015-02-17 | BoYen Therapeutics, Inc. | Gemcitabine prodrugs and uses thereof |
CN109310631A (zh) * | 2016-06-02 | 2019-02-05 | 因华生技制药股份有限公司 | 供癌症医疗的节拍式口服吉西他宾 |
US10463684B2 (en) | 2014-01-29 | 2019-11-05 | Board Of Regents, The Uneversety Of Texas System | Nucleobase analogue derivatives and their applications |
CN110713502A (zh) * | 2019-11-29 | 2020-01-21 | 南京科技职业学院 | 一种吉西他滨杂质的合成方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1998032762A1 (fr) * | 1997-01-24 | 1998-07-30 | Norsk Hydro Asa | Derives de gemcitabine |
US6054136A (en) * | 1993-09-30 | 2000-04-25 | Gattefosse S.A. | Orally administrable composition capable of providing enhanced bioavailability when ingested |
FR2874016A1 (fr) * | 2004-06-30 | 2006-02-10 | Centre Nat Rech Scient | Nanoparticules de derives de la gemcitabine |
WO2006098628A1 (fr) * | 2005-03-18 | 2006-09-21 | Clavis Pharma As | Formes de dosage oral de derives de gemcitabine |
CN1981741A (zh) * | 2005-11-23 | 2007-06-20 | 兰贝克赛实验室有限公司 | 使用自乳化药物送递系统改进前体药物的生物利用度的方法 |
-
2009
- 2009-09-23 WO PCT/NO2009/000331 patent/WO2010039039A1/fr active Application Filing
- 2009-10-01 TW TW098133355A patent/TW201018470A/zh unknown
Patent Citations (5)
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US6054136A (en) * | 1993-09-30 | 2000-04-25 | Gattefosse S.A. | Orally administrable composition capable of providing enhanced bioavailability when ingested |
WO1998032762A1 (fr) * | 1997-01-24 | 1998-07-30 | Norsk Hydro Asa | Derives de gemcitabine |
FR2874016A1 (fr) * | 2004-06-30 | 2006-02-10 | Centre Nat Rech Scient | Nanoparticules de derives de la gemcitabine |
WO2006098628A1 (fr) * | 2005-03-18 | 2006-09-21 | Clavis Pharma As | Formes de dosage oral de derives de gemcitabine |
CN1981741A (zh) * | 2005-11-23 | 2007-06-20 | 兰贝克赛实验室有限公司 | 使用自乳化药物送递系统改进前体药物的生物利用度的方法 |
Non-Patent Citations (1)
Title |
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DATABASE WPI Week 200814, Derwent World Patents Index; AN 2008-B78734, XP003026357 * |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10472677B2 (en) | 2005-12-28 | 2019-11-12 | Translational Therapeutics, Inc. | Translational dysfunction based therapeutics |
US8497292B2 (en) | 2005-12-28 | 2013-07-30 | Translational Therapeutics, Inc. | Translational dysfunction based therapeutics |
EP2501364A1 (fr) * | 2009-11-20 | 2012-09-26 | Clavis Pharma ASA | Formulations parentérales de dérivés de gemcitabine |
EP2501364A4 (fr) * | 2009-11-20 | 2012-10-24 | Clavis Pharma Asa | Formulations parentérales de dérivés de gemcitabine |
WO2011128629A3 (fr) * | 2010-04-14 | 2012-05-18 | Probio Asa | Compositions de médicament à vecteurs lipidiques |
US9890189B2 (en) | 2012-11-13 | 2018-02-13 | BoYen Therapeutics, Inc. | Gemcitabine prodrugs and uses thereof |
US9540410B2 (en) | 2012-11-13 | 2017-01-10 | BoYen Therapeutics, Inc. | Gemcitabine prodrugs and uses thereof |
US8956613B2 (en) | 2012-11-13 | 2015-02-17 | BoYen Therapeutics, Inc. | Gemcitabine prodrugs and uses thereof |
US10463684B2 (en) | 2014-01-29 | 2019-11-05 | Board Of Regents, The Uneversety Of Texas System | Nucleobase analogue derivatives and their applications |
US11219633B2 (en) | 2014-01-29 | 2022-01-11 | Board Of Regents, The University Of Texas System | Nucleobase analogue derivatives and their applications |
US11883423B2 (en) | 2014-01-29 | 2024-01-30 | Board Of Regents, The University Of Texas System | Nucleobase analogue derivatives and their applications |
CN109310631A (zh) * | 2016-06-02 | 2019-02-05 | 因华生技制药股份有限公司 | 供癌症医疗的节拍式口服吉西他宾 |
US10835548B2 (en) * | 2016-06-02 | 2020-11-17 | Innopharmax, Inc. | Metronomic oral gemcitabine for cancer therapy |
CN110713502A (zh) * | 2019-11-29 | 2020-01-21 | 南京科技职业学院 | 一种吉西他滨杂质的合成方法 |
Also Published As
Publication number | Publication date |
---|---|
TW201018470A (en) | 2010-05-16 |
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