WO1999006031A1 - Pharmaceutical formulation for camptothecin analogues in gelatin capsule - Google Patents
Pharmaceutical formulation for camptothecin analogues in gelatin capsule Download PDFInfo
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- WO1999006031A1 WO1999006031A1 PCT/US1998/015908 US9815908W WO9906031A1 WO 1999006031 A1 WO1999006031 A1 WO 1999006031A1 US 9815908 W US9815908 W US 9815908W WO 9906031 A1 WO9906031 A1 WO 9906031A1
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- pharmaceutical composition
- topotecan
- capsule
- matrix
- fatty acid
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- 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
Definitions
- the present invention provides an oral formulation for camptothecin analogues, such as topotecan, in the form of a gelatin capsule.
- camptothecin analogues such as topotecan
- the invention provides a non-aqueous fill matrix which enables camptothecin analogues such as topotecan HCl to be administered in a stable formulation of gelatin capsules.
- the formulation of the topotecan gelatin capsules further provides a fill matrix that minimizes diffusion of the topotecan into the capsule shell as well as migration of water from the shell into the matrix.
- Camptothecin analogues such as (S)-10-[(dimethylamino)methyl]-4-ethyl- 4,9-dihyroxy-lH-pyrano [3', 4': 6,7] indolizino [1, 2-b] quinolone-3, 14 (4H, 12H) dione monohydrochloride, commonly known as topotecan hydrochloride, have demonstrated usefulness as both antineoplastic and antiviral therapeutic agents.
- Topotecan is a semi-synthetic water-soluble analog of camptothecin which is an inhibitor of topoisomerase I.
- Therapeutic use is now focused on analogues such as topotecan since early clinical trials of (S)-camptothecin (CPT) in the sixties and seventies were discontinued due to the high toxicity and low potency of CPT.
- Topotecan like other camptothecin analogs, stabilizes the covalent complex between topoisomerase I and DNA, resulting in enzyme-linked DNA cleavage and single-strand breaks.
- Topotecan HCl for Injection (Hycamtin®, SmithKline Beecham) has been approved as safe and effective by the United States Food and Drug Administration for second line therapy of refractory ovarian cancer.
- parenteral administration requires the patient to travel to the physician's office resulting in patient inconvenience.
- parenteral administration requires the patient to travel to the physician's office resulting in patient inconvenience.
- the need has arisen to develop an oral formulation of topotecan that would allow longer dosing regimens, as with continuous infusion, but without the inconvenience or discomfort to the patient.
- capsules are a convenient form for the oral administration of a variety of active agents.
- the outer shell of capsules typically have gelatin as the main ingredient and are presented as either hard or soft gelatin capsules.
- Gelatin capsules are particularly useful as a means of formulating drug substances, providing the advantage of allowing incorporation of the active ingredient in the form of a semi-solid, liquid or paste.
- the basic ingredients of the outer shell of gelatin capsules are water and gelatin. The presence of water in the capsule shell, however, has presented a disadvantage in the formulation of a drug such as topotecan, which is soluble in water to an appreciable extent.
- Topotecan HCl is hygroscopic and requires moisture protection during manufacture and storage.
- topotecan is classified as a Class I cytotoxic agent.
- any form of leakage from a capsule would present a safety concern. Therefore, formulation as a tablet or powder-filled capsule is not commercially feasible since most manufacturing facilities are not appropriately equipped to handle cytotoxic drugs.
- a thermoplastic (hot-melt) type capsule formulation would result in enhanced stability and minimization of leakage concerns.
- the present invention relates to the discovery of a hydrophobic or lipophilic matrix for formulation of camptothecin analogues such as topotecan HCl wherein the active drug is simply dispersed and not solubilized so as to minimize any chemical reaction between the active drug and the excipients.
- the fill matrix is hydrophobic in character, it melts or disperses at body temperature to allow dissolution of the capsule contents into the gastrointestinal tract. This allows for the desired absorption into the body.
- the present invention provides gelatin capsules constituting a stable formulation of topotecan that, due to the relatively hydrophobic, non-aqueous nature of the fill matrix, minimizes diffusion of the topotecan into the capsule shell while simultaneously curtailing migration of water from the shell into the matrix.
- a suitable fill matrix for the present formulation generally comprises two excipients: (1) a diluting matrix; and (2) thickening or dispersing agents, both of which are hydrophobic in nature.
- the diluting matrix comprises glycerides of fatty acids and polyethylene glycol esters of fatty acids.
- the stable topotecan formulation of the present invention is comprised of: (1) a diluting matrix; and (2) one or more thickening agents.
- the formulation may additionally contain dispersing agents or surfactants. Both the diluting matrix and thickeners are hydrophobic in nature.
- the diluting matrix component is comprised of one or more glycerides of fatty acids and polyethylene glycol esters of fatty acids.
- Suitable fatty acid glycerides for use herein include one or more medium chain (C g to C 12 ) fatty acid glycerides.
- Preferred ones include a mixture of triglycerides of hydrogenated coconut oil or palm kernel oil, commonly known as M grade WecobeeTM (obtained from Stephan, Inc., NJ) or glycerides (e.g. triglycerides) of medium chain (e.g. C 8 - C 10 ) fatty acids (e.g.
- fractionated C 8 -C 10 coconut fatty acids commonly known as Miglyol 812TM (obtained from Dynamit Nobel Co.).
- Additional preferred oily excipients useful as thickeners include mineral oils such as liquid paraffin, solid paraffins such as petrolatum, fatty alcohols such as cetyl and cetostearyl alcohols, and glycerol esters of fatty acids commonly known as WitepsolTM (obtained from Huls America).
- a particularly preferred diluting matrix comprises a mixture of glycerides (e.g. mono, di-and/or tri- glycerides) of long chain (e.g. C 12 -C 18 ) fatty acids.
- glycerides e.g. mono, di-and/or tri- glycerides
- long chain e.g. C 12 -C 18
- Gelucire® available from Gattefosse Corporation.
- the Gelucires® are available with varying physical characteristics and are identified by their melting point/HLB value, where HLB (hydrophile-lipophile balance) value is a measure of the hydrophobic or hydrophilic nature of the substance. The lower the number, the more hydrophobic the material.
- Gelucire® 33/01 is used according to the present invention.
- the stable topotecan formulation also preferably contains at least one or more thickening agents.
- the matrix comprises two excipients.
- the first of which, the thickener or dispersing agent, may constitute from about 2 to 20% (w/w), more preferably from about 5 to 10 % of the filling.
- the second excipient, the diluting matrix may then constitute from about 80 to about 95 % (w/w), more preferably from about 90 to 95 % (w/w) of the filling.
- a preferred embodiment may comprise glyceryl monostearate and hydrogenated vegetable oil.
- the topotecan formulation contains at least one fatty acid glyceride such as Softisan 378 (obtained from Huls America) or glyceryl monostearate.
- Softisan 378 obtained from Huls America
- a more preferred embodiment comprises topotecan hydrochloride, glyceryl monostearate and WecobeeTM.
- the compositions according to the invention may be prepared according to conventional techniques known in the pharmaceutical industry for the manufacture of gelatin capsules.
- the fill matrix may be prepared by adding the topotecan HCl to a molten homogeneous mixture of the fatty acid glyceride(s) and/or mineral oil(s) or paraff ⁇ n(s), and dispersing agent(s). This is then followed by thorough mixing and milling.
- a controlled absorption formulation of topotecan may be incorporated into the gelatin capsule and can be prepared by conventional techniques known to those skilled in the art. For example, suitable techniques are disclosed in U.S. Patent Nos. 4,871,548; 5,009,895; 4,389,393; 5,364,620; and 5,002,776; which are incorporated herein by reference.
- compositions of the invention may be administered to any animal which may experience the beneficial effects of the topotecan formulation of the invention.
- animals Foremost among such animals are humans, although the invention is not intended to be so limited.
- the effective amounts can be administered on the basis of body surface area.
- body surface area The interrelationship of dosages for animals of various sizes, species and humans (based on mg/M 2 of body surface) is described by E.J. Freireich et al., Cancer Chemother. Rep., 50(4):219 (1966).
- Body surface area may be approximately determined from the height and weight of an individual (see, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y. pp. 537-538 (1970).
- the amount of topotecan HCl, in the preferred composition is preferably in the range of about 0.2 to 5.0 mg, more preferably from about 0.25 to about 3.0 mg per dosage unit, expressed as the weight of free base.
- GCSF granulocyte colony stimulating factor
- more topotecan may be administered.
- the m.t.d. maximum tolerated dose
- the m.t.d. is raised to 2.5 mg/kg.
- camptothecin analogues may be used as well. Production of such analogues as well as topotecan may be found in U.S. Application No. 95/004,758 and WO Patent Application No. 92/05785 (published April 16, 1992), incorporated herein by reference.
- thermoplastic or hot-melt formulation the active component is dispersed or solubilized into a melted thermoplastic excipient, filled into capsules as liquid using fluid-filling pumps and allowed to solidify at ambient temperature.
- thermoplastic excipients are selected based on physico-chemical and thermal characteristics, chemical compatibility, and rheological properties. In general, thermoplastic excipients should have a narrow melting temperature range in the region of about 30°C to 70°C and should solidify within about 10-15 minutes at ambient conditions to avoid leakage from capsules after filling and/or during the sealing operation.
- An added advantage of this dispersion type formulation is that dosage strengths can be changed easily without changing the vehicle composition or capsule size.
- the optimal physical stability of the present formulation was determined by heating different concentrations of glyceryl monostearate and WecobeeTM mixtures together to 80°C to obtain a homogenous molten mixture, followed by cooling of the mixture to about 38°C.
- WecobeeTM hydrogenated vegetable oil
- the preferred embodiment of the present invention comprises a matrix of 5% glyceryl monostearate in WecobeeTM which is solid at ambient storage conditions but in molten state at 38-40°C.
- This lipophilic mixture can be filled as liquid at 40°C and allowed to solidify at room temperature.
- the contents of the capsule melt when ingested to release the drug into gastric fluids.
- Example 1 illustrate specific formulations and methods for their preparation. These examples are not intended to be a limitation on the scope of the invention in any respect and should not be so construed. In addition, the following examples are encompassed by the claims and their equivalents. Example 1
- a topotecan dispersion containing 5% glyceryl monostearate in WecobeeTM was prepared, filled into hard gelatin capsules and stored at various conditions. The results indicate that this formulation is stable for six months at 5°C and 30°C. however, it does show some potency loss and increased degradation (by percent peak area) at 40°C after six months. As the formulation exists in two different physical states at 30°C and 40°C, the results from 40°C may not be extrapolated to 30°C or lower temperatures.
- WecobeeTM hydrophilicity-based on the preformulation studies, thermal characteristics, chemical stability and safety considerations, a semi-solid matrix formulation containing 5% of glyceryl monostearate in WecobeeTM (hydrogenated vegetable oil) filled into hard gelatin capsules was selected.
- WecobeeTM is a mixture of triglycerides of hydrogenated coconut or palm kernel oil and has GRAS (generally regarded as safe substance) status as listed in 21 CFR 170.30 (FDA reference). It is also compatible with gelatin capsule shells.
- Imwitor 191 (Glyceryl monostearate/palmitate, approx. 90% 1- monoglycerides) is used as emulsifier, dispersing agent, stabilizer and plasticizer in a variety of pharmaceutical, food and cosmetic products.
- Glyceryl monostearate (Imwitor 191) is compatible with gelatin capsule shells, and is available in NF grade.
- Three clinical grade batches (U94223, U94224 and U94225) of topotecan hard gelatin capsules were manufactured. The capsule formulations for 0.25, 0.5 and 1.0 mg of topotecan per capsule are presented in Table 1. The stability of these batches was monitored and the stability data is summarized in Tables 2 to 4.
- the recommended storage condition for the liquid-filled hard gelatin capsule is 2-8°C (refrigeration condition) based on the available stability data.
- the process for formulation was to prepare the capsule fill by dispersing topotecan in a molten mixture of Imwitor 191/WecobeeTM using a high speed dispenser and media mill. This resulted in a homogenous liquid dispersion having the desired viscosity and drug dispersal uniformity.
- the ball mill was used for size reduction of fine solid particles and disruption of agglomerates.
- a modified version of the ball mill a horizontal media mill from Premier Inc., was evaluated for preparation of topotecan capsule fill dispersion.
- a horizontal grinding chamber with grinding beads ensures a uniform distribution of the grinding media throughout the chamber.
- a variable speed pump moves milling material (e.g., premixed suspension) through the chamber.
- the milling material is subject to both intense impact and high shear created by the grinding media, which quickly and efficiently reduces particle size.
- the grinding chamber is equipped with a water jacketed cooling/heating system, allowing the operator to accurately control the temperature of the milling process.
- a ceramic grinding chamber and ceramic beads are recommended to avoid suspension contamination by metal particles.
- Jacketed blending vessels with an effective temperature control system both for heating and cooling, and adequate stirring capacity are required for preparing topotecan capsule fill suspension.
- Mixers should contain a high-speed rotor/static head, and a low speed stirring blade, as indicated above. Construction should be such that they may be covered so as to protect the product from light during production. All product contact surfaces should preferably be constructed of 316L, electropolished stainless steel, or an equivalent that is not susceptible to corrosion.
- capsule filling and sealing machines are available and should be chosen so as to be able to deliver liquids with a fill weight RSD (relative standard deviation) of 5% or less.
- the filling hopper should be temperature controlled in order to maintain a fluid material throughout the filling process.
- the capsule filler may be outfitted with a cooling station, to facilitate solidification of semi-solid product.
- Sealing equipment should deliver a double-band (for safety), and have a running capacity similar to that of the selected capsule filler.
- the type and size of the production equipment such as compounding vessels, receiving vessels and horizontal bead mills is dependent on batch size and should be selected based on manufacturing needs and economical analysis.
- Glyceryl monostearate 13.75 mg 13.75 mg
- Glyceryl monostearate 13.75 mg 13.75 mg
- glyceryl monostearate and hydrogenated vegetable oil (Formula A) or Gelucire® (Formula B) were added to a heated vessel, and the contents stirred until both excipients had melted and the mixture was clear.
- topotecan hydrochloride was added, mixed and poured back to a heated vessel.
- a mixer was lowered into the vessel and the contents mixed for about 30 minutes.
- the resulting mixture was milled using a suitable milling apparatus to ensure that the powder was adequately wetted and that no aggregates remained.
- the filling was subsequently encapsulated to give hard gelatin capsules containing 0.25 mg or 1 mg topotecan HCl (as free base) per capsule as required.
- the capsules were sealed with clear gelatin using standard equipment.
- the Miglyol 812 and Softisan 378 were mixed to give a homogeneous mixture. While this was being stirred, the topotecan hydrochloride was added slowly. The resulting homogeneous mixture was milled using a suitable apparatus, and subsequently encapsulated to give hard gelatin capsules containing 0.25 mg or 1 mg topotecan per capsule.
- the fill matrix may also be prepared such that one excipient (Softisan 378 obtained from Huls of America, Inc.) may constitute for example 50% to 70% (w/w), more preferably 60% (w/w), of the filling.
- the second excipient e.g., MiglyolTM 812, obtained from Dynamit Nobel Co.
Abstract
The invention relates to a stable topotecan pharmaceutical composition in the form of a gelatin capsule. The invention specifically provides a hydrophobic matrix for formulation with topotecan HC1 that is dispersed so as to minimize any chemical reaction between the active drug, the excipients and ambient moisture.
Description
PHARMACEUTICAL FORMULATION FOR CAMPTOTHECIN ANALOGUES IN GELATIN CAPSULE
FIELD OF THE INVENTION The present invention provides an oral formulation for camptothecin analogues, such as topotecan, in the form of a gelatin capsule. In particular, the invention provides a non-aqueous fill matrix which enables camptothecin analogues such as topotecan HCl to be administered in a stable formulation of gelatin capsules. The formulation of the topotecan gelatin capsules further provides a fill matrix that minimizes diffusion of the topotecan into the capsule shell as well as migration of water from the shell into the matrix.
BACKGROUND OF THE INVENTION
Camptothecin analogues, such as (S)-10-[(dimethylamino)methyl]-4-ethyl- 4,9-dihyroxy-lH-pyrano [3', 4': 6,7] indolizino [1, 2-b] quinolone-3, 14 (4H, 12H) dione monohydrochloride, commonly known as topotecan hydrochloride, have demonstrated usefulness as both antineoplastic and antiviral therapeutic agents. Topotecan is a semi-synthetic water-soluble analog of camptothecin which is an inhibitor of topoisomerase I. Therapeutic use is now focused on analogues such as topotecan since early clinical trials of (S)-camptothecin (CPT) in the sixties and seventies were discontinued due to the high toxicity and low potency of CPT.
Topotecan, like other camptothecin analogs, stabilizes the covalent complex between topoisomerase I and DNA, resulting in enzyme-linked DNA cleavage and single-strand breaks. Early clinical studies of topotecan in which it was administered as a continuous infusion parenteral for up to 21 days, were shown to be safe and well tolerated. Subsequent studies performed in dogs demonstrated it to be very active in animal models of cancer when given orally. Subsequent clinical studies have demonstrated that other parenteral dosing regimens are effective in humans. Topotecan HCl for Injection (Hycamtin®, SmithKline Beecham) has been approved as safe and effective by the United States Food and Drug Administration for second
line therapy of refractory ovarian cancer. One drawback of parenteral administration is patient discomfort. Another drawback is that parenteral administration requires the patient to travel to the physician's office resulting in patient inconvenience. Thus, the need has arisen to develop an oral formulation of topotecan that would allow longer dosing regimens, as with continuous infusion, but without the inconvenience or discomfort to the patient.
It has long been known in the pharmaceutical industry that capsules are a convenient form for the oral administration of a variety of active agents. The outer shell of capsules typically have gelatin as the main ingredient and are presented as either hard or soft gelatin capsules. Gelatin capsules are particularly useful as a means of formulating drug substances, providing the advantage of allowing incorporation of the active ingredient in the form of a semi-solid, liquid or paste. The basic ingredients of the outer shell of gelatin capsules are water and gelatin. The presence of water in the capsule shell, however, has presented a disadvantage in the formulation of a drug such as topotecan, which is soluble in water to an appreciable extent.
Topotecan HCl is hygroscopic and requires moisture protection during manufacture and storage. In addition, topotecan is classified as a Class I cytotoxic agent. As such, any form of leakage from a capsule would present a safety concern. Therefore, formulation as a tablet or powder-filled capsule is not commercially feasible since most manufacturing facilities are not appropriately equipped to handle cytotoxic drugs. Thus, in light of the issues and costs associated with the safe handling of topotecan, it is desirable to formulate it as a dispersion of topotecan HCl filled into hard gelatin capsules. In particular, a thermoplastic (hot-melt) type capsule formulation would result in enhanced stability and minimization of leakage concerns.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were individually and specifically indicated to be incorporated by reference herein as though fully set forth.
SUMMARY OF THE INVENTION
The present invention relates to the discovery of a hydrophobic or lipophilic matrix for formulation of camptothecin analogues such as topotecan HCl wherein the active drug is simply dispersed and not solubilized so as to minimize any chemical reaction between the active drug and the excipients. Although the fill matrix is hydrophobic in character, it melts or disperses at body temperature to allow dissolution of the capsule contents into the gastrointestinal tract. This allows for the desired absorption into the body. Accordingly, the present invention provides gelatin capsules constituting a stable formulation of topotecan that, due to the relatively hydrophobic, non-aqueous nature of the fill matrix, minimizes diffusion of the topotecan into the capsule shell while simultaneously curtailing migration of water from the shell into the matrix. A suitable fill matrix for the present formulation generally comprises two excipients: (1) a diluting matrix; and (2) thickening or dispersing agents, both of which are hydrophobic in nature. The diluting matrix comprises glycerides of fatty acids and polyethylene glycol esters of fatty acids.
DETAILED DESCRIPTION OF THE INVENTION
The stable topotecan formulation of the present invention is comprised of: (1) a diluting matrix; and (2) one or more thickening agents. The formulation may additionally contain dispersing agents or surfactants. Both the diluting matrix and thickeners are hydrophobic in nature.
The diluting matrix component is comprised of one or more glycerides of fatty acids and polyethylene glycol esters of fatty acids. Suitable fatty acid glycerides for use herein include one or more medium chain (Cg to C12) fatty acid glycerides. Preferred ones include a mixture of triglycerides of hydrogenated coconut oil or palm kernel oil, commonly known as M grade Wecobee™ (obtained from Stephan, Inc., NJ) or glycerides (e.g. triglycerides) of medium chain (e.g. C8- C10) fatty acids (e.g. fractionated C8-C10 coconut fatty acids) commonly known as Miglyol 812™ (obtained from Dynamit Nobel Co.). Additional preferred oily excipients useful as thickeners include mineral oils such as liquid paraffin, solid
paraffins such as petrolatum, fatty alcohols such as cetyl and cetostearyl alcohols, and glycerol esters of fatty acids commonly known as Witepsol™ (obtained from Huls America).
A particularly preferred diluting matrix comprises a mixture of glycerides (e.g. mono, di-and/or tri- glycerides) of long chain (e.g. C12-C18) fatty acids. For example, such a mixture may be selected from the range of products commonly known under the trademark Gelucire® available from Gattefosse Corporation. In general such mixtures have in addition surfactant properties. The Gelucires®, in particular, are available with varying physical characteristics and are identified by their melting point/HLB value, where HLB (hydrophile-lipophile balance) value is a measure of the hydrophobic or hydrophilic nature of the substance. The lower the number, the more hydrophobic the material. In a particularly preferred embodiment, Gelucire® 33/01 is used according to the present invention.
The stable topotecan formulation also preferably contains at least one or more thickening agents. In a preferred embodiment of the invention, the matrix comprises two excipients. The first of which, the thickener or dispersing agent, may constitute from about 2 to 20% (w/w), more preferably from about 5 to 10 % of the filling. The second excipient, the diluting matrix, may then constitute from about 80 to about 95 % (w/w), more preferably from about 90 to 95 % (w/w) of the filling. Thus, a preferred embodiment may comprise glyceryl monostearate and hydrogenated vegetable oil. In a further embodiment the topotecan formulation contains at least one fatty acid glyceride such as Softisan 378 (obtained from Huls America) or glyceryl monostearate. A more preferred embodiment comprises topotecan hydrochloride, glyceryl monostearate and Wecobee™. The compositions according to the invention may be prepared according to conventional techniques known in the pharmaceutical industry for the manufacture of gelatin capsules. For example, the fill matrix may be prepared by adding the topotecan HCl to a molten homogeneous mixture of the fatty acid glyceride(s) and/or mineral oil(s) or paraffιn(s), and dispersing agent(s). This is then followed by thorough mixing and milling. Subsequent encapsulation is then achieved using standard techniques.
The process for preparation of the capsule fill involves the production of topotecan in a homogenous liquid dispersion having a viscosity in the range of 200- 500 cps and a drug dispersal uniformity with a relative standard deviation of less then 3% as measured by a content uniformity assay. In a further embodiment of the invention, a controlled absorption formulation of topotecan may be incorporated into the gelatin capsule and can be prepared by conventional techniques known to those skilled in the art. For example, suitable techniques are disclosed in U.S. Patent Nos. 4,871,548; 5,009,895; 4,389,393; 5,364,620; and 5,002,776; which are incorporated herein by reference. Once the controlled absorption composition is formulated, the composition can be filled into the gelatin capsules.
The pharmaceutical compositions of the invention may be administered to any animal which may experience the beneficial effects of the topotecan formulation of the invention. Foremost among such animals are humans, although the invention is not intended to be so limited. For mammals, including humans, the effective amounts can be administered on the basis of body surface area. The interrelationship of dosages for animals of various sizes, species and humans (based on mg/M2 of body surface) is described by E.J. Freireich et al., Cancer Chemother. Rep., 50(4):219 (1966). Body surface area may be approximately determined from the height and weight of an individual (see, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y. pp. 537-538 (1970).
The amount of topotecan HCl, in the preferred composition, is preferably in the range of about 0.2 to 5.0 mg, more preferably from about 0.25 to about 3.0 mg per dosage unit, expressed as the weight of free base. If the topotecan is administered with GCSF (granulocyte colony stimulating factor), more topotecan may be administered. For example, with parenteral administration, the m.t.d. (maximum tolerated dose) for topotecan is 2.0 mg/kg; however, when administered with GCSF, the m.t.d. is raised to 2.5 mg/kg. Although the following examples show the use of topotecan HCl, other camptothecin analogues may be used as well. Production of such analogues as well as topotecan may be found in U.S. Application
No. 95/004,758 and WO Patent Application No. 92/05785 (published April 16, 1992), incorporated herein by reference.
Generally, in a thermoplastic or hot-melt formulation the active component is dispersed or solubilized into a melted thermoplastic excipient, filled into capsules as liquid using fluid-filling pumps and allowed to solidify at ambient temperature.
Such a formulation is solid at ambient conditions, providing better chemical stability and minimizing leakage problems. As is well known, thermoplastic excipients are selected based on physico-chemical and thermal characteristics, chemical compatibility, and rheological properties. In general, thermoplastic excipients should have a narrow melting temperature range in the region of about 30°C to 70°C and should solidify within about 10-15 minutes at ambient conditions to avoid leakage from capsules after filling and/or during the sealing operation. An added advantage of this dispersion type formulation is that dosage strengths can be changed easily without changing the vehicle composition or capsule size. The optimal physical stability of the present formulation was determined by heating different concentrations of glyceryl monostearate and Wecobee™ mixtures together to 80°C to obtain a homogenous molten mixture, followed by cooling of the mixture to about 38°C. Wecobee™ (hydrogenated vegetable oil) was selected since it melts at 35°C; this temperature is a desirable target for preparation of a dispersion formulation as well as for physiological reasons. This resulted in a semisolid to solid dispersion, depending upon the level of glyceryl monostearate.
The preferred embodiment of the present invention comprises a matrix of 5% glyceryl monostearate in Wecobee™ which is solid at ambient storage conditions but in molten state at 38-40°C. This lipophilic mixture can be filled as liquid at 40°C and allowed to solidify at room temperature. In addition, the contents of the capsule melt when ingested to release the drug into gastric fluids.
The following Examples illustrate specific formulations and methods for their preparation. These examples are not intended to be a limitation on the scope of the invention in any respect and should not be so construed. In addition, the following examples are encompassed by the claims and their equivalents.
Example 1
A topotecan dispersion containing 5% glyceryl monostearate in Wecobee™ was prepared, filled into hard gelatin capsules and stored at various conditions. The results indicate that this formulation is stable for six months at 5°C and 30°C. however, it does show some potency loss and increased degradation (by percent peak area) at 40°C after six months. As the formulation exists in two different physical states at 30°C and 40°C, the results from 40°C may not be extrapolated to 30°C or lower temperatures.
Since the formulation is oil based, complete dissolution of drug in water or 0.001 N HCl could not be achieved, thus a surfactant was incorporated in the dissolution media. Preliminary experiments suggested that 1% sodium lauryl sulfate (SLS) was required to obtain adequate dissolution. Results showed no change in the dissolution profile at 5°C upon storage.
Based on the preformulation studies, thermal characteristics, chemical stability and safety considerations, a semi-solid matrix formulation containing 5% of glyceryl monostearate in Wecobee™ (hydrogenated vegetable oil) filled into hard gelatin capsules was selected. Wecobee™ is a mixture of triglycerides of hydrogenated coconut or palm kernel oil and has GRAS (generally regarded as safe substance) status as listed in 21 CFR 170.30 (FDA reference). It is also compatible with gelatin capsule shells.
Imwitor 191 (Glyceryl monostearate/palmitate, approx. 90% 1- monoglycerides) is used as emulsifier, dispersing agent, stabilizer and plasticizer in a variety of pharmaceutical, food and cosmetic products. Glyceryl monostearate (Imwitor 191) is compatible with gelatin capsule shells, and is available in NF grade. Three clinical grade batches (U94223, U94224 and U94225) of topotecan hard gelatin capsules were manufactured. The capsule formulations for 0.25, 0.5 and 1.0 mg of topotecan per capsule are presented in Table 1. The stability of these batches was monitored and the stability data is summarized in Tables 2 to 4. The data indicates that there is no significant potency loss at 5°C and 30°C for up to 12 months. There was also no change in the level of degradation products at 5°C,
however, there was increase in degradation products at 30°C. At present, the recommended storage condition for the liquid-filled hard gelatin capsule is 2-8°C (refrigeration condition) based on the available stability data.
The process for formulation was to prepare the capsule fill by dispersing topotecan in a molten mixture of Imwitor 191/Wecobee™ using a high speed dispenser and media mill. This resulted in a homogenous liquid dispersion having the desired viscosity and drug dispersal uniformity.
A number of different mixers/dispersers were also evaluated. Satisfactory results were obtained using a high speed rotor/stator mixer for preliminary drug dispersion. For production, the combination of a high-shear mixer and a low speed mixing blade produces a uniform, homogenous dispersion. As the scale of production increases, the size of the equipment may typically be scaled up accordingly, with identical mechanical mixing properties.
The ball mill was used for size reduction of fine solid particles and disruption of agglomerates. A modified version of the ball mill, a horizontal media mill from Premier Inc., was evaluated for preparation of topotecan capsule fill dispersion. A horizontal grinding chamber with grinding beads ensures a uniform distribution of the grinding media throughout the chamber. A variable speed pump moves milling material (e.g., premixed suspension) through the chamber. The milling material is subject to both intense impact and high shear created by the grinding media, which quickly and efficiently reduces particle size. The grinding chamber is equipped with a water jacketed cooling/heating system, allowing the operator to accurately control the temperature of the milling process. For pharmaceutical processes, a ceramic grinding chamber and ceramic beads are recommended to avoid suspension contamination by metal particles.
Jacketed blending vessels with an effective temperature control system, both for heating and cooling, and adequate stirring capacity are required for preparing topotecan capsule fill suspension. Mixers should contain a high-speed rotor/static head, and a low speed stirring blade, as indicated above. Construction should be such that they may be covered so as to protect the product from light during
production. All product contact surfaces should preferably be constructed of 316L, electropolished stainless steel, or an equivalent that is not susceptible to corrosion.
Several capsule filling and sealing machines are available and should be chosen so as to be able to deliver liquids with a fill weight RSD (relative standard deviation) of 5% or less. The filling hopper should be temperature controlled in order to maintain a fluid material throughout the filling process. Preferably, the capsule filler may be outfitted with a cooling station, to facilitate solidification of semi-solid product. Sealing equipment should deliver a double-band (for safety), and have a running capacity similar to that of the selected capsule filler. The type and size of the production equipment such as compounding vessels, receiving vessels and horizontal bead mills is dependent on batch size and should be selected based on manufacturing needs and economical analysis.
Preparation of Topotecan Bulk Suspension 1. Add the exact quantity of Imwitor 191 required for the batch into a temperature controlled compounding vessel.
2. Heat the product to 70-80°C and stir gently until a clear, smooth fluid is obtained.
3. Weigh out the exact quantity of Wecobee™ required for the batch. 4. With gentle mixing, add the preweighed amount of Wecobee™ into a temperature controlled compounding vessel and continue mixing until homogeneous mixture is obtained. It is important to have both the Inwitor 191 and Wecobee™ completely melted at this point prior to continuing. Reduce the temperature to about 37-40°C. 5. Weigh out the exact amount of the active drug substance required for the batch.
6. Add the active drug substance to the mixture while blending at a V* speed using rotor/stator head. Blend the ingredients for 20 minutes at Vi speed using both heads. Maintain the temperature at about 37-40°C. Heat or cool as needed.
7. Set up the horizontal supermill. Charge grinding chamber with 1.0-1.25 mm ceramic beads. The beads or powders may be obtained from SEPR Co. Preheat the mill chamber to about 37-40°C.
8. Pass the premixed suspension through the horizontal supermill twice. Collect each pass into a temperature controlled processing vessel. Maintain the product temperature at about 37-40°C. Heat or cool as needed.
9. Degas the suspension if necessary. Maintain the product temperature at about 37-40°C. Heat or cool as needed.
10. Using a suitable sampling device, take samples of the suspension from different sites in the vessel for in-process content uniformity test.
Capsule Filling
1. Fill the capsules with the prepared suspension to meet target and specification limits. Maintain constant gentle stirring during the filling process. Avoid air entrapment. Set each filling hopper temperature control to maintain a product temperature of not more than 40°C. Set each filling pump temperature control to suit product fill.
2. Check and record individual capsule weights at appropriate time intervals.
3. Collect filled capsules onto labeled trays and allow to cool. Remove any damaged capsules.
Capsule Sealing
1. Prepare capsule sealing gelatin mass.
2. Load filled capsules into capsule sealing carriers of capsule sealing machine. 3. Seal filled capsules by applying gelatin band with capsule sealing machine.
4. Collect banded capsules onto labeled trays and store overnight at room temperature to dry gelatin band.
5. Sort capsule visually, transferring good capsules for packing and rejecting damaged capsules.
Table 1. Topotecan Liquid Filled Hard Gelatin Formulation
[per capsule]
1. Capsule Strength 0.25 mg (Lot U94223)
Topotecan 0.255 mg
Imwitor 191 13.750 mg
Wecobee™ 260.995 mg
Total: 275.000 mg
2. Capsule Strength 0.5 mg (Lot U94224)
Topotecan 0.51 mg
Imwitor 191 13.75 mg
Wecobee™ 260.74 mg
Total: 275.00 mg
3. Capsule Strength 1.0 mg (Lot U94225)
Topotecan 1.02 mg
Imwitor 191 13.75 mg
Wecobee™ 260.23 mg
Total: 275.00 mg
Table 2. Stability Data for 0.25 mg Topotecan Liquid Filled Hard Gelatin
Capsules, Lot U94223
ND = not determined
Table 3. Stability Data for 0.5 mg Topotecan Liquid Filled Hard Gelatin Capsules, Lot U94224
Product Stability Data
Product Name Topotecan
Dosage Form Liquid filled hard gelatin capsule
Strength 0.5 mg per capsule (as free base)
Pkg. Components 40 cc amber glass bottle; 33 mm white plastic cap, CR; cotton coil Count 25 capsules/bottle
ND = not determined
Table 4. Stability Data for 1.0 mg Topotecan Liquid Filled Hard Gelatin
Capsules, Lot U94225
Product Stability Data
Product Name Topotecan
Dosage Form Liquid filled hard gelatin capsule
Strength 1.0 mg per capsule (as free base)
Pkg. Components 40 cc amber glass bottle; 33 mm white plastic cap, CR; cotton coil Count 25 capsules/bottle
ND = not determined
Example 2 mg per capsule mg per capsule
Formula A For 0.25 mg capsule For 1 mg capsule
Topotecan hydrochloride 0.25 mg* 1 mg*
Glyceryl monostearate 13.75 mg 13.75 mg
Hydrogenated vegetable oil 261 mg 260.25 mg
Fill weight per capsule 275 mg 275 mg
* as anhydrous free base
mg per capsule mg per capsule
Formula B For 0.25 mg capsule For 1 mg capsule
Topotecan hydrochloride 0.25 mg* 1 mg*
Glyceryl monostearate 13.75 mg 13.75 mg
Gelucire® 33/01 261 mg 260.25 mg
Fill weight per capsule 275 mg 275 mg
* as anhydrous free base
The required quantities of glyceryl monostearate and hydrogenated vegetable oil (Formula A) or Gelucire® (Formula B) were added to a heated vessel, and the contents stirred until both excipients had melted and the mixture was clear. To a small portion of this molten mixture, topotecan hydrochloride was added, mixed and poured back to a heated vessel. A mixer was lowered into the vessel and the contents mixed for about 30 minutes. The resulting mixture was milled using a suitable milling apparatus to ensure that the powder was adequately wetted and that no aggregates remained. The filling was subsequently encapsulated to give hard gelatin capsules containing 0.25 mg or 1 mg topotecan HCl (as free base) per
capsule as required. The capsules were sealed with clear gelatin using standard equipment.
Example 3 mg per capsule mg per capsule
Formula C For 0.25 mg capsule For 1 mg capsule
Topotecan hydrochloride 0.25 mg* 1 mg*
Softisan 378 120 mg 120 mg
Miglyol 812 79.75 mg 79 mg
Fill weight per capsule 200 mg 200 mg
* as anhydrous free base
The Miglyol 812 and Softisan 378 were mixed to give a homogeneous mixture. While this was being stirred, the topotecan hydrochloride was added slowly. The resulting homogeneous mixture was milled using a suitable apparatus, and subsequently encapsulated to give hard gelatin capsules containing 0.25 mg or 1 mg topotecan per capsule.
Based on example formula C, the fill matrix may also be prepared such that one excipient (Softisan 378 obtained from Huls of America, Inc.) may constitute for example 50% to 70% (w/w), more preferably 60% (w/w), of the filling. The second excipient (e.g., Miglyol™ 812, obtained from Dynamit Nobel Co.), may constitute for example 30% to 50% (w/w), more preferably 40% (w/w) of the filling.
Claims
1. A pharmaceutical composition suitable for use as a filling for gelatin capsules comprising an effective amount of a camptothecin analogue, or a physiologically acceptable salt thereof, and matrix consisting essentially of a diluting matrix and one or more thickening agents.
2. A pharmaceutical composition suitable for use as a filling for gelatin capsules comprising an effective amount of topotecan, or a physiologically acceptable salt thereof, and a matrix consisting essentially of a diluting matrix and one or more thickening agents.
3. A pharmaceutical composition according to claim 1, in which said diluting matrix comprises at least one dispersing agent or surfactant.
4. A pharmaceutical composition according to claim 3, wherein said diluting matrix further comprises one or more fatty acids.
5. A pharmaceutical composition of claim 4, wherein said fatty acid is a glyceride or polyethylene glycol ester.
6. A pharmaceutical composition of claim 4, wherein said fatty acid is a glyceride.
7. The pharmaceutical composition of claim 6, wherein said fatty acid glyceride comprises one or more medium chain fatty acid glycerides.
8. The pharmaceutical composition of claim 1, wherein said thickening agent is selected from the following: mineral oil, solid paraffin, fatty alcohol and glycerol esters of fatty acids.
9. The pharmaceutical composition of claim 6, wherein said fatty acid glycerides comprise one or more long chain fatty acids.
10. The pharmaceutical composition of claim 4, wherein said diluting matrix contains a fatty acid as a surfactant.
11. The pharmaceutical composition of claim 1 , wherein said gelatin capsule is a soft gelatin capsule.
12. The pharmaceutical composition of claim 1, further comprising a controlled release component.
13. The pharmaceutical composition of claim 11, wherein said controlled release component comprises a rapid release component and a delayed release component.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU86045/98A AU8604598A (en) | 1997-08-01 | 1998-07-30 | Pharmaceutical formulation for camptothecin analogues in gelatin capsule |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US90476197A | 1997-08-01 | 1997-08-01 | |
US08/904,761 | 1997-08-01 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999006031A1 true WO1999006031A1 (en) | 1999-02-11 |
Family
ID=25419727
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1998/015908 WO1999006031A1 (en) | 1997-08-01 | 1998-07-30 | Pharmaceutical formulation for camptothecin analogues in gelatin capsule |
Country Status (5)
Country | Link |
---|---|
AR (1) | AR013261A1 (en) |
AU (1) | AU8604598A (en) |
CO (1) | CO4970695A1 (en) |
WO (1) | WO1999006031A1 (en) |
ZA (1) | ZA986877B (en) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000061187A1 (en) * | 1999-04-13 | 2000-10-19 | Supergen, Inc. | Radioenhanced cancer treatment using orally administered camptothecin derivatives |
WO2001010443A1 (en) * | 1999-08-10 | 2001-02-15 | Pharmacia & Upjohn S.P.A. | Pharmaceutical formulations in hydroxypropylmethylcellulose capsules |
WO2001030351A1 (en) * | 1999-10-22 | 2001-05-03 | Pharmacia Italia S.P.A. | Oral formulations for anti-tumor compounds |
EP1689400A2 (en) * | 2003-11-12 | 2006-08-16 | Smithkline Beecham Corporation | Novel compound, corresponding compositions, preparation and/or treatment methods |
WO2007017331A2 (en) * | 2005-08-04 | 2007-02-15 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Immediate release therapeutic systems for improved oral absorption of 7- [ (e) -tert-butyloxyiminomethyl] camptothecin |
AU2005222541B2 (en) * | 1999-08-10 | 2008-07-24 | Pharmacia & Upjohn S.P.A. | Pharmaceutical formulations in hydroxypropylmethylcellulose capsules |
WO2012087279A1 (en) | 2010-12-20 | 2012-06-28 | Colgate-Palmolive Company | Gelatin encapsulated oral care composition containing dental occlusion actives, hydrophobic viscosity modifier and oil carrier |
WO2012087280A3 (en) * | 2010-12-20 | 2012-12-27 | Colgate-Palmolive Company | Gelatin encapsulated oral care composition containing hydrophilic active, hydrophobic structuring agent and oil carrier |
US8518961B2 (en) | 2004-11-19 | 2013-08-27 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Pharmaceutical compositions comprising a camptothecin derivate |
JP2013545801A (en) * | 2010-12-20 | 2013-12-26 | コルゲート・パーモリブ・カンパニー | Non-aqueous oral care composition containing a dental occlusive active substance |
US8946416B2 (en) | 2005-06-09 | 2015-02-03 | Novartis Ag | Process for the synthesis of 5-(methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzeneamine |
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US5028432A (en) * | 1989-02-23 | 1991-07-02 | Glaxo Canada, Inc. | Pharmaceutical capsules containing panetidine |
US5225404A (en) * | 1989-11-06 | 1993-07-06 | New York University | Methods of treating colon tumors with tumor-inhibiting camptothecin compounds |
US5633260A (en) * | 1994-04-19 | 1997-05-27 | Bionumerik Pharmaceuticals, Inc. | 11,7 Substituted camptothecin derivatives and formulations of 11,7 substituted camptothecin derivatives and methods for uses thereof |
US5677286A (en) * | 1995-04-27 | 1997-10-14 | The University Of Michigan | Glycosylated analogs of camptothecin |
-
1998
- 1998-07-28 AR ARP980103700A patent/AR013261A1/en unknown
- 1998-07-30 WO PCT/US1998/015908 patent/WO1999006031A1/en active Application Filing
- 1998-07-30 AU AU86045/98A patent/AU8604598A/en not_active Abandoned
- 1998-07-31 ZA ZA986877A patent/ZA986877B/en unknown
- 1998-07-31 CO CO98043769A patent/CO4970695A1/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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US5028432A (en) * | 1989-02-23 | 1991-07-02 | Glaxo Canada, Inc. | Pharmaceutical capsules containing panetidine |
US5225404A (en) * | 1989-11-06 | 1993-07-06 | New York University | Methods of treating colon tumors with tumor-inhibiting camptothecin compounds |
US5633260A (en) * | 1994-04-19 | 1997-05-27 | Bionumerik Pharmaceuticals, Inc. | 11,7 Substituted camptothecin derivatives and formulations of 11,7 substituted camptothecin derivatives and methods for uses thereof |
US5677286A (en) * | 1995-04-27 | 1997-10-14 | The University Of Michigan | Glycosylated analogs of camptothecin |
Cited By (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000061187A1 (en) * | 1999-04-13 | 2000-10-19 | Supergen, Inc. | Radioenhanced cancer treatment using orally administered camptothecin derivatives |
US6281223B1 (en) | 1999-04-13 | 2001-08-28 | Supergen, Inc. | Radioenhanced camptothecin derivative cancer treatments |
WO2001010443A1 (en) * | 1999-08-10 | 2001-02-15 | Pharmacia & Upjohn S.P.A. | Pharmaceutical formulations in hydroxypropylmethylcellulose capsules |
AU2005222541B2 (en) * | 1999-08-10 | 2008-07-24 | Pharmacia & Upjohn S.P.A. | Pharmaceutical formulations in hydroxypropylmethylcellulose capsules |
US6569452B1 (en) | 1999-08-10 | 2003-05-27 | Pharmacia Italia S.P.A. | Pharmaceutical formulations in hydroxypropylmethylcellulose capsules |
EA008284B1 (en) * | 1999-10-22 | 2007-04-27 | Фармация Италия С.П.А. | Oral formulations for anti-tumor compounds |
US7201913B1 (en) | 1999-10-22 | 2007-04-10 | Pfizer Inc. | Oral formulations for anti-tumor compounds |
KR100838097B1 (en) * | 1999-10-22 | 2008-06-13 | 파마시아 이탈리아 에스.피.에이. | Oral formulations for anti-tumor compounds |
WO2001030351A1 (en) * | 1999-10-22 | 2001-05-03 | Pharmacia Italia S.P.A. | Oral formulations for anti-tumor compounds |
EP1689400A4 (en) * | 2003-11-12 | 2006-12-27 | Smithkline Beecham Corp | Novel compound, corresponding compositions, preparation and/or treatment methods |
EP1689400A2 (en) * | 2003-11-12 | 2006-08-16 | Smithkline Beecham Corporation | Novel compound, corresponding compositions, preparation and/or treatment methods |
US8158645B2 (en) | 2003-11-12 | 2012-04-17 | Glaxosmithkline Llc | Compound, corresponding compositions, preparation and/or treatment methods |
US8518961B2 (en) | 2004-11-19 | 2013-08-27 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Pharmaceutical compositions comprising a camptothecin derivate |
US8946416B2 (en) | 2005-06-09 | 2015-02-03 | Novartis Ag | Process for the synthesis of 5-(methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzeneamine |
AU2006278114B2 (en) * | 2005-08-04 | 2011-06-23 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Immediate release therapeutic systems for improved oral absorption of 7- [ (E) -tert-butyloxyiminomethyl] camptothecin |
KR101301548B1 (en) * | 2005-08-04 | 2013-09-06 | 시그마타우 인두스트리에 파르마슈티케 리우니테 에스.피.에이. | Immediaterelease therapeutic systems for improved oral absorption of 7-〔(e)-t-butyloxyminomethyl〕 camptothecin |
WO2007017331A2 (en) * | 2005-08-04 | 2007-02-15 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Immediate release therapeutic systems for improved oral absorption of 7- [ (e) -tert-butyloxyiminomethyl] camptothecin |
CN101287466B (en) * | 2005-08-04 | 2014-11-05 | 希格马托制药工业公司 | Immediate release therapeutic systems for improved oral absorption of 7-[(E)-t-butyloxyminomethyl] camptothecin |
JP2009503013A (en) * | 2005-08-04 | 2009-01-29 | シグマ−タウ・インドゥストリエ・ファルマチェウチケ・リウニテ・ソシエタ・ペル・アチオニ | Rapid-acting therapeutic system for improved oral absorption of 7-[(E) -T-butyloxyminomethyl] camptothecin |
WO2007017331A3 (en) * | 2005-08-04 | 2007-09-27 | Sigma Tau Ind Farmaceuti | Immediate release therapeutic systems for improved oral absorption of 7- [ (e) -tert-butyloxyiminomethyl] camptothecin |
JP2014501241A (en) * | 2010-12-20 | 2014-01-20 | コルゲート・パーモリブ・カンパニー | Gelatin encapsulated oral care composition containing a dental occlusive active agent, a hydrophobic viscosity modifier and an oil carrier |
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JP2013545801A (en) * | 2010-12-20 | 2013-12-26 | コルゲート・パーモリブ・カンパニー | Non-aqueous oral care composition containing a dental occlusive active substance |
CN103260466A (en) * | 2010-12-20 | 2013-08-21 | 高露洁-棕榄公司 | Gelatin encapsulated oral care composition containing hydrophilic active, hydrophobic structuring agent and oil carrier |
WO2012087280A3 (en) * | 2010-12-20 | 2012-12-27 | Colgate-Palmolive Company | Gelatin encapsulated oral care composition containing hydrophilic active, hydrophobic structuring agent and oil carrier |
WO2012087279A1 (en) | 2010-12-20 | 2012-06-28 | Colgate-Palmolive Company | Gelatin encapsulated oral care composition containing dental occlusion actives, hydrophobic viscosity modifier and oil carrier |
AU2010365803B2 (en) * | 2010-12-20 | 2015-02-05 | Colgate-Palmolive Company | Gelatin encapsulated oral care composition containing hydrophilic active, hydrophobic structuring agent and oil carrier |
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US9161891B2 (en) | 2010-12-20 | 2015-10-20 | Colgate-Palmolive Company | Gelatin encapsulated oral care composition containing dental occlusion actives, hydrophobic viscosity modifier and oil carrier |
US9289369B2 (en) | 2010-12-20 | 2016-03-22 | Colgate-Palmolive Company | Non-aqueous oral care composition containing dental occlusion actives |
US9320690B2 (en) | 2010-12-20 | 2016-04-26 | Colgate-Palmolive Company | Gelatin encapsulated oral care composition containing hydrophilic active, hydrophobic structuring agent and oil carrier |
Also Published As
Publication number | Publication date |
---|---|
AU8604598A (en) | 1999-02-22 |
AR013261A1 (en) | 2000-12-13 |
ZA986877B (en) | 1999-06-15 |
CO4970695A1 (en) | 2000-11-07 |
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