Patent Application
20110207804
The invention relates to pharmaceutical compositions. In particular, though not exclusively, it relates to compositions for the treatment of neoplastic disease.
The administration of drugs in oral form provides a number of advantages. The availability of an oral anticancer drug is important when treatment must be applied chronically to be optimally effective e.g., the 5-fluorouracil (5-FU) prodrugs (e.g. capecitabine) and drugs that interfere with signal transduction pathways or with the angiogenesis process [1]. In addition, oral drugs can be administered on an outpatient basis or at home, increasing convenience and patient quality of life, and possibly decreasing costs by reducing hospital admissions [2]. Therefore, it is advantageous to try to administer anticancer drugs orally.
In general, the oral administration of drugs is convenient and practical. However, the majority of anticancer drugs unfortunately have a low and variable oral bioavailability [1]. Typical examples are the widely used taxanes, docetaxel and paclitaxel, which have an oral bioavailability of less than 10% [3, 4]. Several other anticancer agents with higher bioavailability demonstrate higher variability. Examples include the topoisomerase I inhibitors, the vinca alkaloids, and mitoxantrone [1, 5, 6]. In view of the narrow therapeutic window, the variable bioavailability may result in unanticipated toxicity or decreased efficacy when therapeutic plasma levels are not achieved. Hellriegel et al. demonstrated in a study that the plasma levels after oral administration are generally more variable than after i.v. administration [7]. Adequate oral bioavailability is important when the period of drug exposure is a major determinant of anticancer therapy [8]. Adequate oral bioavailability is also important to prevent high local drug concentrations in the gastro-intestinal tract that may give local toxicity.
Therefore, a problem associated with the prior art is that it has not been possible to develop an oral composition comprising a taxane in which the taxane has a high bioavailability with low variability. Clinical studies with oral paclitaxel [e.g. 3] and oral docetaxel [e.g. 9] have been executed by the inventors where the i.v. taxane formulations (also containing excipients such as Cremophor EL and ethanol, or polysorbate 80 and ethanol) were ingested orally. Nausea, vomiting and an unpleasant taste are frequently reported by the patients.
Chen et al. [13] conducted experiments to try to improve the solubility of the anticancer drug docetaxel in order to improve its bioavailability. Chen et al. tried using solid dispersions of docetaxel with various carriers, namely glyceryl monosterate, PVP-K30 or poloxamer 188. Chen et al. found that poloxamer 188 increased the solubility of docetaxel to about 3.3 μg/ml after 20 minutes (in a standard dissolution test) and to a maximum of about 5.5 μg/ml after about 120 minutes when a docetaxel to poloxamer ratio of 5:95 was used (see
In a first aspect, the present invention provides a solid pharmaceutical composition for oral administration comprising a substantially amorphous taxane, a hydrophilic carrier and a surfactant, wherein the amorphous taxane is prepared by a solvent evaporation method.
The advantage provided by the composition of the invention is that the solubility of the taxane, the rate of dissolution of the taxane and/or the amount of time which the taxane remains in solution before starting to crystallise is increased to a surprising degree. These factors result in a significant increase in the bioavailability of the taxane. It is thought that this is due, at least in part, to the taxane being in a more amorphous state compared to the apparent amorphous taxane produced by other methods which are unlikely to be truely amorphous. Crystalline taxanes have very low solubilities.
The carrier helps to maintain the taxane in an amorphous state. Further, when the taxane is placed in aqueous media, the carrier helps to maintain the taxane in a supersaturated state in solution. This helps to stop the taxane from crystallising or increases the length of time before the taxane starts to crystallise in solution. Therefore, the solubility and dissolution rate of the taxane remain high. Further, the carrier gives good physical and chemical stability to the composition. It helps to prevent the degradation of the taxane and also helps to prevent the substantially amorphous taxane from changing to a more crystalline structure over time in the solid state. The good physical stability ensures the solubility of the taxane remains high.
The surfactant also helps to maintain the taxane in an amorphous state when placed in aqueous media and, surprisingly, substantially increases the solubility of the taxane compared to compositions comprising an amorphous taxane and a carrier.
The term “substantially amorphous” means that there should be little or no long range order of the position of the taxane molecules. The majority of the molecules should be randomly orientated. A completely amorphous structure has no long range order and contains no crystalline structure whatsoever; it is the opposite of a crystalline solid. However, it can be hard to obtain a completely amorphous structure for some solids. Therefore, many “amorphous” structures are not completely amorphous but still contain a certain amount of long range order or crystallinity. For example, a solid may be mainly amorphous but have pockets of crystalline structure or may contain very small crystals so that it is bordering on being truly amorphous. Therefore, the term “substantially amorphous” encompasses solids which have some amorphous structure but which also have some crystalline structure as well. The crystallinity of the substantially amorphous taxane should be less than 50%. Preferably, the crystallinity of the substantially amorphous taxane is less than 40%, even more preferably, less than 30%, more preferably still, less than 25%, even more preferably, less than 20%, more preferably still, less than 15%, even more preferably, less than 12.5%, more preferably still, less than 10%, even more preferably, less than 7.5%, more preferably still, less than 5% and most preferably, less than 2.5%. Since crystalline taxanes have low solubility, the lower the crystallinity of the substantially amorphous taxane, the better the solubility of the substantially amorphous taxane.
The substantially amorphous taxane can be prepared using any suitable solvent evaporation method. Suitable solvent evaporation methods are, for example, spray drying and vacuum drying as described in [18]. Preferably, the solvent evaporation method is spray drying. Surprisingly, it has been found that preparing the amorphous taxane using a solvent evaporation method, in particular spray drying, results in the composition having a particularly good solubility, dissolution rate and/or remains in solution for longer before starting to crystallise compared to compositions prepared using other methods. This is thought to be due to the solvent evaporation method producing a more amorphous taxane compared to other methods.
The composition for oral administration is in a solid form. The solid composition can be in any suitable form as long as the taxane is in a substantially amorphous state. For example, the composition can comprise a physical mixture of amorphous taxane, carrier and surfactant. In certain embodiments, the carrier and/or the surfactant are also in a substantially amorphous state. Preferably, the taxane and carrier are in the form of a solid dispersion. The term “solid dispersion” is well known to those skilled in the art and means that the taxane is partly molecularly dispersed in the carrier. More preferably, the taxane and carrier are in the form of a solid solution. The term “solid solution” is well known to those skilled in the art and means that the taxane is substantially completely molecularly dispersed in the carrier. It is thought that solid solutions are more amorphous in nature than solid dispersions. Methods of preparing solid dispersions and solid solutions are well known to those skilled in the art [11, 12]. Using these methods, both the taxane and carrier are in an amorphous state. When the taxane and carrier are in the form of a solid dispersion or solution, the solubility and dissolution rate of the taxane is greater than a physical mixture of amorphous taxane and carrier. It is thought that, when the taxane is in a solid dispersion or solution, the taxane is in a more amorphous state compared to apparently amorphous taxane on its own. It is thought that this results in the improved solubility and dissolution. The crystallinity of the solid dispersion or solution should be less than 50%. Preferably, the crystallinity of the solid dispersion or solution is less than 40%, even more preferably, less than 30%, more preferably still, less than 25%, even more preferably, less than 20%, more preferably still, less than 15%, even more preferably, less than 12.5%, more preferably still, less than 10%, even more preferably, less than 7.5%, more preferably still, less than 5% and most preferably, less than 2.5%.
When the taxane and carrier are in a solid dispersion, the surfactant can be in a physical mixture with the solid dispersion or solution. Preferably, however, the composition comprises a taxane, carrier and surfactant in the form of a solid dispersion or, more preferably, a solid solution. The advantage of having all three components in a solid dispersion or solution is that it enables the use of a lower amount of surfactant to achieve the same improvement in solubility and dissolution rate. Preferably, the taxane, carrier and surfactant are all in a substantially amorphous state.
Solid dispersions or solid solutions of taxane and carrier; or taxane, carrier and surfactant, can be produced using any suitable solvent evaporation method, as described above. Preferably, the solid dispersion or solid solution is prepared by spray drying. Surprisingly, it has been found that preparing the solid dispersion or solid solution using a solvent evaporation method, in particular spray drying, results in the composition having particularly good solubility characteristics so that the taxane has a good solubility, dissolution rate and/or remains in solution for longer before starting to crystallise compared to compositions prepared using other methods. This is thought to be due to the solvent evaporation method producing a composition in which all the components are in a more amorphous state compared to other methods. In other methods, it has been found that one or more of the components may still have some crystalline nature which is thought to result in the composition having reduced solubility characteristics and/or physical stability in solution.
In one embodiment, the composition can be contained in a capsule for oral administration. The capsule can be filled in a number of different ways. For example, the amorphous taxane may be prepared by spray drying, powdered, combined with the carrier and surfactant, and then dispensed into the capsule.
In an alternative embodiment, the composition can be compressed into tablets. For example, the amorphous taxane may be prepared by spray drying, powdered, mixed with the carrier and surfactant (and optionally other excipients), and then an appropriate amount compressed into a tablet.
Taxanes are diterpene compounds which originate from plants of the genus Taxus (yews). However, some taxanes have now been produced synthetically or semi synthetically. Taxanes inhibit cell growth by stopping cell division and are used in treatment of cancer. They stop cell division by disrupting microtubule formation. They may also act as angiogenesis inhibitors. The term “taxane”, as used herein, includes all diterpene taxanes, whether produced naturally or artificially, functional derivatives and pharmaceutically acceptable salts or esters which bind to tubulin.
Derivatives of taxanes containing groups to modify physiochemical properties are also included within the present invention. Thus, polyalkylene glycol (such as polyethylene glycol) or saccharide conjugates of taxanes, with improved or modified solubility characteristics, are included.
The taxane of the composition can be any suitable taxane as defined above. Preferred taxanes are docetaxel, paclitaxel, BMS-275183, functional derivatives thereof and pharmaceutically acceptable salts or esters thereof. BMS-275183 is a C-3′-t-butyl-3′-N-t-butyloxycarbonyl analogue of paclitaxel [10]. More preferably, the taxane is selected from docetaxel, paclitaxel, functional derivatives thereof and pharmaceutically acceptable salts or esters thereof.
The hydrophilic carrier of the composition is an organic compound capable of at least partial dissolution in aqueous media at pH 7.4 and/or capable of swelling or gelation in such aqueous media. The carrier can be any suitable hydrophilic carrier which ensures that the taxane remains in an amorphous state in the composition and increases the solubility and dissolution rate of the taxane. Preferably, the carrier is polymeric. Preferably, the carrier is selected from: polyvinylpyrrolidone (PVP); polyethylene glycol (PEG); polyvinylalcohol (PVA); crospovidone (PVP-CL); polyvinylpyrrolidone-polyvinylacetate copolymer (PVP-VA); cellulose derivatives such as methylcellulose, hydroxypropylcellulose, carboxymethylethylcellulose, hydroxypropylmethylcellulose (HPMC), cellulose acetate phthalate and hydroxypropylmethylcellulose phthalate; polyacrylates; polymethacrylates; sugars, polyols and their polymers such as mannitol, sucrose, sorbitol, dextrose and chitosan; and cyclodextrins. More preferably, the carrier is selected from PVP, PEG and PVP-VA, more preferably still, the carrier is selected from PVP and PVP-VA. In one embodiment, the carrier is PVP. In an alternative embodiment, the carrier is PVP-VA.
If the carrier is PVP, it can be any suitable PVP [16] to act as a carrier and to help keep the taxane in an amorphous state. For example, the PVP may be selected from PVP-K12, PVP-K15, PVP-K17, PVP-K25, PVP-K30, PVP-K60, PVP-K90 and PVP-K120. Preferably, the PVP is selected from PVP-K30, PVP-K60 and PVP-K90. Most preferably, the PVP is PVP-K30.
If the carrier is PEG, it can be any suitable PEG [16] to act as a carrier and to help keep the taxane in an amorphous state. For example, the PEG may be selected from PEG1500, PEG6000 and PEG20000. Preferably, the PEG is selected from PEG1500 and PEG6000, and most preferably, the PEG is PEG1500.
If the carrier is PVP-VA, it can be any suitable PVP-VA [16] to act as a carrier and to help keep the taxane in an amorphous state. For example, the PVP-VA may be PVP-VA 64.
The composition can contain any suitable amount of the carrier relative to the amorphous taxane so that the carrier maintains the amorphous taxane in its amorphous state. Preferably, the taxane to carrier weight ratio is between about 0.01:99.99 w/w and about 75:25 w/w. More preferably, the taxane to carrier weight ratio is between about 0.01:99.99 w/w and about 50:50 w/w, even more preferably, between about 0.01:99.99 w/w and about 40:60 w/w, more preferably still, between about 0.01:99.99 w/w and about 30:70 w/w, even more preferably, between about 0.1:99.9 w/w and about 20:80 w/w, more preferably still, between about 1:99 w/w and about 20:80 w/w, even more preferably, between about 2.5:97.5 w/w and about 20:80 w/w, more preferably still, between about 2.5:97.5 w/w and about 15:85 w/w, even more preferably, between about 5:95 w/w and about 15:85 w/w and most preferably, about 10:90 w/w.
The surfactant can be any suitable pharmaceutically acceptable surfactant and such surfactants are well known to those skilled in the art. For example, the surfactant can be an anionic, cationic or non-ionic surfactant. Preferably, the surfactant is a cationic or anionic surfactant. More preferably, the surfactant is an anionic surfactant.
In one embodiment, the surfactant preferably has an HLB (hydrophilic lipophilic balance) value of greater than about 2. More preferably, the HLB value is grater than about 4, more preferably still, the HLB value is greater than about 10, even more preferably, the HLB value is greater than about 14, more preferably still the HLB value is greater than about 20, even more preferably, the HLB value is greater than about 25, more preferably still the HLB value is greater than about 30, and most preferably, the HLB value is greater than about 35. Preferably, the HLB value should be less than about 45.
Preferably, the surfactant is selected from triethanolamine, sunflower oil, stearic acid, monobasic sodium phosphate, sodium citrate dihydrate, propylene glycol alginate, oleic acid, monoethanolamine, mineral oil and lanolin alcohols, methylcellulose, medium-chain triglycerides, lecithin, hydrous lanolin, lanolin, hydroxypropyl cellulose, glyceryl monostearate, ethylene glycol pamitostearate, diethanolamine, lanolin alcohols, cholesterol, cetyl alcohol, cetostearyl alcohol, castor oil, sodium dodecyl sulphate (SDS), sorbitan esters (sorbitan fatty acid esters), polyoxyethylene stearates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, polyxoyethylene alkyl ethers, poloxamer, glyceryl monooleate, docusate sodium, cetrimide, benzyl benzoate, benzalkonium chloride, benzethonium chloride, hypromellose, non-ionic emulsifying wax, anionic emulsifying wax and triethyl citrate (these compounds are indicated as being emulsifiers and surfactants in the Handbook of Pharmaceutical Excipients (4th Edition, editors: R C Rowe, P J Sheskey, P J Weller)). More preferably, the surfactant is selected from sodium dodecyl sulphate (SDS), sorbitan esters (sorbitan fatty acid esters), polyoxyethylene stearates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, polyxoyethylene alkyl ethers, poloxamer, glyceryl monooleate, docusate sodium, cetrimide, benzyl bezoate, benzalkonium chloride, benzethonium chloride, hypromellose, non-ionic emulsifying wax, anionic emulsifying wax and triethyl citrate (these compounds are indicated as being surfactants in the Handbook of Pharmaceutical Excipients (4th Edition, editors: R C Rowe, P J Sheskey, P J Weller)). More preferably, the surfactant is selected from sodium dodecyl sulphate (SDS), sorbitan esters (sorbitan fatty acid esters), and polyoxyethylene sorbitan fatty acid esters. In one embodiment, the surfactant can be cetylpyridinium chloride (CPC). In another embodiment, the surfactant is selected from SDS, CPC, polyoxyethylene (20) sorbitan monooleate (polysorbate 80) and polysorbitan monooleate. Preferably, the surfactant is selected from SDS, CPC and polysorbate 80. More preferably, the surfactant is selected from SDS and CPC. Most preferably, the surfactant is SDS.
Any suitable amount of surfactant can be used in the composition in order to improve the solubility and dissolution rate of the taxane. Preferably, the weight ratio of surfactant, to taxane and carrier combined, is between about 1:99 w/w and about 50:50 w/w, more preferably, between about 1:99 w/w and about 44:56 w/w, even more preferably, between about 1:99 w/w and about 33:67 w/w, more preferably still, between about 2:98 w/w and about 33:67 w/w, even more preferably, between about 2:98 w/w and about 17:83 w/w, more preferably still, between about 5:95 w/w and about 17:83 w/w and most preferably, about 9:91 w/w.
Alternatively, the weight ratio of surfactant to taxane is preferably between about 1:100 w/w and about 60:1 w/w, more preferably, between about 1:50 w/w and about 40:1 w/w, even more preferably, between about 1:20 w/w and about 20:1 w/w, more preferably still, between about 1:10 w/w and about 10:1 w/w, even more preferably, between about 1:5 w/w and about 5:1 w/w, more preferably still, between about 1:3 w/w and about 3:1 w/w, even more preferably, between about 1:2 w/w and about 2:1 w/w and most preferably, about 1:1 w/w.
In one embodiment, the composition comprises an enteric coating. Any suitable enteric coating can be used, for example, cellulose acetate phthalate, polyvinyl acetate phthalate and suitable acrylic derivates, e.g. polymethacrylates. An enteric coating prevents the release of the taxane in the stomach and thereby prevents acid-mediated degradation of the taxane. Furthermore, it enables targeted delivery of the taxane to the intestines where the taxane is absorbed, thus ensuring that the limited time during which the taxane is present in solution (before crystallisation takes place) is only spent at sites where absorption is possible.
In one embodiment, the composition may further comprise one or more additional pharmaceutically active ingredients. Preferably, one or more of the additional pharmaceutically active ingredients is a CYP3A4 inhibitor. Suitable CYP3A4 inhibitors are grapefruit juice or St. John's wort (or components of either), ritonavir, lopinavir or imidazole compounds, such as ketoconazole. Preferably, the CYP3A4 inhibitor is ritonavir.
Where the composition comprises one or more additional pharmaceutically active ingredients, the pharmaceutically active ingredient(s) can be included into the composition as a physical mixture. Alternatively, the pharmaceutically active ingredient(s) can be in an amorphous form. The pharmaceutically active ingredient(s) can be in an amorphous form in a physical mixture with the other amorphous and/or non-amorphous components. Alternatively, it can be in a solid dispersion, or preferably a solid solution, with the taxane; with the taxane and carrier; or with the taxane, carrier and surfactant. When the additional pharmaceutically active ingredient(s) is in an amorphous state, or is in a solid dispersion or solid solution, it should be prepared using a solvent evaporation method, for example, spray drying.
When the composition is in a tablet form and comprises one or more additional pharmaceutically active ingredients, the one or more additional pharmaceutically active ingredients are preferably in the same tablet as the amorphous taxane, i.e. in a single tablet with the other components.
The pharmaceutical composition may comprise additional pharmaceutically acceptable excipients, adjuvants and vehicles which are well known to those skilled in the art. Pharmaceutically acceptable excipients, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminium stearate, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate and wool fat.
The pharmaceutical compositions can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, a powder or coated granules. Tablets may be formulated to be immediate release, extended release, repeated release or sustained release. They may also, or alternatively, be effervescent, dual-layer and/or coated tablets. Capsules may be formulated to be immediate release, extended release, repeated release or sustained release. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. For tablets and capsules, other pharmaceutical excipients that can be added are binders, fillers, filler/binders, adsorbents, moistening agents, disintegrants, lubricants, glidants, and the like. Tablets and capsules may be coated to alter the appearance or properties of the tablets and capsules, for example, to alter the taste or to colour coat the tablet or capsule.
Other pharmaceutically acceptable additives which may be added to the composition are well known to those skilled in the art.
The present invention also provides the above composition for use in therapy.
Further, the present invention provides the above composition for use in the treatment of neoplastic disease.
The neoplastic disease treated by the present invention is preferably a solid tumour. The solid tumour is preferably selected from breast, lung, gastric, colorectal, head & neck, oesophageal, liver, renal, pancreatic, bladder, prostate, testicular, cervical, endometrial, ovarian cancer and non-Hodgkin's lymphoma (NHL). The solid tumour is more preferably selected from breast, gastric, ovarian, prostate, head & neck and non-small cell lung cancer.
Further neoplastic diseases that may be treated by the present invention are multiple myeloma, chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemia (AML) and Kapsoi's sarcoma. Furthermore, the disease range includes myelodysplastic syndromes (MDS).
The present invention also provides a method of treatment of a neoplastic disease, the method comprising the administration, to a subject in need of such treatment, of an effective amount of the above composition.
Preferably, the method is used to treat a human subject.
The present invention also provides a method of preparing the above composition comprising the steps of:
The amorphous taxane can be produced by any suitable solvent evaporation method, for example, as described above. Preferably, the amorphous taxane is produced by spray drying.
The preparation of the amorphous taxane, and the combining thereof with the carrier and/or surfactant may be carried out in a single step, e.g. where the taxane and the carrier and/or the surfactant are subjected to amorphosing treatment together (for example to form a solid dispersion or solution).
Preferably, the method comprises the steps of preparing a solid dispersion comprising the taxane and the hydrophilic carrier, and combining the solid dispersion with the surfactant.
More preferably, the method comprises the step of preparing a solid dispersion comprising the taxane, the hydrophilic carrier and the surfactant.
In another aspect, the present invention provides a pharmaceutical composition for oral administration comprising a substantially amorphous taxane and a hydrophilic carrier, wherein the substantially amorphous taxane is prepared by spray drying.
The present invention also provides a method of preparing a solid pharmaceutical composition for oral administration comprising a substantially amorphous taxane and a hydrophilic carrier, the method comprising the steps of:
The advantage provided by this composition is that the solubility of the taxane, the rate of dissolution of the taxane and/or the amount of time which the taxane remains in solution before starting to crystallise is increased to a surprising degree. It is thought that this is because the solvent evaporation method produces an even more amorphous taxane compared to other methods of producing amorphous taxanes in which the taxane is unlikely to be truely amorphous. It is thought that the more amorphous nature of the taxane provides the increased solubility characteristics.
Additional optional features of the composition are the same as for the composition comprising an amorphous taxane, a carrier and a surfactant. For example, the composition comprising a substantially amorphous taxane and a carrier, wherein the substantially amorphous taxane is prepared by spray drying, preferably further comprises a surfactant. The preferred embodiments of the taxane, the carrier, the crystallinity of the taxane, the ratio of taxane to carrier, the state of the taxane and carrier, etc. are as defined above.
In another aspect, the present invention also provides a pharmaceutical composition comprising a taxane, a hydrophilic carrier and a surfactant, in solution. The description above relating to the identity, properties, etc. of the taxane, carrier and surfactant are equally applicable to this aspect of the invention. In such a composition, all three components of the composition are in solution.
The pharmaceutical composition may be in the form of a drinking solution for administration to a subject. Alternatively, the pharmaceutical composition can be placed in capsules, for example, gelatin capsules to form liquid filled capsules containing the solution.
The composition can be obtained by dissolving the solid composition described above in a suitable solvent. Therefore, in one embodiment, the composition is obtainable by dissolving the solid composition described above in a suitable solvent such as triacetin. In one embodiment, the solvent is an aqueous solvent.
In another aspect, the invention provides a solid pharmaceutical composition for oral administration comprising a substantially amorphous taxane and one or more pharmaceutically acceptable excipients, wherein the substantially amorphous taxane is prepared by spray drying.
The characteristics and preferred features of this composition are as described above for the other compositions of the invention.
The present invention will now be described by way of example only with reference to the accompanying figures in which:
In this experiment the solubility and dissolution rate of a composition comprising a solid dispersion of paclitaxel and PVP-K17 mixed with SDS was compared to a physical mixture of anhydrous paclitaxel, PVP-K17 and SDS.
A solid dispersion of 20% paclitaxel in PVP-K17 was prepared by dissolving 100 mg of paclitaxel in 10 mL t-butanol and 400 mg PVP-K17 in 6.67 mL water. The paclitaxel/t-butanol solution was added to the PVP-K17/water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1 for conditions). 25 mg of a paclitaxel 20%/PVP-K17 solid dispersion (=5 mg paclitaxel) was mixed with 125 mg Lactose, 30 mg sodium dodecyl sulphate, and 30 mg croscarmellose sodium. The resulting powder mixture was encapsulated (see table 2).
5 mg Capsules of Paclitaxel in a Physical Mixture with PVP-K17
A physical mixture was prepared by mixing 5 mg anhydrous paclitaxel with 20 mg PVP, 125 mg lactose, 30 mg sodium dodecyl sulphate, and 30 mg croscarmellose sodium. The resulting powder mixture was encapsulated.
Both capsule formulations were tested in 900 mL of Water for Injection maintained at 37° C. in a USP 2 (paddle) dissolution apparatus with a rotation speed of 75 rpm. In the first experiment, one capsule of each formulation was used. In the second experiment, two capsules of each formulation were used. Samples were collected at various timepoints and analyzed by HPLC-UV (see table 4).
The results are shown in
In a solid solution or solid dispersion, the amorphous state of the carrier enables thorough mixing of the carrier and taxane. The carrier prevents crystallization during storage as well as during dissolution in aqueous media.
In this experiment, the effect on solubility of the presence or absence of the surfactant SDS in the capsule was determined.
A solid dispersion was prepared by dissolving 100 mg of Paclitaxel in 10 mL t-butanol and 400 mg PVP-K17 in 6.67 mL water. The paclitaxel/t-butanol solution was added to the PVP-K17/water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
5 mg Paclitaxel Capsules without Sodium Dodecyl Sulphate
25 mg of a paclitaxel 20%/PVP-K17 solid dispersion mg paclitaxel) was mixed with 125 mg Lactose and encapsulated (see table 5).
5 mg Paclitaxel Capsules with Sodium Dodecyl Sulphate
25 mg of a paclitaxel 20%/PVP-K17 solid dispersion mg paclitaxel) was mixed with 125 mg Lactose, 30 mg sodium dodecyl sulphate, and 30 mg croscarmellose sodium. The resulting powder mixture was capsulated (see table 6).
Both capsule formulations were tested in 900 mL of Water for Injection maintained at 37° C. in a USP 2 (paddle) dissolution apparatus with a rotation speed of 75 rpm. Samples were collected at various timepoints and analyzed by HPLC-UV (see table 4).
The results are shown in
It can clearly be seen from
In this experiment, the effect on solubility of adding SDS to the solid dispersion was determined.
A solid dispersion was prepared by dissolving 600 mg of Paclitaxel in 60 mL t-butanol and 900 mg PVP-K17 in 40 mL water. The paclitaxel/t-butanol solution was added to the PVP-K17/water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
A solid dispersion was prepared by dissolving 250 mg of Paclitaxel in 25 mL t-Butanol, and 375 mg PVP-K17 and 62.5 mg sodium dodecyl sulphate (SDS) in 16.67 mL water. The paclitaxel/t-butanol solution was added to the PVP-K17/sodium dodecyl sulphate/water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
62.5 mg of a paclitaxel 40%/PVP-K17 solid dispersion (=25 mg paclitaxel) was mixed with 160 mg lactose, 30 mg sodium dodecyl sulphate and 10 mg croscarmellose sodium. The resulting powder mixture was encapsulated (see table 7).
68.75 mg of a paclitaxel 40%/PVP-K17/sodium dodecyl sulphate 10% solid dispersion (=25 mg paclitaxel) was mixed with 160 mg lactose and 10 mg croscarmellose sodium. The resulting powder mixture was encapsulated (see table 8).
Both capsule formulations were tested in 500 mL of Water for Injection maintained at 37° C. in a USP 2 (paddle) dissolution apparatus. Rotation speed was set at 75 rpm for the capsule with paclitaxel/PVP-K17/sodium dodecyl sulphate solid dispersion and at 100 rpm for the capsule with paclitaxel/PVP-K17 solid dispersion. Samples were collected at various timepoints and analyzed by HPLC-UV (see table 4).
The results are shown in
The solid dispersions used in the experiments of example 1.4 were produced after initial experiments did not show clear differences between drugloads. The 40% drugload was selected because these formulations performed equally to 20% drugload formulation in the afore mentioned experiments and offered the possibility to deliver more taxane in one tablet or capsule.
A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL t-butanol and 375 mg PVP-K12 in 16.67 mL water. The paclitaxel/t-butanol solution was added to the PVP-K12 water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
A solid dispersion was prepared by dissolving 600 mg of paclitaxel in 60 mL t-butanol and 900 mg PVP-K17 in 40 mL water. The paclitaxel/t-butanol solution was added to the PVP-K17 water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table I).
A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL t-Butanol and 375 mg PVP-K30 in 16.67 mL water. The paclitaxel/t-butanol solution was added to the PVP-K30 water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL t-butanol and 375 mg HP-cyclodextrin in 16.67 mL water. The paclitaxel/t-butanol solution was added to the HP-cyclodextrin water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1),
62.5 mg of the paclitaxel/carrier solid dispersion (=25 mg paclitaxel) was mixed with 160 mg Lactose, 30 mg sodium dodecyl sulphate and 10 mg croscarmellose sodium. The resulting powder mixture was encapsulated (see table 9).
All capsule formulations were tested in 500 mL of Water for Injection maintained at 37° C. in a USP 2 (paddle) dissolution apparatus with a rotation speed of 100 rpm. Samples were collected at various timepoints and analyzed by HPLC-UV (see table 4).
The average results of 2 to 3 experiments are shown in
The chain length of the polymeric carrier determines the time to crystallization in aqueous environments.
The solid dispersions used in the experiments of example 1.5 were produced after initial experiments did not show clear differences between carriers. These initial experiments were done before the more detailed experiments of Example 1.4. As a result, PVP-K17 was arbitrarily chosen as carrier for further experiments.
A solid dispersion was prepared by dissolving 100 mg of paclitaxel in 10 mL t-butanol and 900 mg PVP-K17 in 40 mL water. The paclitaxel/t-butanol solution was added to the PVP-K17 water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL t-butanol and 750 mg PVP-K17 in 16.67 mL water. The paclitaxel/t-butanol solution was added to the PVP-K17 water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
A solid dispersion was prepared by dissolving 600 mg of paclitaxel in 60 mL t-butanol and 900 mg PVP-K17 in 6.67 mL water. The paclitaxel/t-butanol solution was added to the PVP-K17 water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL t-butanol and 83 mg PVP-K17 in 16.67 mL water. The paclitaxel/t-butanol solution was added to the PVP-K17 water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL t-butanol. The paclitaxel/t-butanol solution was added to 16.67 mL water under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
An amount of solid dispersion powder, equal to approximately 4 mg Paclitaxel, was placed in a 50 mL beaker. A magnetic stirring bar and 25 mL water was added to the beaker. The solution was stirred at 720 rpm. Samples were collected at various timepoints and analyzed by HPLC-UV (see table 4).
The average results of 2 to 3 experiments are shown in
The amount of carrier relative to the amount of drug determines the time to crystallization in aqueous environments.
A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL t-butanol, and 375 mg PVP-K17 and 62.5 mg sodium dodecyl sulphate (SDS) in 16.67 mL water. The paclitaxel/t-butanol solution was added to the PVP-K17/sodium dodecyl sulphate/water solution under constant stirring. The final mixture was transferred to 8 mL vials with a maximum fill level of 2 mL. t-butanol and water were subsequently removed by lyophilisation (see table 1).
68.75 mg of a paclitaxel 20%/PVP-K17/sodium dodecyl sulphate 10% solid dispersion (=25 mg paclitaxel) was mixed with 160 mg lactose and 10 mg croscarmellose sodium. The resulting powder mixture was encapsulated (see table 10).
The capsules were in duplo subjected to two different dissolution tests. The first test was a two tiered dissolution test, consisting of two hours of dissolution testing in 500 mL simulated gastric fluid without pepsin (SGFsp; see table 11) followed by two hours of dissolution testing in 629 mL simulated intestinal fluid without pepsin (SIFsp; see table 11). The second test was conducted in 500 mL fasted state simulated intestinal fluid (FaSSIF; see table 12) medium for four hours.
Both dissolution tests were performed in a USP 2 (paddle) dissolution apparatus with 500 mL medium maintained at 37° C. and paddle rotation speed 75 rpm. The SGFsp medium was changed to SIFsp medium by addition of 129 mL switch medium. Samples were collected at various timepoints and analyzed by HPLC-UV (see table 4).
The results are shown in
An enteric coating will prevent release of the taxane in the stomach, thereby preventing degradation of the active components. Furthermore, it will enable targeted delivery to the intestines where the taxane is absorbed, thus ensuring that the limited time the taxane is present in solution (before crystallization takes place), is only spent at sites where absorption is possible.
The formulations used in the following experiments were prepared according to the procedures outline below and the compositions depicted in table 13.
Anhydrous docetaxel was used as obtained from ScinoPharm, Taiwan.
Docetaxel was amorphized by dissolving 300 mg of Docetaxel anhydrate in 30 mL of t-butanol. The docetaxel/t-butanol solution was added to 20 mL of Water for Injection (WfI) under constant stirring. The final mixture was transferred to a stainless steel lyophilisation box (Gastronorm size 1/9), t-butanol and water were subsequently removed by lyophilisation (see table 14).
Physical mixtures were prepared by mixing 150 mg of docetaxel and corresponding amounts of carrier and surfactant (see table 13) with mortar and pestle.
Solid dispersions were obtained by dissolving 300 mg docetaxel anhydrate in 30 mL of t-butanol, and corresponding amounts of carrier and surfactant (see table 13) in 20 mL of Water for Injection. The docetaxel/t-butanol solution was added to the carrier/surfactant/WfI solution under constant stirring. The final mixture was transferred to a stainless steel lyophilisation box (Gastronorm size 1/9), t-butanol and water were subsequently removed by lyophilisation (see table 14).
1HPβ-CD is hydroxypropyl-β-cyclodextrin
An amount of powder, equal to approximately 6 mg Docetaxel, was placed in a 50 mL beaker. A magnetic stirring bar and 25 mL water were added to the beaker. The solution was stirred at 720 rpm, and kept at approximately 37° C. Samples were collected at various timepoints, and filtrated using a 0.45 μm filter before they were diluted with a 1:4 v/v mixture of methanol and acetonitrile. The filtrated and diluted samples were subsequently analyzed by HPLC-UV (see table 15).
In the first experiment, the influence of the formulation type on the solubility of docetaxel was examined. Data from the dissolution test performed on formulations A to E were compared. The results are shown in
Formulation A (pure docetaxel anhydrate) reaches a maximum concentration of approximately 12 μg/mL (4.7% total docetaxel present) after 5 minutes of stirring and reaches an equilibrium concentration of approximately 6 μg/mL (2%) after 15 minutes of stirring.
Formulation B (pure amorphous docetaxel) reaches a maximum of 32 μg/mL (13%) after 0.5 minutes, from 10 to 60 minutes the solubility is comparable to formulation A.
Formulation C (physical mixture of anhydrous docetaxel, PVP-K30 and SDS) reaches a concentration of approximately 85 μg/mL (37%) after 5 minutes. Between 15 and 25 minutes, the docetaxel concentration sharply declines from 85 μg/mL (37%) to 30 μg/mL (12%), after which it further declines to 20 μg/mL (9%) at 60 minutes.
Formulation D (physical mixture of amorphous docetaxel, PVP-K30 and SDS) reaches a maximum docetaxel concentration of 172 μg/mL (70%) after 7.5 minutes. Between 7.5 and 20 minutes, the amount of docetaxel in solution drops to 24 μg/mL (10%). At 60 minutes, the equilibrium concentration of 19 μg/mL (7%) is reached.
Formulation E (solid dispersion of amorphous docetaxel, PVP-K30 and SDS) has the highest maximum concentration of 213 μg/mL (90%) which is reached after 5 minutes. Between 10 and 25 minutes, the amount of docetaxel in solution rapidly declines resulting in an equilibrium concentration of 20 μg/mL (8%) after 45 minutes.
All formulations initially show a higher solubility, which decreases to an equilibrium solubility after 45 to 60 minutes of stirring. The decrease in solubility is caused by the crystallization of docetaxel as a result of the supersaturated solution. The degree of supersaturation is dependent on the physical state of the drug, i.e. whether it is amorphous or crystalline. When PVP-K30 is the carrier, the supersaturated state is maintained for longer so that the solubility of the docetaxel does not decrease as quickly. Further, the results show that using amorphous docetaxel significantly increases the solubility of docetaxel compared to anhydrous crystalline docetaxel. Further, amorphous docetaxel shows a relatively high dissolution rate, peaking at about 5 to 7.5 minutes.
This experiment shows that the amount of docetaxel in solution is markedly increased by physical mixing of anhydrous docetaxel with PVP-K30 and SDS, and even more by physical mixing of amorphous docetaxel with PVP-K30 and SDS. The biggest increase in solubility, however, is achieved by incorporation of docetaxel in a solid dispersion of PVP-K30 and SDS.
In the second experiment, the influence of the carrier type on the solubility of docetaxel was examined. Data from the dissolution test performed on formulation E and F were compared. The results are shown in
Formulation E (solid dispersion of amorphous docetaxel, PVP-K30 and SDS) has a highest maximum concentration of 213 μg/mL (90% of total docetaxel present) which is reached after 5 minutes. Between 10 and 25 minutes, the amount of docetaxel in solution rapidly declines, resulting in an equilibrium concentration of 20 μg/mL (8%) after 45 minutes.
Formulation F (solid dispersion of amorphous docetaxel, HPβ-CD and SDS) reaches a maximum docetaxel concentration of approximately 200 μg/mL (81%) after about 2 minutes. Between 5 and 10 minutes, the amount of docetaxel in solution drops to a value of 16 μg/mL (6%) and after 45 minutes, an equilibrium concentration of 11 μg/mL (4%) is reached.
This experiment shows that both PVP-K30 and HPβ-CD increase the solubility of docetaxel. When PVP-K30 is used as the carrier compared to HPβ-CD, the maximum docetaxel concentration is slightly higher and the state of supersaturation is maintained longer so that the solubility of docetaxel does not decrease as quickly with time. Further, the equilibrium concentration reached after precipitation of docetaxel is higher with PVP-K30 compared to HPβ-CD.
In the third experiment, the influence of the PVP chain length on the solubility of docetaxel was examined. Data of the dissolution test performed on formulation E and G to J were compared. The results are shown in
Formulation G (PVP-K12) reaches a maximum docetaxel concentration of 206 μg/mL (77% of the total docetaxel present) after 5 minutes. Between 5 and 30 minutes, the amount of docetaxel in solution decreases to 20 μg/mL (7%) and at 45 minutes, the docetaxel concentration is 17 μg/mL (6%).
Formulation H (PVP-K17) reaches a maximum docetaxel concentration of 200 μg/mL (83%) after 5 minutes and maintains this concentration up to 10 minutes of stirring, after which the amount of docetaxel in solution rapidly drops to 44 μg/mL (18%) at 15 minutes and 22 μg/mL (9%) at 30 minutes. The equilibrium concentration between 45 and 60 minutes is approximately 21 μg/mL (8%).
Formulation I (PVP-K25) reaches a maximum docetaxel concentration of 214 μg/mL (88%) after 5 minutes of stirring. The amount of docetaxel in solution decreases between 10 and 30 minutes to 22 μg/mL (9%) and at 60 minutes, the concentration of docetaxel is 19 μg/mL (8%).
Formulation E (PVP-K30) has a maximum docetaxel concentration of 213 μg/mL (90%) which is reached after 5 minutes. Between 10 and 25 minutes, the amount of docetaxel in solution rapidly declines, resulting in an equilibrium concentration of 20 μg/mL (8%) after 45 minutes.
Formulation J (PVP-K90) reaches a maximum docetaxel concentration of 214 μg/mL (88%) after 10 minutes of stirring. At 15 minutes, the amount of docetaxel in solution is still 151 μg/mL (61%). After 60 minutes, the docetaxel concentration has declined to 19 μg/mL (7%).
This experiment shows that the chain length of PVP influences both the degree of supersaturation and the period the supersaturation is maintained. The use of higher PVP chain lengths results in a higher maximum docetaxel concentrations and a longer period of supersaturation, thus, a higher solubility for a longer period of time.
In the fourth experiment, the influence of the drug load on the solubility of docetaxel was examined. Data from the dissolution tests performed on formulations E and K to N were compared. The results are shown in
Formulation N (1/21 docetaxel by weight of total composition; 5:95 w/w docetaxel to PVP) reaches a maximum docetaxel concentration of 197 μg/mL (79% of total docetaxel present) after 10 minutes. After 15 minutes, the amount of docetaxel in solution is still 120 μg/mL (48%) and between 15 and 30 minutes, the docetaxel concentration decreases to 24 μg/mL (12%). At 60 minutes the docetaxel concentration is 20 μg/mL (8%).
Formulation E (1/11 docetaxel by weight of total composition; 10:90 w/w docetaxel to PVP) has a maximum concentration of 213 μg/mL (90%) which is reached after 5 minutes. Between 10 and 30 minutes, the amount of docetaxel in solution rapidly declines and reaches an equilibrium concentration of 20 μg/mL (8%) after 45 minutes.
Formulation M (1/6 docetaxel by weight of total composition; 20:80 w/w docetaxel to PVP) has a docetaxel concentration of 196 μg/mL (80%) after 10 minutes of stirring. The amount of docetaxel in solution decreases between 10 and 30 minutes to 25 μg/mL (10%) and at 60 minutes, the concentration of docetaxel is 18 μg/mL (7%).
Formulation L (1/3 docetaxel by weight of total composition; 40:60 w/w docetaxel to PVP) reaches a docetaxel concentration of 176 μg/mL (71%). Between 10 and 15 minutes, the amount of docetaxel in solution rapidly drops to 46 μg/mL (18%) and after 60 minutes, the amount of docetaxel in solution is 18 μg/mL (7%).
Formulation K (5/7 docetaxel by weight of total composition; 75:25 w/w docetaxel to PVP) reaches a maximum docetaxel value of 172 μg/mL (71%) after 5 minutes of stirring. Between 5 and 10 minutes, the docetaxel concentration sharply declines to 42 μg/mL (17%) and after 60 minutes, a docetaxel concentration of 18 μg/mL (7%) is reached.
This experiment shows that the amount of PVP-K30 relative to the amount of docetaxel used in the solid dispersions influences both the degree of supersaturation and the period the supersaturation is maintained. The use of higher drugloads results in lower maximum docetaxel concentrations and a shorter period of supersaturation, thus, a lower solubility over time.
2.5: Solubility Comparison with a Prior Art Composition
In this experiment, a composition containing a solid dispersion of 15 mg docetaxel, 135 mg PVP-K30 and 15 mg SDS was compared to the literature data of a composition comprising a solid dispersion of 5 mg docetaxel and PVP-K30 as disclosed in Chen et al. [13]. The solubility results were obtained using the dissolution test described in Chen et al. [13] and are shown in
From
In
In
From these results, it can be seen that the docetaxel, PVP-K30 and SDS composition gave a faster dissolution rate and a higher solubility compared to the composition of Chen. For bioavailability, it is important to look at how fast a drug dissolves and what solubility is reached in 0.5 to 1.5 h.
From the results of Chen, a skilled person would not consider that increasing the amount of docetaxel in the composition would increase the absolute solubility of docetaxel. Since the composition of Chen dissolves only 80% of 5 mg docetaxel (i.e. 4 mg) in 900 ml water, you would not expect that increasing the amount of docetaxel to 15 mg would cause any more than 4 mg docetaxel to dissolve. Thus, you would expect a 15 mg docetaxel composition according to Chen to dissolve a maximum of about 27% docetaxel compared to 100% for the docetaxel, PVP-K30 and SDS composition. Therefore, the docetaxel, PVP-K30 and SDS composition provides surprisingly good results compared to Chen.
In this experiment, the dissolution of capsules, containing a solid dispersion of docetaxel, PVP-K30 and SDS, was tested in Simulated Intestinal Fluid sine Pancreatin (SIFsp). The capsules contained 15 mg docetaxel according to Formulation E (see table 13). SIFsp was prepared according to USP 28, Capsules containing 15 mg docetaxel were dissolved in 500 mL USP SIFsp at 37° C. with stirring at 75 rpm. The results are shown in
It was found that the solid dispersion of docetaxel, PVP-K30 and SDS according to Formulation E (see table 13) and which was used in capsules for clinical trials (see following Example) is stable both chemically (no degradation) and physically (no changes in solubility characteristics) for at least 180 days when stored between 4-8° C.
10 patients participated in an ongoing clinical phase I trial.
These patients were given the following numbers:
301, 302, 303, 304, 305, 306, 307, 308, 309 and 310.
These patients were given medication which consisted of a liquid formulation of docetaxel or a solid composition comprising a solid dispersion of docetaxel, PVP-K30 and SDS (referred to hereinafter as MODRA).
Docetaxel dose: 30 mg for all patients (with the exception of patient 306 who received 20 mg docetaxel). The 30 mg dose was prepared as follows: 3.0 mL Taxotere® premix for intravenous administration (containing 10 mg docetaxel per ml in polysorbate 80 (25% v/v), ethanol (10% (w/w), and water) was mixed with water to a final volume of 25 mL. This solution was orally ingested by the patient with 100 mL tap water.
Docetaxel dose: 30 mg; 2 capsules with 15 mg docetaxel per capsule were ingested. Formulation E from the previous example (1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS) was selected for further testing in the clinical trial. A new batch of formulation E was produced by dissolving 1200 mg docetaxel anhydrate in 120 mL of t-butanol, and 10800 mg PVP-K30 and 1200 mg SDS (see table 13) in 80 mL of Water for Injection. The docetaxel/t-butanol solution was added to the PVP-K30/SDS/WfI solution under constant stirring. The final mixture was transferred to a stainless steel lyophilisation box (Gastronorm size 1/3), t-butanol and water were subsequently removed by lyophilisation (see table 14).
A total of 60 gelatine capsules of size 0 were filled with an amount of solid dispersion equivalent to 15 mg docetaxel, an HPLC assay was used to determine the exact amount of docetaxel per mg of solid dispersion. The assay confirmed that the capsules contained 15 mg docetaxel. Patients took the medication orally on an empty stomach in the morning with 100 mL tap water.
Patients 301, 302, 303, 304 and 305 received only liquid formulation.
Patient 306 received 20 mg docetaxel as liquid formulation+ritonavir in the first cycle and in the second cycle the same medication but with extra ritonavir 4 hours after docetaxel ingestion.
Patients 307, 308, 309 and 310 received liquid formulation and/or MODRA. Cycles were administered in a weekly interval.
According to institutional guidelines, for both oral and i.v. docetaxel all patients were treated with oral dexamethason. A dose of 4 mg dexamethason was given 1 hour prior to the study drugs, followed by 4 mg every 12 hours (2 times). One hour prior to docetaxel treatment, patients also received 1 mg granisetron (Kytril®) to prevent nausea and vomiting.
After drug administration, blood samples were collected for pharmacokinetic analyses. A blank sample was taken before dosing. Blood samples were centrifuged, plasma was separated and immediately stored at −20° C. until analyses. Analysis were performed with validated HPLC methods in a GLP (Good Laboratory Practice) certified laboratory [17].
Table 16 gives an overview of the individual pharmacokinetic results.
Patients 301, 302, 303, 304, 305, 307, 309 and 310 received the liquid formulation. The mean, and the 95% confidence interval for the mean of the AUC (extrapolated to infinity) is: 1156 (+348) ng*h/mL. The inter-individual variability is 85%.
Patient 306 received 20 mg docetaxel (as liquid formulation) concomitantly with 100 mg ritonavir in the first cycle and the same combination, one week later, in the second cycle but with 100 mg extra ritonavir 4 hours after ingestion of docetaxel, i.e. two doses of ritonavir were taken, one at t=0 and the second at t=4 h. The pharmacokinetic curves are depicted in
Patients 307, 308, 309 and 310 received liquid formulation and/or MODRA. The pharmacokinetic curves are depicted in
The pharmacokinetic results of the liquid formulation versus MODRA, both in combination with 100 mg ritonavir, are summarized below:
AUCinf(95% confidence interval of the mean): 1156 (808-1504) ng*h/ml
Inter-individual variability: 85% (n=8)
AUCinf(95% confidence interval of the mean): 768 (568-968) ng*h/ml
Inter-individual variability: 29% (n=4)
Intra-individual variability: 33% (n=2)
The average AUC of MODRA was calculated using the 6 curves from four patients. The first dose of MODRA administered to each patient, was used to calculate the inter-individual variability. The intra-individual variability is based on data from patients 307 and 308 who received two doses of MODRA.
The tested docetaxel Liquid Formulation results in an AUC value that is approximately 1.5 fold higher than the same dose (30 mg) given in the novel capsule formulation (MODRA).
The inter-individual variability of the liquid formulation is high (85%) while the inter-individual variability of the capsule formulation is substantially lower (29%). This is an important feature of the novel capsule formulation and provides a much better predictable docetaxel exposure. Also for safety reasons low inter-individual variability is very much desired in oral chemotherapy regimens.
The intra-individual variability (limited data) is in the same order of magnitude as the inter-individual variability.
A second boosting dose of 100 mg ritonavir ingested 4 hours after docetaxel administration increases the docetaxel AUC 1.5 fold.
Comparison of Oral Capsule Formulations Compared to i.v. Administration
The bioavailability of the MODRA capsules was calculated by:
(AUC 30 mg oral/AUC 20 mg iv)×(20/30)×100%=73% (SD 18%).
This shows that the bioavailability of the capsules is relatively high with a low inter-individual variability.
Formulations produced by spray drying are fully amorphous and have a prolonged duration of the supersaturated state upon dissolution testing compared to formulations produced by lyophilization (see section 7 below).
The equilibrium solubility of docetaxel after precipitation upon dissolution testing is significantly increased in formulations with PVP-VA 64 (40 μg/mL) compared to formulations with PVP-K30 (20 μg/mL) and formulations without a carrier (7 μg/mL) (see section 8 below).
Effect of the type of surfactant on the dissolution of docetaxel (section 1):
Effect of the amount of SDS on the dissolution of docetaxel (section 2):
Amorphous nature of docetaxel (section 3):
Amorphous nature of paclitaxel (section 4):
Characterization of solid dispersions of docetaxel (section 5):
Characterization of solid dispersions of paclitaxel (section 6):
Effect of the production method on the characteristics and performance of docetaxel solid dispersion (section 7):
Effect of the type of carrier on the dissolution performance of docetaxel solid dispersions (section 8):
Production of tablets (section 9):
The formulations used in the tests were prepared according to the procedures outlined below and the compositions depicted in Table 18, Table 19, Table 20 and Table 17. The tested drugs were paclitaxel and docetaxel
Crystalline drug was used as obtained from the supplier.
Drugs were amorphized by dissolving 300 mg of drug in 30 mL of t-Butanol. The drug/t-Butanol solution was added to 20 mL of Water for Injection (WfI) under constant stirring. The final mixture was transferred to a stainless steel lyophilization box (Gastronorm size 1/9), t-Butanol and water were subsequently removed by lyophilization (see Table 20)
Physical mixtures were prepared by mixing 150 mg of docetaxel and corresponding amounts of carrier and surfactant (see Table 17) with mortar and pestle.
Physical mixtures were prepared by mixing accurately weighed amounts of crystalline and amorphous docetaxel (see Table 18).
Solid dispersions were obtained by dissolving docetaxel in 30 mL of t-Butanol, and corresponding amounts of carrier and surfactant (see Table 19) in 20 mL of Water for Injection. The docetaxel/t-Butanol solution was added to the carrier/surfactant/Wff solution under constant stirring. The final mixture was transferred to a stainless steel lyophilization box (Gastronorm size 1/9), t-Butanol and water were subsequently removed by lyophilization (see Table 20).
Solid dispersions were obtained by dissolving docetaxel in 45 mL of ethanol and 5 mL of WfI. After the drug was completely dissolved, PVP-K30 and SDS (see table 21) were added to the drug/ethanol/WfI solution under constant stirring. The final mixture was transferred to a flask and ethanol and water were subsequently removed by spray drying (see Table 22).
Capsules were produced by weighing an amount of lyophilized solid dispersion powder (1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS) equivalent to 10-15 mg drug. The solid dispersion powder was grinded with mortar and pestle to a fine powder and encapsulated with a manual capsulation apparatus in size 0 hard gelatin capsules. The amount of docetaxel per capsules was estimated after production by subtracting the net capsule weight from the gross capsule weight and multiplying it by the docetaxel ratio of the solid dispersion powder (see Table 19). The contents of the capsules were confirmed by HPLC quality control.
Clinical trial capsules were produced by weighing an amount of lyophilized solid dispersion powder (1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS) equivalent to 10 mg drug, 110 mg lactose monohydrate and 1.1 mg colloidal silicon dioxide. All components were mixed with mortar and pestle until a homogeneous mixture was obtained. The mixture was encapsulated with a manual capsulation apparatus in size 0 hard gelatine capsules.
Tablets were produced by weighing an amount of spray dried solid dispersion powder equivalent (1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS) to 20 mg docetaxel, 110 mg lactose monohydrate and 110 mg crosslinked polyvinylpyrrolidone. All components were mixed with mortar and pestle until a homogeneous mixture was obtained. The mixture was compacted manually on a excentric press equipped with 13 mm flat tooling. Filling volume was fixed at 13.5 mm and the upper pressure was set at 10.5 mm. Tablets were weighed after compaction and the amount of docetaxel was estimated by multiplying the tablet weight by the product of the weight fraction of drug in the solid dispersion powder (see Table 21) and the weight fraction of the solid dispersion powder in the tablet. The contents of the tablets were confirmed by HPLC quality control.
An amount of powder, equal to approximately 6 mg drug, was placed in a 50 mL beaker. A magnetic stirring bar and 25 mL water were added to the beaker. The solution was stirred at 720 rpm, and kept at approximately 37° C. Samples were collected at various timepoints, and filtrated using a 0.45 μm filter before they were diluted with a 1:4 v/v mixture of methanol and acetonitrile. The filtrated and diluted samples were subsequently analyzed by HPLC-UV (see Table 23). The amount of drug dissolved is expressed as concentration in μg/mL.
Capsules or tablets were placed in a type 2 (paddle) dissolution apparatus, filled with 500 mL WfI at 37° C., the rotational speed of the paddle was 75 rpm. Samples were collected at various timepoints, and filtrated using a 0.45 μm filter before they were diluted 1:1 with a 1:4 v/v mixture of methanol and acetonitrile. The filtrated and diluted samples were subsequently analyzed by HPLC-UV (see Table 23). The amount of docetaxel dissolved is either expressed as concentration in μg/mL or as percentage of the label claim (% RLC). The label claim is the estimated amount of drug present in each capsule or tablet after production.
DSC measurements were performed on a Q2000 DSC (TA Instruments, New Castle, Del., USA). Temperature scale and heat flow were calibrated with indium. Samples of approximately 10 mg powder were transferred into Tzero Aluminium pans (TA instruments), hermetically closed and placed in the autosampler. The program listed in Table 24 was used for all samples.
X-ray powder diffraction measurements were performed on a Phlips X'pert pro diffractiometer equipped with an X-celerator. Samples of approximately 0.5 mm thick were placed in a metal sample holder, placed in the diffractiometer and scanned with the settings depicted in Table 25.
To determine the effect of the surfactant type, five formulations (see Table 19, formulation 1-5) with different surfactants (see Table 26) were prepared by lyophilization (see Table 20). The selection of surfactants was based on the surfactant class and HLB-value. The chosen surfactants represent all three surfactant classes (anionic, cationic and non-ionic) and a broad range of HLB-values (4.3 to 40) Each formulation had the same amount of docetaxel, PVP-K30 and surfactant. From each formulation three capsules were produced without any additives and subjected to a dissolution test.
All solid dispersion systems with surfactants increase the dissolution of docetaxel compared to the same solid dispersion system without a surfactant. The effect of CPC and SDS on the dissolution of docetaxel is comparable, the initial differences between these two surfactants are probably a result of the variation in dissolution of the capsule shell. The HLB value of the surfactants seems to correlate well with the performance of the solid dispersion formulations.
Furthermore, dissolution tests with capsules produced from paclitaxel solid dispersion systems have shown even greater changes in dissolution rates due to the incorporation of a surfactant (SDS) in the solid dispersion system. This difference in effect is probably related to the difference in solubility of the active components (paclitaxel vs. docetaxel), it is therefore likely that the differences between the various surfactants will be greater for dosage forms produced from paclitaxel containing solid dispersion systems.
1Handbook of Pharmaceutical excipients
2Choi et al. Journal of Hazardous Materials, 2009, 161 (2-3): 1565-1568
3Korhonen et al. Int. J. Pharm. 2004, 269 (1): 227-239
To determine the influence of the amount of SDS four solid dispersion powders containing docetaxel (see Table 19, formulation 4-7) were prepared by lyophilization (see Table 20). The amount of SDS varied between the four formulations while the amount of docetaxel and PVP-K30 were kept constant. From each formulation three capsules were produced without any additives and subjected to a dissolution test.
While the 1/11 SDS formulation reaches an amount of docetaxel dissolved of 90% RLC within 30 minutes, the formulation without SDS reaches only an amount of docetaxel dissolved of 70% RLC (Relative to Label Claim) after 60 minutes. Furthermore the variation in the release rate of docetaxel between capsules of the formulation without an surfactant is much higher than the variation between the capsules of the formulation with 1/11 SDS.
The incorporation of higher amounts of SDS into the solid dispersion system results in a faster dissolution rate. Incorporation of 1/11 w/w SDS results in the fastest dissolution rate.
It is likely that the compaction of solid dispersion powder necessitates the use of a surfactant. Because the production of tablets results in even higher compaction than the production of capsules, incorporation of a surfactant will be even more necessary in solid dispersion tablets.
Incorporation of SDS into the solid dispersion system ensures a homogeneous distribution of the surfactant improving the wettability of the solid dispersion powder after encapsulation and tabletting.
The physical form of docetaxel after lyophilization was investigated by means of differential scanning calorimetry (DSC) (see Table 24) and X-ray powder diffraction (see Table 25) to determine the degree of crystallinity after lyophilization of docetaxel.
Lyophilization of docetaxel results in a reduction of crystallinity to such a degree that X-ray powder diffraction spectra of lyophilized docetaxel do not show diffraction peaks, as well as DSC thermograms do not show the endothermic peak associated with crystal rearrangement. Furthermore in the DSC thermogram a glass transition appears. This all is indicative that after lyophilization docetaxel is in an amorphous state.
The peak area of the endothermic peak associated with crystal rearrangement correlates well with the crystalline docetaxel content in physical mixtures of amorphous and crystalline docetaxel.
The physical form of paclitaxel after lyophilization was investigated by means of X-ray diffraction and Differential scanning calorimetry to determine the degree of crystallinity of paclitaxel after lyophilization.
Lyophilization of paclitaxel results in a reduction of crystallinity to such a degree that X-ray powder diffraction spectra of lyophilized paclitaxel do not show diffraction peaks, as well as DSC thermograms do not show the endothermic peak associated with crystal rearrangement. Furthermore in the DSC thermogram a glass transition appears. This all is indicative that after lyophilization paclitaxel is in an amorphous state.
Section 5: Characterization of Solid Dispersions with Docetaxel
To characterize the solid dispersion of docetaxel X-ray diffraction measurements and DSC measurements were performed on physical mixtures and solid dispersions of docetaxel, PVP-K30 and SDS.
In
SDS has a phase transition near 67° C. probably caused by a small amorphous fraction, and a large endothermic region between 80 and 120° C. containing multiple peaks. These peaks are partly caused by melting of the crystalline bulk of SDS and partly caused by unknown non-reversible endothermic events.
An X-ray powder diffraction spectrum of the solid dispersion does not show diffraction peaks belonging to docetaxel, while the X-ray powder diffraction spectrum of a physical mixture containing docetaxel, PVP-K30 and SDS shows diffraction peaks belonging to docetaxel. A DSC thermogram of a lyophilized mixture of docetaxel, PVP-K30 and SDS shows a glass transition at 155° C., probably caused by the molecular mixing of amorphous docetaxel and PVP-K30, while a DSC thermogram of a physical mixture containing docetaxel, PVP-K30 and SDS shows a glass transition temperature at 163°, probably caused by PVP-K30. In addition to this the endothermic peak near 162° is only visible in the DSC thermogram of the physical mixture and not in the DSC thermogram of the solid dispersion.
SDS is present in a crystalline state in both the solid dispersion and the physical mixture and causes the diffraction peaks between 20 and 22° 2 Theta in the X-ray diffraction spectra of both the solid dispersion and physical mixture, and the endothermic peaks near 100° C. and 113° C. in the DSC thermograms of the physical mixture and the solid dispersion respectively.
Furthermore, because the lyophilization of docetaxel alone resulted in amorphous docetaxel (see section 3), it is very likely that lyophilization of a mixture containing docetaxel also results in amorphous docetaxel.
The available data indicates that paclitaxel solid dispersion systems are comparable to docetaxel solid dispersion systems, i.e. paclitaxel is present in an amorphous state after lyophilization while SDS is not.
To determine the influence of the production method on the solid dispersion properties, both lyophilization and spray drying were used to produce a solid dispersion system with 1/11 docetaxel, 9/11 PVP-K30 and 1/11 SDS (see Table 19 and Table 21). Both systems were examined by X-ray diffraction, DSC and a dissolution screening test.
The use of spray drying compared to lyophilization in the production of solid dispersions of docetaxel lead to a more amorphous system which results in an improved performance in dissolution screening tests in terms of a prolonged supersaturated state.
Furthermore, the powder obtained after spray drying is less static and has a more uniform particle size, making it more suitable for further processing compared to the lyophilized product.
To test the influence of different carriers on the dissolution performance of docetaxel solid dispersions. Various carriers were used in the production of solid dispersion systems containing 1/11 docetaxel, 9/11 carrier and 1/11 SDS (see Table 19, formulation 8-11). All systems were subjected to a dissolution screening test.
Solid dispersion systems containing PEG perform worse in dissolution screening tests than solid dispersion systems containing PVP-K30.
Solid dispersion systems containing PVP-VA 64 reach significantly higher concentrations of docetaxel after precipitation than solid dispersion systems containing PVP-K30.
Furthermore, because paclitaxel has a lower solubility than docetaxel, the use of PVP-VA 64 might especially be helpful in paclitaxel containing solid dispersion systems.
To investigate the feasibility of the production of tablets from docetaxel solid dispersions.
Production of tablets of docetaxel containing solid dispersion systems is feasible. The dissolution rate of docetaxel tablets is comparable to the dissolution rate of the docetaxel capsules currently used in clinical trials.
300 mg ritonavir
45 mL ethanol
5 mL water for injection
Ritonavir was dissolved in the ethanol water mixture and spray dried with a Buchi 290 mini spray dryer (see table 27).
1 gram of docetaxel anhydrate
4 grams of ritonavir
25 grams of PVP-K30
5 grams of SDS
900 ml ethanol
All solid components were dissolved in the ethanol-water mixture and spray dried with a Buchi 290 mini spray dryer (see table 27). This resulted in a visually homogenous white powder. This solid dispersion powder, equivalent to approximately 12.5 mg docetaxel and 50 mg ritonavir (per capsule), was manually encapsulated in size 0 hard gelatine capsules.
The foregoing Examples are intended to illustrate specific embodiments of the present invention and are not intended to limit the scope thereof, the scope being defined by the appended claims. All documents cited herein are incorporated herein by reference in their entirety.
| Number | Date | Country | Kind |
|---|---|---|---|
| PCT/GB2008/002854 | Aug 2008 | GB | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/GB2009/002068 | 8/24/2009 | WO | 00 | 5/11/2011 |
