JP2010536837A - Composition - Google Patents

Abstract

  Pharmaceutical compositions and methods comprising a combination of a taxane, such as docetaxel, and a CYP3A4 inhibitor, such as ritonavir, for the treatment of neoplastic diseases. Also included are methods of treating neoplastic diseases that incorporate administration of taxanes and simultaneous or separate administration of CYP3A4 inhibitors. Further included is a kit for performing the method. Also included are solid taxane pharmaceutical compositions for oral administration comprising a substantially amorphous taxane, a carrier and a surfactant.

Description

  The present invention relates to a pharmaceutical composition. Specifically, but not limited to, compositions and methods for treating neoplastic diseases.

  There are several advantages to administering drugs in oral form. When treatment must be applied chronically so that the effect is optimal, oral anticancer agents such as 5-fluorouracil (5-FU) prodrugs (eg, capecitabine) and interfere with signaling pathways or angiogenic processes Drug availability is important [1]. In addition, oral medications are increasingly convenient because they can be administered to outpatients or at home, improving patient quality of life and possibly reducing costs by reducing inpatients [ 2]. Therefore, it is advantageous to attempt oral administration of anticancer agents.

  In general, oral administration of drugs is convenient and practical. However, most anticancer drugs unfortunately have poor oral bioavailability and are subject to variability [1]. Common examples are the commonly used taxanes, docetaxel and paclitaxel, but oral bioavailability is less than 10% [3,4]. Some other anticancer agents with higher bioavailability exhibit high variability. Examples include topoisomerase I inhibitors, vinca alkaloids and mitoxantrone [1, 5, 6]. Due to the narrow therapeutic window, variability in bioavailability can result in unexpected toxicity or reduced efficacy when therapeutic plasma levels are not achieved. Helleriegel et al. Generally observed i.p. v. Studies have shown that it is more variable than plasma levels after administration [7]. Proper oral bioavailability is important when the duration of drug exposure is a major determinant of anticancer drug treatment [8]. Appropriate oral bioavailability is also important to reduce local drug concentrations in the gastrointestinal tract, which can lead to local toxicity.

  Chen et al. [95] conducted experiments to increase the solubility of the anticancer drug docetaxel to improve its bioavailability. Chen et al. Attempted to use a solid dispersion of docetaxel with various carriers, namely glyceryl monostearate, PVP-K30 or poloxamer 188. Chen et al., When poloxamer 188 was used at a docetaxel to poloxamer ratio of 5:95, the solubility of docetaxel increased to about 3.3 μg / ml after 20 minutes (standard dissolution test) and after about 120 minutes. It was found to increase up to about 5.5 μg / ml. With PVP-K30 alone, the solubility of docetaxel increased to about 0.8 μg / ml after 20 minutes and increased to a maximum of about 4.2 μg / ml after about 300 minutes. Glycerol monostearate did not increase the solubility of docetaxel at all. Thus, the solubility and dissolution rate of docetaxel did not increase to very high levels.

  There are several important mechanisms that can explain the variability and / or low oral bioavailability of anticancer drugs, such as the high affinity of drug transporters in the gastrointestinal tract and limiting absorption, and the small intestine and / or Alternatively, drug removal is high due to active metabolism in the liver (first pass effect) [1, 4, 9]. Other important factors include structural instability and limited drug solubility in the gastrointestinal fluid, drug-drug and drug-food interactions, movement disorders, obstructive disorders, presence of nausea and vomiting or local in the gastrointestinal tract Toxicity is included.

  Regarding metabolic enzymes that affect the bioavailability of drug transporters and oral drugs, the metabolic enzymes involved in the low / fluctuating oral bioavailability of major drug transporters and anticancer agents are P-glycoprotein ( P-gp) and cytochrome P450 (CYP) isozymes have been speculated.

  P-glycoprotein (P-gp) is a membrane-bound multidrug transporter that functions as an efflux pump that reduces energy-dependent transport or intracellular accumulation of drugs by excretion of xenobiotics from cells. P-gp is a normal tissue with an exclusion function, such as the bile tubule membrane of hepatocytes, the luminal membrane of endothelial cells at the blood brain barrier and the blood-testis barrier, the apical membrane of the placental syncytium trophoblast, the small intestine It has been identified in the apical endothelium as well as in the renal proximal tubule. P-gp can have an important barrier function to protect tissues against foreign toxins [9-12].

  P-gp is believed to prevent certain pharmaceutical compounds from passing through the small intestinal mucosal cells and thus being absorbed into the systemic circulation. A wide variety of drugs with different physicochemical properties and pharmacological activities such as verapamil, quinidine and cyclosporin A (CsA) and the novel active blockers GF120918 (Elacridal), LY335999 (Zoschidar) and R101933 regulate P-gp Clinical studies have shown that [13-18]. The P-gp modulator is i. v. Mechanisms that can affect the pharmacokinetics of anticancer drugs after administration are cytochrome P450 (CYP) -mediated competition with small or large intestine or liver metabolism, inhibition of P-gp-mediated bile excretion, inhibition of small intestinal transport and renal clearance [ 19, 20]. A small number of prospective randomized trials with or without anticancer drugs and modulators were conducted. These studies revealed that dose reduction of anticancer drugs when combined with modulators is necessary to protect against severe drug-related toxicities. Furthermore, these studies did not show any survival benefit of the combination of anticancer agent and modulator [21-23].

  In many anticancer drugs, cytochrome P450 (CYP) is the major oxidative drug-metabolizing enzyme system. CYP isozymes are strongly expressed in the liver and small intestine, but the exact involvement of each isozyme in drug metabolism is not known. It has been recognized that removal in the small intestine by this enzyme system plays an important role in limiting the oral bioavailability of drugs [31]. In humans, four functional CYP3A enzymes have been identified that are major drug-metabolizing enzymes, accounting for about 30% of liver CYP and more than 70% of small intestinal CYP expression [24, 30, 32, 33]. .

  Some P-gp modulators also appear to be substrates for the CYP-based isozyme, CYP3A. The overlapping substrate selectivity of P-gp and CYP3A suggests that these two proteins work together as an absorption barrier against toxic xenobiotics when taken together with tissue localization. [24-26]. Cummins et al. Confirmed this and showed that P-gp can affect drug metabolism in the small intestine (especially isozyme CYP3A4) by controlling the access of the drug to the intracellular metabolic enzyme system [27] ]. Thus, it is believed that CYP3A and P-gp can contribute to the limited and / or variable oral bioavailability of common substrate drugs in the small intestine.

  Taxanes, paclitaxel and docetaxel have demonstrated anticancer activity in several tumors (eg, breast cancer, ovarian cancer, head and neck cancer and non-small cell lung cancer [NSCLC]). Currently, drugs are administered intravenously in various doses and dosages [34]. However, taxanes have very low bioavailability in oral formulations. This is presumed to be due to the action of P-gp and CYP3A. Studies that attempt to increase the bioavailability of orally administered drugs have been conducted with several anticancer agents (eg, taxanes) in mice and humans.

  When paclitaxel is administered orally, the bioavailability is very low (<10%). This is due to the high affinity of paclitaxel for P-gp present in the gastrointestinal tract [4, 10, 35, 36]. Furthermore, presystemic clearance by CYP isozymes 3A4 and 2C8 in the intestinal wall and liver may also contribute to the low oral bioavailability of paclitaxel [37-39]. Recent studies with wild-type and mdrla P-gp knockout mice clearly showed that P-gp limits the absorption of paclitaxel. In a proof-of-concept study in knockout mice compared to wild-type mice, we found that the area under the plasma concentration-time curve (AUC) of paclitaxel increased 6-fold after oral administration, i. v. It showed a 2-fold increase after administration [4]. The fraction of unchanged paclitaxel recovered from the stool of wild type mice after oral administration was 87% of the dose compared to 3% of the dose in mdrla P-gp knockout mice. Despite complete absorption from the gastrointestinal tract, bioavailability did not increase to 100%, probably due to first pass removal in the small intestine / liver [4, 40].

  Based on this finding, several new studies with P-gp inhibitors in combination with paclitaxel were initiated to increase oral bioavailability. In studies in mice, co-administration of SDZ PSC833, cyclosporine D analogs and potent P-gp inhibitors with paclitaxel caused a 10-fold increase in systemic exposure [41]. Similar studies showing similar effects were performed with CsA and paclitaxel [42]. Co-administration of CsA increased oral bioavailability in wild type mice from 9% to 67%. The plasma levels of paclitaxel obtained in wild type mice treated together with CsA were even higher than those obtained in knockout mice treated with oral paclitaxel without CsA. This can be explained by increased uptake due to inhibition of P-gp in the gastrointestinal tract and decreased clearance due to inhibition of CYP3A [42-45]. However, blocking other unidentified drug transporters or drug exclusion pathways cannot be ignored.

  The use of CsA for long-term oral administration has been associated with immunosuppressive effects that are detrimental to patient health. Therefore, to increase the oral bioavailability of paclitaxel, another non-immunosuppressive P-gp blocker, GF120918 was examined. GF120918 was originally developed to reverse P-gp mediated multidrug resistance in tumors [16]. In a recently published study, Bardelmeijer et al. Showed that GF120918 significantly increased the oral bioavailability of paclitaxel [46]. The oral bioavailability of paclitaxel in wild type mice increased from 8.5% to 40% and the pharmacokinetics of paclitaxel in wild type mice administered GF120918 was found in mdrla / b P-gp knockout mice Similar to dynamics. Thus, GF120918 effectively blocks P-gp in the small intestine and probably does not affect other pathways involved in paclitaxel uptake or elimination. Of note, in recent years GF120918 has also been shown to be an effective inhibitor of the ABC drug transporter BCRP (ABCG2) [28, 29].

  Docetaxel was also first shown by Wils et al. In 1994 to be a substrate for P-gp [47, 48]. Because promising results were obtained with paclitaxel in combination with p-gp inhibitors, studies of docetaxel were also conducted in mice. These studies confirmed that P-gp also plays an important role in the low bioavailability of docetaxel. Oral docetaxel AUC was increased 9-fold by co-administration with CsA [49]. In addition, mice were tested for co-administration with ritonavir, an inhibitor of CYP3A4 with the ability to slightly inhibit P-gp. CYP3A4 is a major enzyme involved in the metabolic degradation of docetaxel in humans [50]. The inventors conducted a preclinical study in which ritonavir was co-administered with docetaxel in mice and showed that the apparent bioavailability increased from 4% to 183%. Active first-pass metabolism may also be largely responsible for the low bioavailability of oral docetaxel in mice [49]. The cytochrome P450 enzyme (referred to as Cyp) in the mouse small intestine has a different substrate specificity, unlike that found in humans. Furthermore, the regulation of CYP expression between mice and humans varies considerably depending on differences in the activity, expression and regulation of PXR in transcription factors such as human CYP3A [88-92]. Therefore, these studies in mice cannot be a basis for suggesting results in humans because mouse physiology, enzymes, etc. are completely different from humans. Therefore, mouse data cannot simply be applied to humans. In addition, this study in mice also used very high doses of docetaxel (10-30 mg / kg) and high doses of ritonavir (12.5 mg / kg), which are lethal in human subjects. In a 72 kg individual, this means docetaxel 720-2160 mg. However, now patients are usually treated clinically with docetaxel at dosages between 100 and 200 mg (intravenous). Clearly, this approach is not possible in humans due to the high level of drug administered. Furthermore, the data in mice does not provide any evidence for the safety of this combination oral approach in humans.

Several clinical proof-of-concept trials have been initiated based on extensive preclinical results in mice. Patients with solid tumors received one course of oral paclitaxel 60 mg / m ² as a single agent or oral paclitaxel 60 mg / m ² combined with 15 mg / kg CsA. Co-administration of oral CsA resulted in an 8-fold increase in systemic exposure to oral paclitaxel, and the apparent bioavailability of oral paclitaxel in this study increased from 4% without CsA to 47% with CsA [3 ]. This increase in systemic exposure is probably due to inhibition of P-gp in the gastrointestinal tract, but inhibition of paclitaxel metabolism may also be implicated in this effect as judged from paclitaxel studies [41, 42]. To further increase systemic exposure to paclitaxel, a dose escalation study of oral paclitaxel in combination with CsA reveals that the maximum tolerated dose is 300 mg / m ² and the increase in AUC at high doses is not dose proportional [52]. At this highest dose level, a mass balance test was conducted to measure stool clearance. At the highest dose level of 300 mg / m ² , fecal exclusion is 76%, of which 61% is the parent drug, which is explained by incomplete absorption of orally administered paclitaxel from the gastrointestinal tract [53]. Paclitaxel used for oral administration i. v. A large amount of co-solvent Cremophor EL in the formulation appears to have prevented complete absorption of orally administered paclitaxel. In addition, i. v. Cremophor EL, which is responsible for the non-linear pharmacokinetics of paclitaxel and severe hypersensitivity reactions, was not absorbed by oral administration of paclitaxel because no plasma levels were detected [54-56]. This may be an additional advantage of oral administration of paclitaxel [51, 52]. Thereafter, the oral paclitaxel twice daily (bid) combination with CsA was used in patients to prolong the systemic exposure period of oral paclitaxel above the threshold level of 0.1 μM. At the 2 × 90 mg / m ² dose level, long-term systemic exposure to paclitaxel appropriately reached levels above 0.1 μM, and a good safety profile was observed [57]. In these studies, patients took an oral paclitaxel formulation (which also contains Cremophor EL and ethanol) [57]. Furthermore, a dose-study study of oral paclitaxel with CsA showed that P-gp inhibition by CsA was maximal with a single dose of 10 mg / kg [58].

In another phase I study, patients received 1000 mg of GF120918 1 hour prior to oral paclitaxel [59]. The increase in systemic exposure to paclitaxel was comparable to CsA combination. Based on the results of these Phase I studies, Phase II studies were initiated to determine whether repeated oral administration of paclitaxel was feasible and effective. Oral paclitaxel for several types of tumors: first and second-line treatment for NSCLC [60], first-line treatment for advanced gastric cancer [99], second-line treatment for advanced breast cancer [100], once a week b. i. d. Administered. All patients received 90 mg / m ² oral paclitaxel at a dose b. i. d. Treated weekly. CsA was administered at a dose of 10 mg / kg 30 minutes prior to each paclitaxel dose. In patients with advanced NSCLC, response rate (ORR) was 26% in 23 evaluable patients [60]. The median progression-free period was 3.5 months and the median survival was 6 months, which was comparable to previous studies. These trials using several single agents such as vinorelbine, gemcitabine and taxane revealed a response rate of 8% to 40% and a median survival range of 6-11 months. [61-66].

  In advanced gastric cancer, chemotherapy is given for symptomatic treatment. Combination chemotherapy with drugs such as 5-FU / doxorubicin in combination with mitomycin or methotrexate or epirubicin / cisplatin / 5-FU regimen is often used and may have a response rate between 20% and 50% Indicated [67-70]. Paclitaxel has also shown anticancer activity in patients with advanced gastric cancer with primary and secondary treatment (ORR: 5% -23%) [71-73]. The ORR in this study was 32% in 24 evaluable patients. This b. i. d. The toxicity profile of the weekly plan is well controlled [99]. The most common toxicity in the NSCLC patient group was grade 3/4 neutropenia observed in 54% of patients. This is a standard 3 week interval paclitaxel i. v. Same as planned [65, 66].

  The incidence of neurotoxicity is low compared to the 3-week interval schedule, which can be explained by the low peak of paclitaxel plasma concentration in this study. This was also observed in patients who were infused at 24 hours versus paclitaxel 3 hour infusion [74], i. v. It may be asked whether paclitaxel plasma levels after administration (thus in the presence of Cremophor EL) can be equivalent to that after oral paclitaxel (and thus not including Cremophor EL).

For docetaxel, a similar clinical proof-of-concept study was conducted in patients with solid tumors. Patients received one course of 75 mg / m ^{2 of} oral docetaxel with or without a single oral dose of 15 mg / kg CsA. Pharmacokinetic results indicated that co-administration of oral CsA resulted in a 7.3-fold increase in systemic exposure to docetaxel. The apparent bioavailability of oral docetaxel increased from 8% without CsA to 90% with CsA [75]. This increased systemic exposure can be explained by inhibition of CYP3A4 as well as inhibition of P-gp by CsA in the gastrointestinal tract, but the size of both mechanisms cannot be accurately determined. The effect of CsA on docetaxel bioavailability is less pronounced in mice [49] compared to humans [75], but the reason for the reduction in effects in these mice is not clear. A phase II study with weekly oral docetaxel and CsA was also conducted in advanced breast cancer. In this plan, they were administered every week for 6 weeks and then withdrawn for 2 weeks. Docetaxel 100 mg dose administered orally every week gives 40 mg / m ² weekly i. v. An AUC equivalent to administration was produced and was reasonably well tolerated [76]. CsA was administered 30 minutes before taking the oral docetaxel 15 mg / kg dose. Docetaxel i. v. The formulation was used as a drinking solution. In 25 patients whose response could be evaluated, ORR 52% was observed.

  The most frequently recorded toxicities were neutropenia, diarrhea, nail toxicity and fatigue. However, the severity of hematological toxicity is i. v. It appears to be less than after administration [77]. The response rate in this test is within the upper range of results described in the literature [76-79].

  The inter-patient and intra-patient variation of docetaxel AUC after oral administration is determined by i. v. The same range observed after administration (29% to 53%) [80, 81].

  Oral administration of CsA weekly or once every two days in combination with oral docetaxel or paclitaxel could result in nephrotoxicity or immunosuppressive infection [82]. Therefore, in our view, other drugs are preferred to improve the clinical bioavailability of oral docetaxel or paclitaxel.

  Intensive weekly oral dosing regimens of taxanes are feasible and show clinically significant activity in advanced breast cancer, gastric cancer and NSCLC. The oral regimen is simple, has an advantageous hematological toxicity profile, and non-hematological toxicity is acceptable.

  The prior art seems to focus primarily on inhibiting the action of P-gp to improve the bioavailability and pharmacokinetic properties of anticancer agents. This has been performed using various drugs, such as CsA and GF120918. P-gp appears to have been recognized as the most important protein to block in order to increase the bioavailability of oral drugs.

  Accordingly, in a first aspect, the present invention provides a pharmaceutical composition for oral administration comprising a taxane and an inhibitor of CYP3A4, such as ritonavir, together with one or more pharmaceutically acceptable excipients. .

  The advantage of using ritonavir in combination with a taxane is that the oral bioavailability of the taxane is increased and thus more drug is absorbed from the small intestine into the bloodstream. This is due to the inhibition of CYP3A4 and the slight P-gp inhibitory properties that prevent drug metabolism. Ritonavir also suppresses taxane elimination from the body by inhibiting CYP3A4 metabolism in the liver. This means that the taxane reaches high plasma levels over a long period of time. For example, docetaxel metabolites have less pharmacological activity than docetaxel itself. Thus, by inhibiting docetaxel metabolism, the most pharmacologically active form is present in the bloodstream at higher levels and for longer periods of time. This provides a greater therapeutic effect. As a result, it may be possible to suppress the amount of taxane per dose. Furthermore, inhibition of CYP3A4 reduces inter-patient variability in bioavailability and elimination due to differences in CYP activity levels in various patients.

  Targeting and inhibiting CYP3A4 with ritonavir enhances the bioavailability of oral taxanes by blocking metabolism rather than targeting P-gp. This is an overall effort different from that of the prior art.

  The pharmaceutical compositions of the present invention include any taxane, or pharmaceutically acceptable salts and esters thereof, and ritonavir (or their) together with any pharmaceutically acceptable carrier, adjuvant or vehicle. Pharmaceutically acceptable salts and esters). Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, Buffer substances such as phosphate, glycerin, 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 salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylic acid, wax, polyethylene-polyoxypropylene-block polymer, polyethylene Include glycol and wool fat. The pharmaceutical compositions of the present invention can contain conventional non-toxic pharmaceutically acceptable carriers, adjuvants or vehicles.

  The pharmaceutical compositions of the present invention can be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders or coated granules. Suspensions, solutions and emulsions preferably dissolved in an aqueous medium can also be used. Tablets can be formulated for immediate release, slow release, repeated release or sustained release. Alternatively, it may be effervescent, bilayer and / or coated tablets. Slow release, repeated release and sustained release formulations may be for one or both active ingredients. Tablets can be formed from solid dispersions or solid solutions of taxanes and / or ritonavir. Capsules can be formulated for immediate release, slow release, repeated release or sustained release. It may be a solid filled or liquid filled capsule. Slow release, repeated release and sustained release formulations may be for one or both active ingredients. Capsules can be formed from a solid dispersion or solution of taxane and / or ritonavir, or the taxane and / or ritonavir can be dissolved or dispersed in a liquid. For example, a possible solvent for liquid-filled capsules is triacetin. This is believed to be a particularly good solvent for paclitaxel. Aqueous solutions can be “ready to use” prepared from powders or powders, prepared from solid dispersions or dispersions, or by mixing a solution of taxane and ritonavir. The aqueous solution can also include other pharmaceutical additives such as polysorbate 80 and ethanol. For tablets and capsules for oral use, commonly used carriers include sucrose, cyclodextrin, polyethylene glycol, polymethacrylate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, mannitol, inulin, sugars (dextose Galactose, sucrose, fructose or lactose), HPMC (hydroxypropylmethylcellulose), PVP (polyvinylpyrrolidone) and corn starch. A lubricant, such as magnesium stearate, is also usually added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. For tablets and capsules, other pharmaceutical additives that can be added are binders, fillers, fillers / binders, adsorbents, wetting agents, disintegrants, lubricants, glidants, surfactants, etc. is there. Tablets and capsules can be coated to modify the appearance or properties of the tablets and capsules, for example to modify the taste or to color coat the tablets or capsules. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents can be added.

  Solid dispersions and solid solutions of taxanes and ritonavir can be formed using any suitable method and can include a carrier, such as a polymer. Such methods are well known to those skilled in the art [93, 94]. The taxane and ritonavir in the solid dispersion may be in an amorphous, crystalline or partially amorphous / partially crystalline state. In the preparation of the solid dispersion, an organic solvent is often used. These may be any suitable organic solvent, for example TBA (tertiary butyl alcohol), ethanol, methanol, DMSO (dimethyl sulfoxide) and IPA (isopropyl alcohol). Any method can be used to remove the organic and / or aqueous solvent from the solid dispersion solution, such as lyophilization, spray drying, spray lyophilization and vacuum drying.

  In compositions for oral administration, particularly solid compositions, the taxane and ritonavir may be present in the same dosage form or in separate dosage forms. When present in the same dosage form, the taxane and ritonavir may be formulated together, or may be present in separate compartments of a multi-compartment dosage form, such as a multi-layer tablet or multi-compartment capsule.

  In compositions that contain modified release formulations, eg, slow release, repeated release and sustained release formulations, the goal is to maintain adequate blood levels of one or both active ingredients over a prolonged period after administration.

  Repeated release formulations, such as tablets or capsules, can release the appropriate dose of taxane (eg, docetaxel) and ritonavir immediately (eg, at t = 0 h) and later (eg, the ritonavir Cmax is It is possible to release additional doses of ritonavir (typically achieved at t = 4 h). This can be achieved, for example, by separating the initial dose of docetaxel and ritonavir from the additional dose of ritonavir by an enteric coating or polymer coating that contains an enzymatic cleavage bond that allows degradation and dissolution in the small intestine. Can do. Alternatively, this can be achieved by filling capsules with coated and uncoated granules, the coated granules containing only ritonavir and the uncoated granules containing docetaxel and ritonavir. it can. This could of course also be achieved by combining immediate release docetaxel tablets / capsules with ritonavir repeated release tablets / capsules. Any suitable enteric coating can be used, such as cellulose acetate phthalate, polyvinyl acetate phthalate, and suitable acrylic acid derivatives such as polymethacrylate.

  In one embodiment, the second additional dose of ritonavir (and therefore a total of three doses) is similar in principle, ie several hours after the first additional dose (eg, the first additional dose of ritonavir is Could be performed by repeated release (when Cmax was reached).

  A sustained release formulation is, for example, a formulation that releases an appropriate dose of a taxane and an initial initial / loading dose of ritonavir and then slowly releases a sustained dose of ritonavir. For example, this can be accomplished by a single oral dosage form of docetaxel and ritonavir, or by combining an immediate release tablet / capsule of docetaxel and a sustained release tablet / capsule of ritonavir.

  Modified release formulations may utilize, for example, inert insoluble substrates, hydrophilic substrates, ion exchange resins, osmotic pressure control formulations and storage systems. Common controlled release systems include, for example, the following substances, active drug (s), release control agent (s) (eg, matrix forming agent, film forming agent), matrix or membrane modulating agent, solubilizing agent, Consists of pH modifiers, lubricants and flow aids, auxiliary coating agents and density modifiers [84]. Suitable inert excipients include calcium hydrogen phosphate, ethyl cellulose, methacrylate copolymer polyamide, polyethylene, polyvinyl acetate. Suitable lipid excipients include carnauba wax, acetyl alcohol, hydrogenated vegetable oil, microcrystalline wax, mono and triglycerides, PEG monostearate and PEG. Suitable hydrophilic excipients include alginate, carbopol, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose and methylcellulose [84].

  In one embodiment of the invention, a composition comprising a taxane and ritonavir can be formulated such that ritonavir is released a little earlier or faster than the taxane. This will have the effect of inhibiting the CYP3A4 enzyme in the intestine before a substantial amount of taxane is released from the composition. Thus, the amount of taxane that is degraded by the CYP3A4 enzyme before reaching the bloodstream is reduced, and the effect of ritonavir on CYP3A4 in the liver reduces the metabolism and elimination of the taxane reaching the bloodstream during the early stages of taxane absorption. It also has an effect. This effect is illustrated in FIG. 1 and shows that ritonavir administration increases 60 minutes prior to docetaxel and increases oral bioavailability and AUC. Although this result was not statistically significant in Example 2, this tendency was observed.

  Taxanes are diterpene compounds derived from the plant Taxus genus (yew). However, some taxanes are currently produced synthetically. Taxanes inhibit cell proliferation by preventing cell division and are used in the treatment of cancer. Taxanes block cell division by disrupting microtubule formation. Taxanes can also act as angiogenesis inhibitors. As used herein, the term “taxane” includes all diterpentane, whether naturally occurring or artificially bound, functional derivatives and tubulin, and / or CYP3A4. And pharmaceutically acceptable salts or esters which are substrates. 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'-Nt-butyloxycarbonyl analog of paclitaxel [83]. The most preferred taxanes are docetaxel, functional derivatives thereof or pharmaceutically acceptable salts or esters thereof, especially derivatives that are substrates for CYP3A4.

  Derivatives of taxanes that contain groups that modify physiochemical properties are also included within the invention. Thus, included are taxane polyalkylene glycols (eg, polyethylene glycol) or sugar conjugates that have improved solubility characteristics or are modified.

  The pharmaceutical composition of the present invention may contain appropriate amounts of taxane and ritonavir. Preferably, the composition comprises between about 0.1 mg and about 1000 mg of taxane. Preferably, the composition also includes between about 0.1 mg and about 1200 mg of ritonavir. The amount of each taxane and ritonavir depends on the intended frequency of administration of the composition. For example, the composition may be three times a day, twice a day or daily, once every two days, once a week, once every two weeks, once every three weeks, or any other suitable dosage interval. Can be administered. Combinations of these usages may also be used, for example, the composition may be for administration once a week or once every two weeks or once every three weeks twice a day. For example, paclitaxel or docetaxel can be administered once a week, twice a day. The normal weekly dose is divided so that the subject takes, for example, once a week, half the dose in the morning and the other half at night. This has the effect of reducing the peak level of the drug in the plasma and can help to suppress side effects. It also increases the total time of systemic exposure to the drug.

  When the composition is for daily administration, the composition is preferably between about 0.1 mg and about 100 mg of taxane, more preferably between about 5 mg and about 40 mg of taxane, more preferably about 5 mg of taxane. Between about 30 mg, more preferably between about 10 mg and about 20 mg of taxane, most preferably about 15 mg of taxane. Preferably, the composition also contains between about 50 mg and about 1200 mg of ritonavir, more preferably between about 50 mg and about 500 mg of ritonavir, more preferably between about 50 mg and about 200 mg of ritonavir, most preferably ritonavir. Contains about 100 mg.

  Where the composition is for weekly administration, the composition preferably comprises between about 30 mg and about 500 mg of taxane, more preferably between about 50 mg and about 200 mg of taxane, and most preferably about 100 mg of taxane. Preferably, the composition also contains between about 50 mg and about 1200 mg of ritonavir, more preferably between about 50 mg and about 500 mg of ritonavir, more preferably between about 50 mg and about 200 mg of ritonavir, most preferably ritonavir. Contains about 100 mg.

  Surprisingly, the use of ritonavir at low doses, eg, 100 mg, has desirable properties that increase the bioavailability of taxanes and provide enhanced therapeutic effects. This means that low doses of ritonavir can be used to produce the desired effect while minimizing the risk of side effects.

  The present invention also provides compositions comprising CYP3A4 inhibitors, such as taxanes and ritonavir, for use in therapy.

  In addition, the present invention also provides compositions comprising CYP3A4 inhibitors, such as taxanes and ritonavir, for use in the treatment of neoplastic diseases.

  The neoplastic disease treated by the present invention is preferably a solid tumor. The solid tumor is preferably breast cancer, lung cancer, stomach cancer, colon cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer, endometrial cancer, ovarian cancer and Selected from non-Hodgkin lymphoma (NHL). The solid tumor is more preferably selected from breast cancer, stomach cancer, ovarian cancer, prostate cancer, head and neck cancer and non-small cell lung cancer.

  In one embodiment, treatment of neoplastic disease includes administration of the composition followed by administration of additional doses of ritonavir after a predetermined period of time. The additional administration is preferably between about 0 hours and about 12 hours after administration of the composition, more preferably between about 1 hour and about 10 hours after administration of the composition, more preferably about Between 2 hours and about 8 hours, more preferably between about 3 hours and about 5 hours after administration of the composition, most preferably about 4 hours after administration of the composition. The additional dose is preferably between about 50 mg and about 1200 mg of ritonavir, more preferably between about 50 mg and about 500 mg of ritonavir, more preferably between about 50 mg and about 200 mg of ritonavir, and most preferably about 100 mg of ritonavir.

  Surprisingly, it has been discovered that administration of additional doses of ritonavir results in therapeutic levels of taxanes in the bloodstream for extended periods of time, thereby having a greater therapeutic effect.

  In a related aspect, the invention also provides a method of treating a neoplastic disease comprising administering to a subject in need of such treatment an effective amount of a CYP3A4 inhibitor such as taxane and ritonavir. .

  Similar to the composition, the taxane may be any suitable taxane. Preferably, the taxane is selected from docetaxel, paclitaxel, BMS-275183, functional derivatives thereof and pharmaceutically acceptable salts or esters thereof, more preferably the taxane is docetaxel, functional derivatives thereof or These are pharmaceutically acceptable salts or esters.

  When the taxane and ritonavir are administered to the subject, they can be administered substantially simultaneously with each other. Alternatively, they can be administered separately from each other. When administered separately, ritonavir is preferably administered before the taxane, more preferably about 60 minutes before the taxane.

  As used herein, “substantially simultaneously” means that taxane or ritonavir administration is within about 20 minutes, more preferably within 15 minutes, more preferably within 10 minutes, even more preferably within 5 minutes, most preferably Ritonavir or taxane means administration within 2 minutes. In general, ritonavir should be administered at the same time or before the taxane. Ritonavir and the taxane may be administered in some embodiments at the same time, ie, together in one formulation or simultaneously in two separate formulations.

  Any suitable amount of taxane or ritonavir can be administered according to this method. The taxane and / or ritonavir dose can be administered in a fixed dose (ie, the same for all patients regardless of body weight or body surface area) or a body weight or body surface area based dose. Preferably, the taxane and / or ritonavir is administered at a fixed dose. Preferably, the taxane is administered between about 0.1 mg and about 1000 mg. Preferably, ritonavir is administered between about 0.1 mg and about 1200 mg. The amount of each taxane and ritonavir administered depends on the intended frequency of administration of the taxane and ritonavir. For example, administration may be three times daily, twice daily or once daily, once every two days, once a week, twice every two weeks, once every three weeks, or any other suitable dosage interval. May be. Combinations of these usages may also be used, for example, once a week or once every two weeks or once every three weeks, twice daily.

  Where the method involves daily administration of taxane and ritonavir, preferably the taxane is administered between about 0.1 mg and about 100 mg, more preferably the taxane is administered between about 5 mg and about 40 mg, more preferably The taxane is administered between about 5 mg and about 30 mg, more preferably the taxane is administered between about 10 mg and about 20 mg, and most preferably the taxane is about 15 mg. Preferably, ritonavir is also administered between about 50 mg and about 1200 mg, more preferably ritonavir is administered between about 50 mg and about 500 mg, more preferably ritonavir is administered between about 50 mg and about 200 mg, most Preferably about 100 mg of ritonavir is administered.

  Where the method involves weekly administration of taxane and ritonavir, preferably the taxane is administered between about 30 mg and about 500 mg, more preferably the taxane is administered between about 50 mg and about 200 mg, most preferably the taxane. Approximately 100 mg is administered. Preferably, ritonavir is also administered between about 50 mg and about 1200 mg, more preferably ritonavir is administered between about 50 mg and about 500 mg, more preferably ritonavir is administered between about 50 mg and about 200 mg, most Preferably about 100 mg of ritonavir is administered.

  The method may be for treating any neoplastic disease. Preferably, the neoplastic disease is a solid tumor. Preferably, the solid tumor is breast cancer, lung cancer, stomach cancer, colon cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer, endometrial cancer, ovarian cancer and Selected from NHL. More preferably, the solid tumor is selected from breast cancer, ovarian cancer, prostate cancer, stomach cancer, head and neck cancer and non-small cell lung cancer.

  Preferably, the method is used to treat a human subject.

  In one embodiment, the method further includes administration of a CYP3A4 inhibitor, such as an additional dose of ritonavir, after a predetermined period of time following administration of an initial dose of ritonavir (ie, a dose of ritonavir together with a taxane dose). . The additional dose is preferably between about 0 hours and about 12 hours after the composition, more preferably between about 1 hour and about 10 hours after administration of the composition, more preferably about 2 hours after administration of the composition. It is administered between time and about 8 hours, more preferably between about 3 hours and about 5 hours after administration of the composition, most preferably about 4 hours after administration of the composition. The additional dose is preferably between about 50 mg and about 1200 mg of ritonavir, more preferably between about 50 mg and about 500 mg of ritonavir, more preferably between about 50 mg and about 200 mg of ritonavir, and most preferably about 100 mg of ritonavir.

  The present invention also provides a method of treating a neoplastic disease comprising: combining a composition comprising a taxane and one or more pharmaceutically acceptable excipients with a CYP3A4 inhibitor such as ritonavir with a taxane. Administering to a subject being administered separately, separately or sequentially.

  The present invention further provides a method of treating a neoplastic disease comprising: a composition comprising a CYP3A4 inhibitor such as ritonavir and one or more pharmaceutically acceptable excipients; a taxane as ritonavir; Administering to a subject being administered simultaneously, separately or sequentially with the CYP3A4 inhibitor.

  Furthermore, the present invention includes a first pharmaceutical composition comprising a taxane and a second pharmaceutical composition comprising a CYP3A4 inhibitor such as ritonavir, wherein the first and second pharmaceutical compositions are for neoplastic disease treatment. Kits suitable for simultaneous, separate or sequential administration are provided.

  In one embodiment, the kit further comprises a third pharmaceutical composition comprising a CYP3A4 inhibitor, such as ritonavir, suitable for administration after a second pharmaceutical composition comprising a CYP3A4 inhibitor, such as ritonavir. be able to. It should be understood that the second and third pharmaceutical compositions of the kit each containing a CYP3A4 inhibitor such as ritonavir may be a single dosage form of substantially the same composition.

  Alternatively, the kit can include a first pharmaceutical composition comprising CYP3A4 inhibitors such as taxanes and ritonavir for the treatment of neoplastic diseases. In this case, the kit can further comprise a second pharmaceutical composition comprising a CYP3A4 inhibitor, such as ritonavir, suitable for administration after the first pharmaceutical composition.

  In addition, the present invention provides a taxane and one or more pharmacological agents for use in the treatment of neoplastic disease in a subject that has been administered a CYP3A4 inhibitor, such as ritonavir, concurrently, separately, or sequentially. Compositions comprising acceptable excipients are provided.

  Furthermore, the present invention provides a CYP3A4 inhibitor, such as ritonavir, and one for use in the treatment of neoplastic disease in a subject that has been administered a taxane with a CYP3A4 inhibitor, such as ritonavir, simultaneously, separately or sequentially. Alternatively, a composition comprising a plurality of pharmaceutically acceptable excipients is provided.

  Those skilled in the art will recognize that any or all of the aforementioned preferred properties associated with compositions, methods or kits using ritonavir are equivalent and other CYP3A4 inhibitors such as grapefruit juice or hypericum (or any component) It will be understood that this is applicable to those using lopinavir or imidazole compounds, such as ketoconazole.

  Another problem associated with the prior art is the inability to develop oral compositions containing taxanes with high bioavailability and low variability. i. v. Clinical trials with oral paclitaxel [eg 3] and oral docetaxel [eg 75] were ingested orally with taxane formulations (which also contain Cremophor EL and ethanol, or polysorbate 80 and excipients such as ethanol). Nausea, nausea and unpleasant taste are often reported by patients.

  As previously discussed, Chen et al. [95] attempted to improve the solubility and dissolution rate of docetaxel using a solid dispersion of docetaxel in combination with poloxamer 188 or PVP-K30. Poloxamers increased the solubility of docetaxel to about 3.3 μg / ml after 20 minutes and up to about 5.5 μg / ml after about 120 minutes when using a docetaxel to poloxamer ratio of 5:95 (chen) (See FIG. 7). PVP-K30 increased the solubility of docetaxel to about 0.8 μg / ml after 20 minutes and up to about 4.2 μg / ml after about 300 minutes (see FIG. 2). In order to achieve good oral bioavailability, the drug has a relatively high solubility and dissolution rate, so that there is a sufficiently large amount of drug in solution in the first about 0.5 to 1.5 hours. Must be.

  In another aspect, the present invention provides a solid pharmaceutical composition for oral administration comprising a substantially amorphous taxane, a hydrophilic, preferably polymerized carrier, and a surfactant.

  The advantage provided by the composition of this embodiment is that the solubility of the taxane is increased to a surprising degree. In addition, the taxane dissolution rate increases to an astonishing degree. Either of these factors causes a significant increase in the taxane bioavailability. This is believed to be due at least in part to the taxane being in an amorphous state. Crystalline taxanes have very low solubility. Furthermore, in clinical trials, it was discovered that the oral composition of the present invention has a high AUC and the interindividual variability is significantly lower than the interindividual variability exhibited by liquid formulations. This results in taxane exposure with much better predictability that is highly desirable in terms of safety in oral chemotherapy regimens. Intra-individual variability also appears to be significantly lower. Another advantage is that the oral composition of the present invention appears to be at least equivalent to or better tolerated than liquid oral taxane solutions (ie, with respect to side effects).

  The advantage provided by the carrier is that it helps to maintain the taxane in an amorphous state when placed in an aqueous medium. This serves to prevent taxane crystallization or to prolong the time until taxane crystallization begins in solution. Therefore, the solubility and dissolution rate of the taxane are kept high. Furthermore, the carrier provides excellent physical and chemical stability to the composition. It helps to prevent taxane decomposition and also helps to prevent the substantially amorphous taxane from gradually changing to a more crystalline structure in the solid state. Good physical stability ensures that the taxane solubility remains high.

  Surfactants also help maintain the taxane in an amorphous state when placed in an aqueous medium, surprisingly reducing the solubility of the taxane compared to a composition comprising an amorphous taxane and a carrier. Increase substantially.

  The term “substantially amorphous” means that there is little or no ordering of taxane molecule positions over a wide range. Most molecules will be in a random direction. A completely amorphous structure is broadly unordered, contains no crystalline structure, and is the exact opposite of a crystalline solid. However, some individuals may have difficulty obtaining a completely amorphous structure. Thus, many “amorphous” structures are not completely amorphous, but still contain a certain amount of extensive order or crystallinity. For example, a solid is predominantly amorphous, but may have crystal structure pockets, or contain a very small amount of crystals so that it can be said to be truly amorphous. . Thus, the term “substantially amorphous” includes solids that have some amorphous structure but also some crystal structure as well. The crystallinity of the taxane that is substantially amorphous is less than 50%. Preferably, the substantially amorphous taxane has a crystallinity of less than 40%, even more preferably less than 30%, even more preferably less than 25%, even more preferably less than 20%, Even more preferably less than 15%, even more preferably less than 12.5%, even more preferably less than 10%, even more preferably less than 7.5%, even more preferably less than 5%, most Preferably it is less than 2.5%. Crystalline taxanes have lower solubility, and the lower the crystallinity of the substantially amorphous taxane, the higher the solubility of the substantially amorphous taxane.

  The substantially amorphous taxane can be prepared by any suitable method and technique apparent to those skilled in the art. For example, it can be prepared using a solvent evaporation method or lyophilization. Preferably, the amorphous taxane is prepared by lyophilization. Surprisingly, preparing an amorphous taxane using lyophilization yields a composition with superior solubility and dissolution rate compared to the distillation method. This is thought to be due to the fact that the freeze-drying method produces more amorphous taxane than the solvent distillation method.

  The composition for oral administration is in solid form. The solid composition may be in any suitable form as long as the taxane is in a substantially amorphous state. For example, the composition can include a physical mixture of an amorphous taxane, a carrier and a surfactant. 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 partially molecularly dispersed in the carrier. More preferably, the taxane and the 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. Solid solutions are considered to be more amorphous in nature than solid dispersions. Methods for preparing solid dispersions and solid solutions are well known to those skilled in the art [93, 94]. Using these methods, both the taxane and the support are brought into an amorphous state. When the taxane and carrier are in the form of a solid dispersion or solid solution, the solubility and dissolution rate of the taxane is greater than the physical mixture of the amorphous taxane and the carrier. When the taxane is a solid dispersion or solid solution, the taxane is considered to be in a more amorphous state compared to the amorphous taxane itself. This is believed to provide improved solubility and solubility. The crystallinity of the solid dispersion or solid solution is less than 50%. Preferably, the crystallinity of the solid dispersion or solid solution is less than 40%, even more preferably less than 30%, even more preferably less than 25%, even more preferably less than 20%, even more preferably 15%. %, Even more preferably less than 12.5%, even more preferably less than 10%, even more preferably less than 7.5%, even more preferably less than 5%, most preferably 2.5%. %.

  When the taxane and carrier are solid dispersions, the surfactant may be a solid dispersion or a physical mixture with a solid solution. Preferably, however, the composition comprises a taxane, a carrier and a surfactant in the form of a solid dispersion, more preferably a solid solution. The advantage of having all three components in a solid dispersion or solution is that a small amount of surfactant can be used to achieve a similar improvement in solubility and dissolution rate.

  In one embodiment, the composition can be included in a capsule for oral administration. Capsules can be filled in several different ways. For example, an amorphous taxane can be prepared by lyophilization, pulverization, mixing with a carrier and surfactant, and then dispensing into capsules. In another preferred embodiment, the amorphous taxane is prepared by lyophilizing the taxane solution in a capsule for oral administration. A taxane solution containing the required amount of taxane is dispensed into capsules and then lyophilized while contained within the capsule. This facilitates the dispensing of the required amount of taxane into the capsule, since it is easier to dispense a liquid than a powder. Also, the capsule filling step is omitted, and the process becomes more effective. Next, the powdered carrier and surfactant can be added. Preferably, the capsule is an HPMC capsule.

  When the taxane and carrier are in the form of a solid dispersion or solid solution, the solution containing the taxane and carrier is preferably dispensed into capsules and then lyophilized while in the capsule. In this method, a solid dispersion or solid solution is prepared by lyophilizing the taxane and carrier solution in a capsule for oral administration. This also eliminates the capsule filling step. Next, a powdered surfactant can be added.

  When the taxane, carrier and surfactant are in the form of a solid dispersion or solid solution, the solution containing the taxane, carrier and surfactant is preferably dispensed into capsules and then lyophilized within the capsule. In this method, a solid dispersion or solid solution is prepared by lyophilizing a taxane, carrier and surfactant solution in a capsule for oral administration. This also eliminates the capsule filling step and eliminates the need to handle difficult to process powders.

  The taxane of the composition may be any suitable taxane as defined above. Preferably, the taxane is selected from docetaxel, paclitaxel, BMS-275183, functional derivatives thereof and pharmaceutically acceptable salts or esters thereof. More preferably, the taxane is selected from docetaxel, paclitaxel, functional derivatives thereof and pharmaceutically acceptable salts or esters thereof.

  The carrier of the hydrophilic, preferably polymerized composition, is organic, which can be at least partially dissolved in an aqueous medium at pH 7.4 and / or can be swollen or gelatinized with such an aqueous medium. A polymerized compound is preferred. The carrier can be any suitable hydrophilic, preferably polymerized carrier that ensures the amorphous state of the taxane in the composition and ensures increased solubility and dissolution rate of the taxane. Preferably, the carrier is polyvinyl pyrrolidone (PVP), polyethylene glycol (PEG), polyvinyl alcohol (PVA), crospovidone (PVP-CL), polyvinyl pyrrolidone-polyvinyl acetate copolymer (PVP-PVA), 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 selected from chitosan and cyclodextrin. More preferably, the carrier is selected from PVP, PEG and HPMC, most preferably the carrier is PVP.

  When the support is PVP, it may be any suitable PVP [98] to act as a support and promote maintenance of the amorphous taxane. For example, the PVP can be selected from PVP-K12, PVP-K15, PVP-K17, PVP-K25, PVP-K30, PVP-K60, PVP-K90 and PVPK120. Preferably, the PVP is selected from PVP-K30, PVP-K60 and PVP-K90.

  The composition can contain any suitable amount of carrier relative to the amorphous taxane so that the carrier maintains the amorphous state of the amorphous taxane. Preferably, the weight ratio of taxane to carrier is between about 0.01: 99.99 w / w and about 75:25 w / w. More preferably, the weight ratio of taxane to carrier is between about 0.01: 99.99 w / w and about 50:50 w / w, even more preferably about 0.01: 99.99 w / w and about 40 : Between 60 w / w, even more preferably 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, even more preferably 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 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, most preferably about 10:90 w / W.

  The surfactant may be any suitable pharmaceutically acceptable surfactant, and such surfactants are well known to those skilled in the art. Preferably, the surfactant is triethanolamine, sunflower oil, stearic acid, sodium dihydrogen phosphate, sodium citrate dihydrate, propylene glycol alginate, oleic acid, monoethanolamine, mineral oil and lanolin alcohol, methylcellulose , Medium chain triglycerides, lecithin, hydrous lanolin, lanolin, hydroxypropyl cellulose, glyceryl monostearate, ethylene glycol pamitostearate, diethanolamine, lanolin alcohol, cholesterol, cetyl alcohol, cetostearyl alcohol, castor oil, sodium dodecyl sulfate (SDS ), Sorbitan ester (sorbitan fatty acid ester), polyoxyethylene stearate, polyoxyethylene sorbitan fatty acid ester, polio Siethylene castor oil derivative, polyoxyethylene alkyl ether, poloxamer, glyceryl monooleate, sodium docusate, cetrimide, benzyl benzoate, benzalkonium chloride, benzethonium chloride, hypromellose, nonionic emulsifying wax, anionic emulsifying wax and Selected from triethyl citrate. More preferably, the surfactant is sodium dodecyl sulfate (SDS), sorbitan ester (sorbitan fatty acid ester), polyoxyethylene stearate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, polyoxyethylene alkyl ether, Poloxamer, glyceryl monooleate, sodium docusate, cetrimide, benzyl benzoate, benzalkonium chloride, benzethonium chloride, hypromellose, nonionic emulsifying wax, anionic emulsifying wax and triethyl citrate. Most preferably, the surfactant is SDS.

  Any suitable amount of surfactant can be used in the composition to increase the solubility and dissolution rate of the taxane. Preferably, the weight ratio of surfactant to the combined taxane and carrier is between about 1:99 w / w and about 50:50 w / w, more preferably about 1:99 w / w and about 44: Between 56 w / w, even more preferably between about 1:99 w / w and about 33:67 w / w, even more preferably between about 2:98 w / w and about 33:67 w / w, even more preferred Is between about 2:98 w / w and about 17:83 w / w, even more preferably between about 5:95 w / w and about 17:83 w / w, most preferably about 9:91 w / w .

  Alternatively, the weight ratio of surfactant to taxane is 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, More preferably, between about 1:20 w / w and about 20: 1 w / w, even more preferably between about 1:10 w / w and about 10: 1 w / w, even more preferably about 1: 5 w / w. w and between about 5: 1 w / w, even more preferably 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. Most preferably, it is about 1: 1 w / w.

  The unit dose of taxane contained in the composition depends on the intended frequency of administration of the composition. Appropriate dosages and frequency of administration are described above for the taxane and ritonavir compositions.

  In one embodiment, the composition includes an enteric coating. Suitable enteric coatings are described above. The enteric coating protects the release of the taxane in the stomach, thereby preventing acid-mediated degradation of the taxane. Furthermore, it enables targeted transport of the taxane into the intestine where the taxane is absorbed, thus ensuring that only a limited amount of time the taxane is in solution (before crystallization occurs) can be absorbed. Is spent on.

  In one embodiment, the composition can further comprise one or more other pharmaceutically active ingredients. Preferably, the one or more other pharmaceutically active ingredients are CYP3A4 inhibitors. Suitable CYP3A4 inhibitors are described above. Preferably, the CYP3A4 inhibitor is ritonavir.

  The pharmaceutical composition may further comprise other pharmaceutically acceptable adjuvants and vehicles well known to those skilled in the art. Pharmaceutically acceptable adjuvants and vehicles that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, serum proteins such as human serum albumin, buffer substances, For example, phosphate, glycerin, sorbic acid, potassium sorbate, partial glyceride mixture of saturated plant fatty acids, water, salt or electrolyte, eg protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt , Colloidal silica, magnesium trisilicate and wool fat.

  The pharmaceutical composition can be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders or coated granules. Tablets can be formulated for immediate release, slow release, repeated release or sustained release. Alternatively, it may be effervescent, bilayer and / or coated tablets. Capsules can be formulated for immediate release, slow release, repeated release or sustained release. A lubricant, such as magnesium stearate, is also commonly added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. For tablets and capsules, other pharmaceutical additives that can be added are binders, fillers, fillers / binders, adsorbents, wetting agents, disintegrants, lubricants, glidants and the like. Tablets and capsules can be coated to modify the appearance or properties of the tablets and capsules, for example to modify the taste or to color coat the tablets or capsules.

  Other pharmaceutically acceptable additives that can be added to the composition are well known to those skilled in the art, some of which have been described above with respect to the composition in accordance with the first aspect of the invention.

  The present invention also provides the composition for use in therapy.

  Furthermore, the present invention provides the composition for use in the treatment of neoplastic diseases. Suitable neoplastic diseases are described above.

  The invention also provides a method of treating neoplastic disease comprising administering an effective amount of the composition to a subject in need of such treatment.

  Preferably, this method is used to treat a human subject.

  One skilled in the art will appreciate that the compositions of the invention comprising a substantially amorphous taxane and a carrier can be used in the manner described above with respect to the use of a taxane and a CYP3A4 inhibitor or ritonavir, if appropriate.

  In another aspect, the present invention provides a pharmaceutical composition for oral administration comprising a substantially amorphous taxane and a carrier, wherein the substantially amorphous taxane is prepared by lyophilization.

  The advantage provided by this composition is that it provides increased taxane solubility and also increased dissolution rate. This is thought to be because the lyophilization method produces more amorphous taxanes than other methods that produce amorphous taxanes. It is believed that the more amorphous nature of the taxane results in increased solubility and dissolution rate.

  Other optional features of this composition are similar to compositions comprising an amorphous taxane, a carrier and a surfactant. For example, a composition comprising a substantially amorphous taxane and a carrier, wherein the substantially amorphous taxane is prepared by lyophilization, preferably further comprises a surfactant. Preferred embodiments such as the taxane, the carrier, the crystallinity of the taxane, the ratio of the taxane to the carrier, the state of the taxane and the carrier and the like are as described above.

  The present invention will now be described, by way of example only, with reference to the accompanying drawings.

i. v. FIG. 5 shows docetaxel plasma concentration versus time comparing ritonavir oral administration (RTV) (simultaneously and ritonavir administered 60 minutes before docetaxel) versus administration (no ritonavir). Docetaxel oral dose: 100 mg. To form a 10 mg / ml docetaxel solution that the patient drank with 100 ml of tap water (10 ml of a 10 mg / ml solution). v. A docetaxel formulation (Taxotere®; 2 ml = docetaxel 80 mg, excipient polysorbate 80) was diluted with ethanol 95%: water (13:87). Ritonavir dose: 100 mg ritonavir (Norvir®) per capsule. FIG. 5 shows ritonavir plasma concentration versus time compared to oral ritonavir administered orally 60 minutes prior to oral docetaxel (dose 100 mg: Norvir®, capsule). T = 0 is when docetaxel is administered. Thus, the first part of the curve corresponding to ritonavir administered before docetaxel is not visible. Oral docetaxel dose: 100 mg. To form a 10 mg / ml docetaxel solution that the patient drank with 100 ml of tap water (10 ml of a 10 mg / ml solution). v. A docetaxel formulation (Taxotere®; 2 ml = docetaxel 80 mg, excipient polysorbate 80) was diluted with ethanol 95%: water (13:87). Ritonavir dose: 100 mg ritonavir (Norvir®) per capsule. FIG. 5 shows a pharmacokinetic model of oral docetaxel in combination with ritonavir (RTV). The various compartments in the pharmacokinetic model are as follows. C1-Gastrointestinal tract (oral portion of oral docetaxel) C2-central portion (docetaxel) C3-first peripheral portion (docetaxel) C4-second peripheral portion (docetaxel) C5-gastrointestinal tract (portion of ritonavir) C6-central portion (Ritonavir) C7-active CYP3A4 enzyme C8-inactive CYP3A4 enzyme For several subjects, the relative amount of active CYP3A4 enzyme versus time for oral docetaxel in combination with ritonavir, with each line representing one subject. It is the figure which showed the result of the dissolution test of the paclitaxel solid dispersion with respect to a paclitaxel physical mixture (conditions: 900 mL WfI, 37 degreeC, 75 rpm). It is the figure which showed the result of the dissolution test of the paclitaxel (PCT) solid dispersion capsule with and without sodium dodecyl sulfate (conditions: 900 mL WfI, 37 ° C., 75 rpm). It is the figure which showed the result of the dissolution test of the paclitaxel solid dispersion in which sodium dodecyl sulfate was incorporated in the solid dispersion, or was added to the capsule (Condition: 500 mL WfI, 37 ° C., 75 rpm (SDS was added to the capsule) In the case 100 rpm)). It is the figure which showed the result of the dissolution test of the paclitaxel solid dispersion which has various support | carriers (conditions: 500 mL WfI, 37 degreeC, 100 rpm). It is the figure which showed the result of the solubility test of the paclitaxel / PVP-K17 solid dispersion of various chemical | medical agent-carrier ratios (conditions: 25 mL WfI, 37 degreeC, 7200 rpm). FIG. 5 shows the results of dissolution testing of paclitaxel solid dispersions dissolved in various media (conditions: 500 mL FaSSIF (light gray), 37 ° C., 75 rpm or 500 mL SGF _sp and 629 mL SIF _sp , 37 ° C., 75 rpm (concentrated). gray)). It is the figure which showed the docetaxel solubility of five types of different formulations (refer Table 15). A: anhydrous docetaxel, B: amorphous docetaxel, C: anhydrous docetaxel, physical mixture of PVP-K30 and SDS, D: physical mixture of amorphous docetaxel, PVP-K30 and SDS, E: amorphous docetaxel , PVP-K30 and SDS (dissolution conditions: docetaxel ± 6 mg, 25 mL WFI, 37 ° C., 720 rpm). It is the figure which showed the docetaxel solubility of the solid dispersion which has a different support | carrier (refer Table 15). E: solid dispersion of amorphous docetaxel, PVP-K30 and SDS, F: solid dispersion of amorphous docetaxel, HPβ-CD and SDS (dissolution conditions: docetaxel ± 6 mg, 25 mL WfI, 37 ° C., 720 rpm). FIG. 16 shows docetaxel solubility of solid dispersions with various chain lengths of PVP (see Table 15). E: Solid dispersion of amorphous docetaxel, PVP-K30 and SDS, G: Solid dispersion of amorphous docetaxel, PVP-K12 and SDS, H: Solid dispersion of amorphous docetaxel, PVP-K17 and SDS , I: solid dispersion of amorphous docetaxel, PVP-K25 and SDS, J: solid dispersion of amorphous docetaxel, PVP-K90 and SDS (dissolution conditions: docetaxel ± 6 mg, 25 mL WfI, 37 ° C., 720 rpm) . FIG. 16 shows docetaxel solubility of solid dispersions with various drug loads (see Table 15). E: 1/11 docetaxel, K: 5/7 docetaxel, L: 1/3 docetaxel, M: 1/6 docetaxel, N: 1/21 docetaxel (dissolution conditions: docetaxel ± 6 mg, 25 mL WfI, 37 ° C., 720 rpm) . FIG. 6 shows the solubility results for the relative amount of docetaxel dissolved in solid dispersions of docetaxel, PVP-K30 and SDS compared to literature data [Chen et al., 95] for solid dispersions of docetaxel and PVP-K30. is there. FIG. 6 shows the solubility results by absolute amount of dissolved docetaxel of solid dispersions of docetaxel, PVP-K30 and SDS compared to literature data [Chen et al., 95] for solid dispersions of docetaxel and PVP-K30. is there. FIG. 3 shows the results of dissolution testing of docetaxel capsules (Dcetaxel (DXT) 15 mg per capsule containing PVP-K30 + SDS) compared to literature data [Chen et al. [95]. It is the figure which showed the solubility result by the absolute amount of the docetaxel which the solid dispersion of docetaxel, PVP-K30, and SDS melt | dissolved. The dissolution test was performed with simulated intestinal fluid (SIFsp) without pancreatin. It is the figure which showed the solubility result by the relative quantity of the docetaxel which the solid dispersion of docetaxel, PVP-K30, and SDS melt | dissolved. The dissolution test was performed with simulated intestinal fluid (SIFsp) without pancreatin. It is the figure which showed the pharmacokinetic curve of the patient who received docetaxel and ritonavir simultaneously in the 1st course. In the second course, patients received docetaxel and ritonavir simultaneously at t = 0, and then an additional dose of ritonavir at t = 4h. FIG. 5 shows the pharmacokinetic curves of four patients who were administered a liquid formulation of docetaxel and / or a solid dispersion containing docetaxel (referred to as MODRA). FIG. 5 shows the pharmacokinetic curve of a patient receiving a liquid oral formulation of docetaxel compared to a patient receiving a solid oral formulation of docetaxel (MODRA). Docetaxel i. v. It is the figure which showed the pharmacokinetic curve after administration and oral administration. i. v. Both docetaxel administration, both oral and oral, was combined with administration of ritonavir. N. B. The calculated bioavailability is corrected for the dose administered.

  A ritonavir dose of 100 mg was orally administered to 22 patients simultaneously with a docetaxel dose of 100 mg. 1 hour i. v. Administered as an infusion (standard method) i. v. Compared to docetaxel administered (100 mg) (Taxotere®) (without ritonavir).

  Oral ritonavir: 1 capsule contains 100 mg of ritonavir (Norvir®). Oral docetaxel dose: 100 mg. To form a 10 mg / ml docetaxel solution that the patient drank with 100 ml of tap water (10 ml of a 10 mg / ml solution). v. A docetaxel formulation (Taxotere®; 2 ml = docetaxel 80 mg, excipient polysorbate 80) was diluted with ethanol 95%: water (13:87).

The obtained pharmacokinetic data is as follows.
AUC 0.29 ± 0.26 (mg.h / L) of oral docetaxel without ritonavir
AUC of oral docetaxel containing ritonavir 2.4 ± 1.5 (mg.h / L)
AUC 1.9 ± 0.4 (mg. H / L) of intravenous docetaxel without ritonavir

  This result demonstrates the dual effect of ritonavir on both docetaxel absorption and elimination. Oral administration in combination with ritonavir increases docetaxel AUC by a factor of 8.2. Surprisingly, the exposure is even more than that achieved after intravenous administration, reflecting the effect of ritonavir addition on docetaxel exclusion inhibition.

CONCLUSION The concept that ritonavir can increase systemic exposure to oral docetaxel to a level similar to or higher than that after intravenous administration of the same dose level of docetaxel has been clearly demonstrated in patients. The combination appears to be safe and exhibit very favorable pharmacokinetic properties.

  Treatment of solid malignancies with a combination of oral docetaxel and ritonavir.

  Patients were randomized into two treatment groups, X and Y. Group X received 100 mg ritonavir in the first week and 100 mg oral docetaxel after 60 minutes, and in the second week, these patients received 100 mg ritonavir and 100 mg oral docetaxel simultaneously. Patients in group Y received ritonavir 100 mg and oral docetaxel 100 mg simultaneously in the first week, and ritonavir 100 mg and oral docetaxel 100 mg 60 minutes later in the second week. Neither group X nor group Y contains ritonavir 15 days after the start of oral administration. v. 100 mg of docetaxel (Taxotere®, standard method, 1 hour infusion) was administered.

  Oral docetaxel dose: 100 mg. To form a 10 mg / ml docetaxel solution that the patient drank with 100 ml of tap water (10 ml of a 10 mg / ml solution). v. A docetaxel formulation (Taxotere®; 2 ml = docetaxel 80 mg, excipient polysorbate 80) was diluted with ethanol 95%: water (13:87). Ritonavir dose: 1 capsule contains 100 mg of ritonavir (Norvir®).

  The pharmacokinetic results are listed below.

CONCLUSION There was no significant difference between the administration of ritonavir 60 minutes before docetaxel and the simultaneous administration of docetaxel and ritonavir. The AUC for oral administration is larger than the AUC for intravenous administration (see FIG. 1). This is explained by the effect of ritonavir on inhibition of docetaxel exclusion.

Observations This clinical trial was conducted with relatively low doses of docetaxel, but resulted in high AUC values (2.4 ± 1.5 mg.h / L, docetaxel 100 mg), and AUC values after intravenous administration of the same dose It was even higher than. As a result, a pharmaceutical medium that exists after intravenous administration but does not reach the systemic circulation after oral administration limits the tissue distribution of docetaxel, so naturally the amount of distribution after the oral route (immediately after administration) is intravenous It will be larger than after the route. The inventors have constructed a pharmacokinetic model to understand these effects (see below). This model also shows that the effect of ritonavir on docetaxel exclusion disappears when ritonavir is no longer present in the bloodstream. Ritonavir inhibits docetaxel elimination to 35% of the level without ritonavir.

  Compared to the doses used in prior art preclinical studies in mice, this clinical study uses ritonavir 100 mg and docetaxel 100 mg, while mice preclinical studies use ritonavir 12.5 mg / kg and docetaxel 10-30 mg. / Kg was used. Docetaxel doses of 10-30 mg / kg are extremely toxic (life-threatening) in humans. The ritonavir dose of 12.5 mg / kg is substantially higher than that normally used to inhibit CYP3A4 in humans.

  In conventional preclinical studies, ritonavir was administered 30 minutes before docetaxel. In clinical trials, drugs were also administered at the same time, but there was no significant difference in docetaxel pharmacokinetic improvement between co-administration and 60 minutes prior to ritonavir. This indicates that both drugs can be given in a single pharmaceutical form (eg, a tablet, capsule or drinking solution containing both docetaxel and ritonavir).

  The docetaxel AUC value (2.4 ± 1.5 mg.h / L) obtained when ritonavir 100 mg is co-administered (at a docetaxel dose of 100 mg) is considered to have therapeutic effects on a weekly schedule, for example, in metastatic breast cancer Can do. This is exactly the same as the previous phase II study in which docetaxel 100 mg was orally administered with CsA at a dose of 15 mg / kg on a weekly schedule, with a response rate of 50% for patients with metastatic breast cancer and docetaxel AUC of about 2.3 mg. . resulting in h / L.

  For completeness, ritonavir pharmacokinetic data is listed below (see FIG. 2).

薬物動態プロファイル
前記の試験から得られたデータの薬物動態（ＰＫ）分析は、薬物動態プロファイルを作製するためのＮＯＮＭＥＮ（非線形混合効果モデリング）プログラム（ＧｌｏｂｏＭａｘ ＬＬＣ、Ｈａｎｏｖｅｒ、ＭＤ、ＵＳＡ）を使用して実施した。これは、様々な区画を使用した薬物の吸収、排除および分布をモデル化したものである。経口投与と静脈内投与の間の薬理学的な違いを以下に提示する。

Pharmacokinetic Profile Pharmacokinetic (PK) analysis of the data obtained from the above study was performed using the NONGEN (Nonlinear Mixed Effects Modeling) program (GloboMax LLC, Hanover, MD, USA) to generate a pharmacokinetic profile. Carried out. This models the absorption, exclusion and distribution of drugs using various compartments. The pharmacological differences between oral and intravenous administration are presented below.

  Oral docetaxel exposure was investigated after a single dose of docetaxel alone and in combination with ritonavir. Ritonavir was administered at the same time as oral docetaxel or 1 hour before.

  After drug administration, blood samples were collected for pharmacokinetic analysis. Blind samples were collected before dosing. The blood sample was centrifuged to separate the crystals and stored immediately at -20 ° C until analysis. The analysis was carried out with an effective HPLC method in a GLP (standard for conducting non-clinical studies on drug safety) accredited laboratories. This is involved in all the pharmacokinetic studies presented here by the inventor.

PK model The PK model is an i. v. Based on docetaxel PK model. This model uses three types of compartments and is described in detail by Bruno et al. [85]. Data obtained from orally administered docetaxel was implemented in this model with an additional storage compartment modeling the gastrointestinal tract. The pharmacokinetic model of ritonavir was best described using the two-compartment model described by Kappelhoff et al. [87]. FIG. 3 illustrates the final pharmacokinetic model. The effect of ritonavir on docetaxel pharmacokinetics is due to two different mechanisms: a) improved absorption of docetaxel in the presence of ritonavir (line connecting ritonavir (RTV) compartment and docetaxel absorption from C1 to C2), b Ritonavir inhibited active CYP3A4 (line connecting C6 and C7), and active CYP3A4 was modeled by being involved in docetaxel elimination (line connecting C7 and docetaxel elimination pathway).

Absorption Absorption of docetaxel was significantly improved when co-administered with ritonavir. The calculated bioavailability of oral docetaxel alone is 14% (based on data from 3 patients who received 100 mg of docetaxel orally). The bioavailability of oral docetaxel in combination with ritonavir was 4 times higher at 56%. This effect can be attributed to the inhibition of ritonavir on the CYP3A4 enzyme present in the GI tract.

Exclusion Docetaxel is metabolized mainly by CYP3A4. Ritonavir inhibits CYP3A4. Thus, co-administration of ritonavir with docetaxel causes suppression of elimination. The removal of docetaxel is associated with the amount of CYP3A4 and therefore changes gradually. FIG. 4 shows the relative estimated enzyme concentration over time. Docetaxel removal correlates 1: 1 with enzyme concentration. Thus, docetaxel removal versus time would be similar to FIG.

Distribution amount The amount of the central section (C2 in FIG. v. There is a significant difference between administration (± 6 L) and oral administration (± 60 L). This is probably due to polysorbate 80, one of the major excipients of docetaxel formulations. Polysorbate 80 forms micelles that can capture docetaxel [86]. Polysorbate 80 is i. v. In the case of administration, it enters the circulation, but in the case of oral administration, it is not absorbed. Thus, polysorbate does not affect the pharmacokinetic properties of docetaxel after oral administration due to the fact that it is not absorbed.

CONCLUSION Oral docetaxel bioavailability increased approximately 4-fold when co-administered with ritonavir. Systemic exposure was increased 8.2-fold for AUC due to the combined effect of ritonavir on CYP3A4 in the GI tract and liver (ie, absorption and elimination, respectively).

  Docetaxel elimination is reduced when combined with ritonavir.

  The amount of distribution (the amount of the central section) is small when the polysorbate 80 is present and large when the polysorbate 80 is not present.

  In the oral docetaxel test described above, a commercially available i. v. A docetaxel formulation (Taxotere®; 2 ml = docetaxel 80 mg, excipient polysorbate 80) was diluted with ethanol 95%: water (13:87). This solution, prepared by the pharmacist, was taken orally by the patient as a drinking solution (10 ml of a 10 mg / ml solution at a dose of 100 mg) with 100 ml of tap water. For research purposes, this is feasible, but not for routine use and home. Preparation of this drinking solution by a pharmacist takes time. This solution has limited stability. Patients often complained about the poor and unpleasant taste of this drinking solution (possibly due to polysorbate and ethanol excipients). Clearly, oral solid dosage forms (eg taken as capsules or tablets) are preferred and highly supported by patients.

  In summary, the present invention improves the bioavailability and systemic exposure of taxanes, improves the clinical effects of taxanes, especially oral taxanes, and possibly reduces possible side effects associated with treatment. This is economically and clinically beneficial.

Paclitaxel Oral Formulation 3.1: Solid Dispersion and Physical Mixture In this experiment, the solubility and dissolution rate of a composition comprising paclitaxel mixed with SDS and a solid dispersion of PVP-K17 was compared with anhydrous paclitaxel, PVP-K17 and SDS. Compared to a physical mixture of

Paclitaxel solid dispersion 5 mg capsule in PVP-K17 Paclitaxel 20% solid dispersion in PVP-K17 dissolves 100 mg paclitaxel in 10 mL t-butanol and 400 mg PVP-K17 in 6.67 mL water. It was prepared by. The paclitaxel / t-butanol solution was added to the PVP-K17 / water solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. t-Butanol and water were then removed by lyophilization (see Table 3 for conditions). 25 mg of paclitaxel 20% / PVP-K17 solid dispersion (= 5 mg of paclitaxel) was mixed with 125 mg of lactose, 30 mg of sodium dodecyl sulfate and 30 mg of croscarmellose sodium. The resulting powder mixture was encapsulated (see Table 4).

Paclitaxel 5 mg capsule in physical mixture with PVP-K17 The physical mixture was prepared by mixing 5 mg anhydrous paclitaxel with 20 mg PVP, 125 mg lactose, 30 mg sodium dodecyl sulfate and 30 mg croscarmellose sodium. The resulting powder mixture was encapsulated.

Dissolution Test Both capsule formulations were tested in a USP2 (paddle) dissolution apparatus in 900 mL water for injection maintained at 37 ° C. at a rotational 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 taken at various time points and analyzed by HPLC-UV (see Table 4).

Results and Conclusions The results are shown in FIG. The amount of dissolved paclitaxel is expressed relative to the indicated amounts (5 and 10 mg). It can clearly be seen that the dissolution of paclitaxel is greatly improved by incorporation into a solid dispersion containing PVP. Using a physical mixture, the maximum amount of dissolved paclitaxel is kept below 20% of the indicated amount. If a solid dispersion is used, the solubility is about 65% (paclitaxel 5 mg) or more than 70% (paclitaxel 10 mg). In the 10 mg paclitaxel experiment, this corresponds to an absolute solubility of about 8 μg / ml, which is achieved after about 15 minutes. Thus, solid dispersions have a significantly increased solubility and also provide a rapid dissolution rate that is important for bioavailability.

  For solid solutions or solid dispersions, the amorphous support allows for thorough mixing of the support and the taxane. The carrier protects against crystallization during storage and dissolution in an aqueous medium.

3.2: Addition of sodium dodecyl sulfate to the capsule formulation In this experiment, the effect of the presence or absence of the surfactant SDS in the capsule on the solubility was measured.

20% paclitaxel solid dispersion in PVP-K17 The solid dispersion was prepared by dissolving 100 mg 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 with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. t-Butanol and water were then removed by lyophilization (see Table 3).

5 mg paclitaxel capsules without sodium dodecyl sulfate Paclitaxel 20% / PVP-K17 solid dispersion 25 mg (= paclitaxel 5 mg) was mixed with lactose 125 mg and encapsulated (see Table 7).

5 mg paclitaxel capsules containing sodium dodecyl sulfate 25 mg paclitaxel / PVP-K17 solid dispersion (= 5 mg paclitaxel) was mixed with 125 mg lactose, 30 mg sodium dodecyl sulfate and 30 mg croscarmellose sodium. The resulting powder mixture was encapsulated (see Table 8).

Dissolution Test Both capsule formulations were tested in a USP2 (paddle) dissolution apparatus in 900 mL water for injection maintained at 37 ° C. at a rotational speed of 75 rpm. Samples were taken at various time points and analyzed by HPLC-UV (see Table 6).

Results and Conclusions The results are shown in Table 6. The amount of dissolved paclitaxel is expressed relative to the indicated amount (in this case 5 mg). The porosity of the lyophilized taxane and carrier solid dispersion is high enough to ensure rapid dissolution when in powder form (results not shown). However, when the powder is compressed into capsules, hydration is dramatically reduced. Therefore, a surfactant is required to wet the solid dispersion when compressed into capsules or tablets.

  It can be clearly seen from FIG. 6 that the dissolution of paclitaxel is greatly improved by adding the surfactant sodium dodecyl sulfate. Previous experiments have shown that adding croscarmellose sodium or more lactose or using larger capsules does not increase the dissolution rate of the capsule formulation. It was also shown that maximum dissolution was achieved in about 10-15 minutes with a surfactant such as SDS.

3.3: Addition of sodium dodecyl sulfate to the solid dispersion formulation In this experiment, the effect of the addition of SDS to the solid dispersion on the solubility was measured.

40% paclitaxel solid dispersion in PVP-K17 The solid dispersion was prepared by dissolving 600 mg 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 with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. t-Butanol and water were then removed by lyophilization (see Table 3).

40% paclitaxel solid dispersion in 10% PVP-K17 and sodium dodecyl sulfate The solid dispersion was obtained by dissolving 250 mg paclitaxel in 25 mL t-butanol, 375 mg PVP-K17 and 62.5 mg sodium dodecyl sulfate (SDS) Prepared by dissolving in 16.67 mL. The paclitaxel / t-butanol solution was added to the PVP-K17 / sodium dodecyl sulfate / water solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. t-Butanol and water were then removed by lyophilization (see Table 3).

Paclitaxel / PVP-K17 solid dispersion 25 mg paclitaxel capsules Paclitaxel 40% / PVP-K17 solid dispersion 62.5 mg (= paclitaxel 25 mg) was mixed with 160 mg lactose, 30 mg sodium dodecyl sulfate and 10 mg croscarmellose sodium. The resulting powder mixture was encapsulated (see Table 9).

Paclitaxel / PVP-K17 / sodium dodecyl sulfate 25 mg paclitaxel capsule Paclitaxel 40% / PVP-K17 / sodium dodecyl sulfate 10% solid dispersion 68.75 mg (= paclitaxel 25 mg) with 160 mg lactose and 10 mg croscarmellose sodium Mixed. The resulting powder mixture was encapsulated (see Table 10).

Dissolution Test Both capsule formulations were tested in 500 mL of water for injection maintained at 37 ° C. in a USP2 (paddle) dissolution apparatus. The rotation speed was set at 75 rpm for the paclitaxel / PVP-K17 / sodium dodecyl sulfate solid dispersion capsule and 100 rpm for the paclitaxel / PVP-K17 solid dispersion capsule. Samples were taken at various time points and analyzed by HPLC-UV (see Table 6).

Results and Conclusions The results are shown in Table 7. The amount of dissolved paclitaxel is expressed relative to the indicated amount (in this case 25 mg). The dissolution of paclitaxel from capsules containing sodium dodecyl sulfate incorporated into the solid dispersion is comparable to the dissolution of paclitaxel from capsules of sodium dodecyl sulfate added to the capsule. Furthermore, when incorporated into a solid dispersion, only 6.25 mg of sodium dodecyl sulfate was used, while 30 mg of sodium dodecyl sulfate was used when added to the capsule formulation. This indicates that less surfactant is required when incorporated into solid dispersions than capsules to achieve similar results. Another surprising result of this experiment is that both compositions have an absolute solubility of paclitaxel of about 26 μg / ml, and this level is reached in 20-30 minutes. This result has a higher solubility and faster dissolution rate than previously achieved.

3.4: Effect of carrier After the first experiment showed no obvious difference between drug loadings, the solid dispersion used in the experiment of Example 3.4 was produced. These formulations worked equally well with the 20% drug loading formulation of the previous experiment, and offered the possibility of delivering more taxanes in one tablet or capsule, so 40% drug loading was chosen. .

40% paclitaxel solid dispersion in PVP-K12 The solid dispersion was prepared by dissolving 250 mg 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 aqueous PVP-K12 solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. t-Butanol and water were then removed by lyophilization (see Table 3).

40% paclitaxel solid dispersion in PVP-K17 The solid dispersion was prepared by dissolving 600 mg 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 aqueous solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. t-Butanol and water were then removed by lyophilization (see Table 3).

40% paclitaxel solid dispersion in PVP-K30 The solid dispersion was prepared by dissolving 250 mg 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 aqueous solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. t-Butanol and water were then removed by lyophilization (see Table 3).

40% Paclitaxel Solid Dispersion in HP-Cyclodextrin A solid dispersion was prepared by dissolving 250 mg 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 aqueous solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. t-Butanol and water were then removed by lyophilization (see Table 3).

25 mg paclitaxel solid dispersion capsule 62.5 mg paclitaxel / carrier solid dispersion (= 25 mg paclitaxel) was mixed with 160 mg lactose, 30 mg sodium dodecyl sulfate and 10 mg croscarmellose sodium. The resulting powder mixture was encapsulated (see Table 11).

Dissolution Test All capsule formulations were tested in 500 mL water for injection maintained at 37 ° C. in a USP2 (paddle) dissolution apparatus at a rotation speed of 100 rpm. Samples were taken at various time points and analyzed by HPLC-UV (see Table 6).

Results and Conclusions The average results of experiments 2 to 3 are shown in FIG. The amount of dissolved paclitaxel is expressed relative to the indicated amount (in this case 25 mg). It can be clearly seen that the dissolution of paclitaxel from the PVP-K30 solid dispersion is as fast as the dissolution of paclitaxel from the PVP-K17 solid dispersion. However, the amount of dissolved paclitaxel remains high during the 4 hour experiment in the case of the PVP-K30 solid dispersion.

  The chain length of the polymer support determines the crystallization time in an aqueous environment.

3.5: Effect of drug / carrier ratio The solid dispersion used in the experiment of Example 3.5 was produced after the first experiment showed no obvious difference between the carriers. These initial experiments were performed prior to the more detailed experiment of Example 3.4. As a result, PVP-K17 was arbitrarily selected as a carrier for further experimentation.

10% paclitaxel solid dispersion in PVP-K17 A solid dispersion was prepared by dissolving 100 mg 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 aqueous solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. t-Butanol and water were then removed by lyophilization (see Table 3).

25% Paclitaxel Solid Dispersion in PVP-K17 The solid dispersion was prepared by dissolving 250 mg 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 aqueous solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. t-Butanol and water were then removed by lyophilization (see Table 3).

40% paclitaxel solid dispersion in PVP-K17 A solid dispersion was prepared by dissolving 600 mg 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 aqueous solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. t-Butanol and water were then removed by lyophilization (see Table 3).

75% paclitaxel solid dispersion in PVP-K17 The solid dispersion was prepared by dissolving 250 mg 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 aqueous solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. t-Butanol and water were then removed by lyophilization (see Table 3).

Paclitaxel 100% solid dispersion A solid dispersion was prepared by dissolving 250 mg of paclitaxel in 25 mL of t-butanol. The paclitaxel / t-butanol solution was added to 16.67 mL of water with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. t-Butanol and water were then removed by lyophilization (see Table 3).

Dissolution test An amount of solid dispersion powder equal to about 4 mg of paclitaxel was placed in a 50 mL beaker. A magnetic stir bar and 25 mL of water were added to the beaker. The solution was stirred at 7200 rpm. Samples were taken at various time points and analyzed by HPLC-UV (see Table 6).

Results and Conclusions The average results of experiments 2 to 3 are shown in FIG. The amount of dissolved paclitaxel (PCT) is expressed against the indicated amount (in this case about 4 mg). The effect of the drug / carrier ratio is readily apparent from FIG. The peak concentration value of paclitaxel is inversely proportional to the drug / carrier ratio. The highest peak concentration is reached with the lowest drug / carrier ratio (10%) and the lowest peak concentration is reached with the highest drug / carrier ratio (100%). Further, the AUC values for solid dispersions with 10% drug / carrier ratio are highest, followed by the AUC values for solid dispersions with 25, 40, 75 and 100% drug / carrier ratio.

  The amount of carrier relative to the amount of drug determines the crystallization time in an aqueous environment.

3.6: Effect of enteric coating 40% paclitaxel solid dispersion in 10% PVP-K17 and sodium dodecyl sulfate The solid dispersion was obtained by dissolving 250 mg paclitaxel in 25 mL t-butanol, 375 mg PVP-K17 and dodecyl sulfate Sodium (SDS) 62.5 mg was prepared by dissolving in 16.67 mL of water. The paclitaxel / t-butanol solution was added to the PVP-K17 / sodium dodecyl sulfate / water solution with constant stirring. The final mixture was transferred to an 8 mL vial with a maximum fill level of 2 mL. t-Butanol and water were then removed by lyophilization (see Table 3).

Paclitaxel / PVP-K17 / sodium dodecyl sulfate 25 mg paclitaxel capsule Paclitaxel 20% / PVP-K17 / sodium dodecyl sulfate 10% solid dispersion 68.75 mg (= paclitaxel 25 mg) with 160 mg lactose and 10 mg croscarmellose sodium Mixed. The resulting powder mixture was encapsulated (see Table 12).

Dissolution test The capsules were subjected to two different dissolution tests. The first test is a two-step dissolution test, a simulated gastric fluid without pepsin (SGF _sp ; Table 13), a 2-hour dissolution test in 500 mL, followed by a simulated intestinal fluid without pepsin (SIF _sp ; Table 13). Consists of a 2 hour dissolution test at 629 mL. The second test was performed with 500 mL of fasted simulated intestinal fluid (FaSSIF; Table 14) medium for 4 hours.

  Both dissolution tests were performed with a USP2 (paddle) dissolution apparatus with 500 mL of medium maintained at 37 ° C. and a paddle rotation speed of 75 rpm. SGFsp medium was exchanged for SIFsp medium by adding 129 mL of conversion medium. Samples were taken at various time points and analyzed by HPLC-UV (see Table 6).

Results and Conclusions The results are shown in FIG. The amount of dissolved paclitaxel is expressed relative to the indicated amount (in this case 25 mg). The dissolution of paclitaxel in fasted simulated intestinal fluid is about 20% more than simulated gastric fluid (SGFsp). After 2 hours in SGFsp, the amount of paclitaxel in solution increases slightly when the medium is replaced with simulated intestinal fluid (SIFsp).

  Enteric coatings protect against the release of taxanes in the stomach, thereby preventing dissolution of the active ingredient. Furthermore, targeted transport to the intestine where the taxane is absorbed is possible, thus ensuring that the limited time that the taxane is in solution (before crystallization occurs) is only spent at sites where absorption is possible. It is.

Docetaxel Oral Formulation Materials and Methods The formulations used in the following experiments were prepared according to the methods outlined below and the compositions described in Table 15.

Pure anhydrous docetaxel Anhydrous docetaxel was obtained and used from ScinoPharm, Taiwan.

Pure amorphous docetaxel Docetaxel was amorphized by dissolving 300 mg of anhydrous docetaxel in 30 mL of t-butanol. The docetaxel / t-butanol solution was added to 20 mL of water for injection (WfI) with constant stirring. The final mixture was transferred to a stainless steel lyophilization box (gastronome size 1/9), after which t-butanol and water were removed by lyophilization (see Table 16).

Physical mixture The physical mixture was prepared by mixing docetaxel 150 mg and the corresponding amount of carrier and surfactant (see Table 15) in a mortar and pestle.

Solid dispersion The solid dispersion was obtained by dissolving 300 mg of anhydrous docetaxel in 30 mL of t-butanol and dissolving the corresponding amount of carrier and surfactant (see Table 15) in 20 mL of water for injection. The docetaxel / t-butanol solution was added to the carrier / surfactant / WfI solution with constant stirring. The final mixture was transferred to a stainless steel lyophilization box (gastronome size 1/9), after which t-butanol and water were removed by lyophilization (see Table 16).

Dissolution test An amount of powder equal to about 6 mg of docetaxel was placed in a 50 mL beaker. A magnetic stir bar and 25 mL of water were added to the beaker. The solution was stirred at 720 rpm and maintained at about 37 ° C. Samples were taken at various time points, filtered through a 0.45 μm filter and then diluted with a 1: 4 v / v mixture of methanol and acetonitrile. The filtered and diluted sample was then analyzed by HPLC-UV (see Table 17).

4.1: Type of formulation In the first experiment, the effect of the type of formulation on the solubility of docetaxel was examined. Data from dissolution tests performed on formulations A to E were compared. The results are shown in FIG. Formulation E was tested in quadruplicate and formulations A through D were tested in duplicate.

Results Formulation A (pure anhydrous docetaxel) reached a maximum concentration of about 12 μg / mL (4.7% of total docetaxel present) after stirring for 5 minutes, and after stirring for 15 minutes, an equilibrium concentration of about 6 μg / mL ( 2%).

  Formulation B (pure amorphous docetaxel) reaches a maximum of 32 μg / mL (13%) after 0.5 minutes, and the solubility is comparable to Formulation A from 10 to 60 minutes.

  Formulation C (a physical mixture of anhydrous docetaxel, PVP-K30 and SDS) reaches a concentration of about 85 μg / mL (37%) after 5 minutes. Between 15 and 25 minutes, the docetaxel concentration suddenly decreases from 85 μg / mL (37%) to 30 μg / mL (12%) and then further decreases to 20 μg / mL (9%) at 60 minutes .

  Formulation D (a physical mixture of amorphous docetaxel, PVP-K30 and SDS) reaches a maximum docetaxel concentration of about 172 μg / mL (70%) after 7.5 minutes. Between 7.5 and 20 minutes, the amount of docetaxel in the solution decreases to 24 μg / mL (10%). At 60 minutes, an equilibrium concentration of 19 μg / mL (7%) is reached.

  Formulation E (a solid dispersion of amorphous docetaxel, PVP-K30 and SDS) reaches a maximum maximum concentration of about 213 μg / mL (90%) after 5 minutes. Between 10 and 25 minutes, the amount of docetaxel in the solution decreases rapidly, yielding an equilibrium concentration of 20 μg / mL (8%) after 45 minutes.

Conclusion All formulations initially exhibit high solubility and decrease to equilibrium solubility after 45 to 60 minutes of stirring. The decrease in solubility is caused by crystallization of docetaxel as a result of the supersaturated solution. The degree of supersaturation depends 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 a long time and therefore the solubility of docetaxel does not decrease very rapidly. Furthermore, the results show that the use of amorphous docetaxel significantly increases the solubility of docetaxel compared to anhydrous docetaxel. In addition, amorphous docetaxel exhibits a relatively fast dissolution rate and peaks in about 5 to 7.5 minutes.

  This experiment shows that the amount of docetaxel in solution is significantly increased by physically mixing anhydrous docetaxel with PVP-K30 and SDS, and by physically mixing amorphous docetaxel with PVP-K30 and SDS. Further increase is shown. However, the greatest increase in solubility is achieved by incorporating docetaxel into the solid dispersion of PVP-K30 and SDS.

4.2: Type of carrier In the second experiment, the effect of the type of carrier on the solubility of docetaxel was examined. Data from dissolution tests performed on formulations E and F were compared. The results are shown in FIG. Formulation E was tested in quadruplicate and Formulation F was tested in duplicate.

Results The maximum concentration of Formulation E (a solid dispersion of amorphous docetaxel, PVP-K30 and SDS) is 213 μg / mL (90% of all docetaxel present), reaching after 5 minutes. Between 10 and 25 minutes, the amount of docetaxel in the solution decreases rapidly, yielding an equilibrium concentration of 20 μg / mL (8%) after 45 minutes.

  Formulation F (a solid dispersion of amorphous docetaxel, HPβ-CD and SDS) reaches a maximum docetaxel concentration of about 200 μg / mL (81%) after about 2 minutes. Between 5 and 10 minutes, the amount of docetaxel in the solution decreases to a value of 16 μg / mL (6%) and reaches an equilibrium concentration of 11 μg / mL (4%) after 45 minutes.

Conclusion This experiment shows that both PVP-K30 and HPβ-CD increase the solubility of docetaxel. When PVP-K30 is used as a carrier compared to HPβ-CD, the maximum docetaxel concentration is slightly higher and the supersaturated state is maintained longer, so the solubility of docetaxel does not decrease rapidly with time. Furthermore, the equilibrium concentration reached after docetaxel precipitation is higher for PVP-K30 compared to HPβ-CD.

4.3: Chain length In the third experiment, the effect of the type of PVP chain length on the solubility of docetaxel was examined. Data from dissolution tests performed on formulations E and G to J were compared. The results are shown in FIG. 13 below. Formulation E was tested in quadruplicate and formulations G through J were tested in duplicate.

Results Formulation G (PVP-K12) reaches a maximum docetaxel concentration of 206 μg / mL (77% of total docetaxel present) after 5 minutes. Between 5 and 30 minutes, the amount of docetaxel in the solution decreases to a value of 20 μg / mL (7%) and after 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 this concentration is maintained up to 10 minutes with stirring, after which the amount of docetaxel in the solution is 44 μg / ml in 15 minutes. Decrease rapidly to mL (18%) to 22 μg / mL (9%) in 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%) 5 minutes after stirring. Between 10 and 30 minutes, the amount of docetaxel in the solution decreases to a value of 22 μg / mL (9%) and after 60 minutes the docetaxel concentration is 19 μg / mL (8%).

  The maximum docetaxel concentration of Formulation E (PVP-K30) is 213 μg / mL (90%), which is reached after 5 minutes. Between 10 and 25 minutes, the amount of docetaxel in the solution decreases rapidly, yielding 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%) 10 minutes after stirring. After 15 minutes, the amount of docetaxel in the solution is still 151 μg / mL (61%). After 60 minutes, the docetaxel concentration was reduced to 19 μg / mL (7%).

Conclusion This experiment shows that the chain length of PVP affects both the degree of supersaturation and the period during which supersaturation is maintained. The longer the PVP chain length used, the higher the maximum docetaxel concentration and the longer the supersaturation period, thus leading to higher solubility than the longer period.

4.4: Drug loading In a fourth experiment, the effect of drug loading on the solubility of docetaxel was examined. Data from dissolution tests performed on formulations E and K to N were compared. The results are shown in FIG. Formulation E was tested in quadruplicate and formulations K through N were tested in duplicate.

  Formulation N (docetaxel is 1/21 of the total composition weight, docetaxel vs. PVP is 5:95 w / w) 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 the solution is still 120 μg / mL (48%), and between 15 and 30 minutes the docetaxel concentration is reduced to 24 μg / mL (12%). After 60 minutes, the docetaxel concentration is 20 μg / mL (8%).

  The docetaxel concentration of Formulation E (docetaxel is 1/11 of the total composition weight, docetaxel to PVP is 10:90 w / w) is 213 μg / mL (90%) and is reached after 5 minutes. Between 10 and 30 minutes, the amount of docetaxel in the solution decreases rapidly, reaching an equilibrium concentration of 20 μg / mL (8%) after 45 minutes.

  The docetaxel concentration of Formulation M (docetaxel is 1/6 of the total composition weight, docetaxel to PVP is 20:80 w / w) is 196 μg / mL (80%) 10 minutes after stirring. Between 10 and 30 minutes, the amount of docetaxel in the solution decreases to 25 μg / mL (10%), and after 60 minutes the docetaxel concentration is 18 μg / mL (7%).

  Formulation L (docetaxel is 1/3 of the total composition weight, docetaxel versus PVP is 40:60 w / w) reaches a docetaxel concentration of 176 μg / mL (71%). Between 10 and 15 minutes, the amount of docetaxel in the solution decreases rapidly to 46 μg / mL (18%), and after 60 minutes the amount of docetaxel in the solution is 18 μg / mL (7%).

  Formulation K (docetaxel is 5/7 of the total composition weight, docetaxel to PVP is 75:25 w / w) reaches a maximum docetaxel value of 172 μg / mL (71%) after 5 minutes of stirring. Between 5 and 10 minutes, the docetaxel concentration suddenly decreases to 42 μg / mL (17%), and after 60 minutes the docetaxel concentration reaches 18 μg / mL (7%).

Conclusion This experiment shows that the amount of PVP-K30 relative to the amount of docetaxel used in the solid dispersion affects both the degree of supersaturation and the period during which supersaturation is maintained. The higher the drug load use, the lower the maximum docetaxel concentration, the shorter the supersaturation period, and hence the gradually lower solubility.

4.5: Comparison of Solubility with Prior Art Compositions In this experiment, a composition containing a solid dispersion of 15 mg docetaxel, 135 mg PVP-K30 and 15 mg SDS was converted to 5 mg docetaxel and PVP disclosed in Chen et al. [95]. -Compared to literature data for compositions containing a solid dispersion of K30. Solubility results were obtained using the dissolution test described in Chen et al. [95] and are shown in FIGS. Dissolution tests were also performed in simulated intestinal fluid and compared to Chen literature data. The results are shown in FIG.

Results From FIG. 15, it can be seen that the Chen et al. Composition can dissolve up to about 80% of 5 mg of docetaxel in the composition in 900 ml of water. It takes more than 5 hours to reach this maximum. The docetaxel, PVP-K30 and SDS composition dissolved 100% of 15 mg docetaxel in about 60 minutes.

  FIG. 16 shows the absolute concentration of docetaxel. The Chen composition exhibited a maximum docetaxel concentration of about 4.2 μg / ml after about 5 hours. The composition of docetaxel, PVP-K30 and SDS showed a maximum concentration of docetaxel of about 16.7 μg / ml after about 60 minutes.

  In FIG. 17, docetaxel capsules reach a solubility of 28 μg / ml (solubility> 90%). The solid dispersion described by Chen et al. (Docetaxel + PVPK30) reaches a solubility of 4.2 μg / ml (less than 80% of the docetaxel 5 mg solid dispersion tested at 900 ml dissolution). The capsule formulation thus reaches 6.6 times higher solubility at a faster dissolution rate (maximum after 30 minutes vs. 90-120 minutes with Chen).

Conclusion From these results, it can be seen that the composition of docetaxel, PVP-K30 and SDS has a higher dissolution rate and higher solubility compared to the composition of Chen. For bioavailability, it is important to observe how fast the drug dissolves and what solubility is reached from 0.5 h to 1.5 h.

  From the Chen results, those skilled in the art will think that increasing the amount of docetaxel in the composition does not increase the absolute solubility of docetaxel. Since Chen's composition only dissolves 80% (ie, 4 mg) of 5 mg of docetaxel in 900 ml of water, it is expected that increasing docetaxel will not exceed 4 mg even if the amount of docetaxel is increased to 15 mg. Thus, the 15 mg docetaxel composition by Chen is expected to dissolve up to about 27% docetaxel compared to 100% of the docetaxel, PVP-K30 and SDS composition. Thus, the results obtained with the docetaxel, PVP-K30 and SDS composition are surprisingly superior compared to Chen.

4.6: Dissolution test in simulated intestinal fluid without pancreatin (SIFsp) In this experiment, dissolution of capsules containing a solid dispersion of docetaxel, PVP-K30 and SDS was simulated in intestinal fluid without pancreatin (SIFsp). Tested. This capsule contained 15 mg of docetaxel according to formulation E (see Table 15). SIFsp was prepared according to USP28. Capsules containing 15 mg of docetaxel were dissolved in 500 mL of USP SIFsp with stirring at 37 ° C. and 75 rpm. The results are shown in FIGS. 18 and 19.

  Figures 18 and 19 show that almost 100% of the docetaxel was dissolved. This is equivalent to an absolute concentration of docetaxel of about 29 μg / mL and is achieved in about 30 minutes. Thus, this composition provides a relatively high solubility in a relatively short period of time.

4.7: Stability Solid dispersions of docetaxel, PVP-K30 and SDS according to formulation E (see Table 15) used in capsules for clinical trials (see examples below) at 4-8 ° C When stored, it was found to be chemically (no degradation) and physically (no change in solubility properties) stable for at least 80 days.

Formulation Clinical Trial Data Materials and Methods Ten patients participated in an ongoing Phase 1 clinical trial.

These patients were numbered as follows:
301, 302, 303, 304, 305, 306, 307, 308, 309 and 310.

  These patients were given a therapeutic agent consisting of a liquid formulation of docetaxel or a solid composition (hereinafter referred to as MODRA) comprising a solid dispersion of docetaxel, PVP-K30 and SDS.

Liquid formulation Docetaxel dose: 30 mg for all patients (except patients 306 who received 20 mg of docetaxel). A 30 mg dose was prepared as follows. 3.0 ml Taxotere® premix for intravenous administration (polysorbate 80 (25% v / v), ethanol (10% (w / w) and 10 mg docetaxel / ml water) mixed with water) The final volume was 25 mL, and the patient was orally ingested with 100 mL of tap water.

MODRA
Docetaxel dose: 30 mg. Two capsules of 15 mg docetaxel per capsule were ingested. For further testing in clinical trials, formulation E from previous examples (docetaxel 1/11, PVP-K30 9/11 and SDS 1/11) was selected. A new batch of Formulation E was made by dissolving 1200 mg anhydrous docetaxel in 120 mL t-butanol and 10800 mg PVP-K30 and 1200 mg SDS (see Table 15) in 80 mL water for injection. The docetaxel / t-butanol solution was added to the PVP-K30 / SDS / WfI solution with constant stirring. The final mixture was transferred to a stainless steel lyophilization box (gastronome size 1/3) and t-butanol and water were immediately removed by lyophilization (see Table 16).

  All 60 size 0 gelatin capsules were filled with an amount of solid dispersion corresponding to 15 mg docetaxel, and an HPLC assay was used to determine the exact amount of docetaxel per mg solid dispersion. The assay confirmed that the capsules contained 15 mg docetaxel.

  The patient was orally dosed with 100 mL of tap water on an empty stomach.

Patient Treatment Patients 301, 302, 303, 304 and 305 received only liquid formulations.

  Patient 306 received docetaxel 20 mg + ritonavir as a liquid formulation in the first course, and received the same therapeutic agent in the second course, but received additional ritonavir 4 hours after taking docetaxel.

  Patients 307, 308, 309 and 310 were administered liquid formulations and / or MODRA. The course was administered at weekly intervals.

  Oral and i. v. For both docetaxel, all patients were treated with oral dexamethasone. A dexamethasone dose of 4 mg was administered 1 hour before the test drug and thereafter every 12 hours (twice). One hour prior to treatment with docetaxel, the patient also received 1 mg of granisetron (Kytril®) to reduce nausea and nausea.

  After drug administration, blood samples were collected for pharmacokinetic analysis. Blind samples were collected before dosing. Blood samples were centrifuged and plasma was separated and stored immediately at -20 ° C until analysis. The analysis was performed with an effective HPLC method in a GLP (Standard for Conducting Nonclinical Studies on Drug Safety) accredited laboratories [101].

  result

Patients 301, 302, 303, 304, 305, 307, 309 and 310 were administered liquid formulations. The mean and AUC mean 95% confidence interval (extrapolated to infinity) is 1156 (± 348) ng ^* / mL. The interindividual variation is 85%.

  Patient 306 received 20 mg of docetaxel (as a liquid formulation) simultaneously with 100 mg of ritonavir in the first course, and one week later, in the second course, the same combination, but was further administered 100 mg of ritonavir 4 hours after ingestion of docetaxel. That is, ritonavir was taken twice, the first time t = 0, the second time t = 4 h. The pharmacokinetic curve is shown in FIG.

  Patients 307, 308, 309 and 310 were administered liquid formulations and / or MODRA. The pharmacokinetic curve is shown in FIG.

  FIG. 22 shows the pharmacokinetic curves of patients who received liquid formulations (307, 309 and 310) and the overall course (n = 6) of 4 patients (307, 308, 309 and 310) who received MODRA. Show.

The results of the pharmacokinetics of the liquid formulation versus MODRA combined with 100 mg of ritonavir are summarized below.
Liquid preparation (docetaxel 30mg)
AUC _inf (average 95% confidence interval): 1156 (808-1504) ng ^* h / ml
Inter-individual variation: 85% (n = 8)

MODRA (Docetaxel 30mg)
AUC _inf (average 95% confidence interval): 756 (568-968) ng ^* h / ml
Inter-individual variation: 29% (n = 4)
Intra-individual variation: 33% (n = 2)

  The average AUC for MODRA was calculated using 6 curves of 4 patients. The initial dose of MODRA administered to each patient was used to calculate interindividual variability. Intra-individual variability is based on data for patients 307 and 308 who received MODRA twice.

Conclusion The docetaxel liquid formulation tested yielded an AUC value approximately 1.5 times higher than the same dose (30 mg) obtained with the new capsule formulation (MODRA).

  Inter-individual variability in liquid formulations is high (85%) and inter-individual variability in capsule formulations is significantly lower (29%). This is an important feature of the new capsule formulation and can be expected to result in better docetaxel exposure. For safety reasons, low inter-individual variability is highly desirable for oral chemotherapy regimens.

  Intra-individual variation (limited data) is as large as inter-individual variation.

  A second dose of 100 mg ritonavir taken 4 hours after docetaxel administration increases docetaxel AUC by a factor of 1.5.

i. v. Comparison of oral capsule formulations for administration FIG. v. After administration (docetaxel 20 mg, Taxotere® as 1 hour infusion by iv) (patient n = 5) and oral administration (docetaxel 30 mg, MODRA capsule, see above) (patient n = 4, 6 courses) The pharmacokinetic curve of is shown. i. v. Both oral and oral docetaxel administration was combined with the administration of 100 mg of ritonavir (capsule, Norvir®). Oral and i. v. For both docetaxel, all patients were treated with oral dexamethasone. A dexamethasone dose of 4 mg was administered 1 hour before the test drug and thereafter every 12 hours (twice). One hour prior to treatment with docetaxel, the patient also received 1 mg of granisetron (Kytril®) to reduce nausea and nausea.

The bioavailability of MODRA capsules is
(AUC 30 mg oral / AUC 20 mg iv) × (20/30) × 100% = 73% (SD 18%).

  Capsule bioavailability was relatively high and inter-individual variability was low.

The foregoing examples are illustrative of specific embodiments of the invention and are not intended to limit its scope, which is defined by the appended claims. All documents cited herein are hereby incorporated by reference in their entirety.
(References)

Claims (78)

  A solid pharmaceutical composition for oral administration comprising a substantially amorphous taxane, a hydrophilic, preferably polymerized carrier and a surfactant.   The composition of claim 1, wherein the taxane and the carrier are in the form of a solid dispersion.   The composition of claim 2, wherein the taxane, the carrier and the surfactant are in the form of a solid dispersion.   8. A composition according to any preceding claim, wherein the taxane is selected from docetaxel, paclitaxel, BMS-275183, functional derivatives thereof and pharmaceutically acceptable salts or esters thereof.   5. The composition of claim 4, wherein the taxane is selected from docetaxel, paclitaxel, functional derivatives thereof and pharmaceutically acceptable salts or esters thereof.   A composition according to any preceding claim, wherein the carrier is PVP.   The composition according to claim 6, wherein the PVP is selected from PVP-K12, PVP-K15, PVP-K17, PVP-K25, PVP-K30, PVP-K60 and PVP-K90.   The composition according to claim 7, wherein the PVP is selected from PVP-K30, PVP-K60 and PVP-K90.   The surfactant is sodium dodecyl sulfate (SDS), sorbitan ester (sorbitan fatty acid ester), polyoxyethylene stearate, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, polyoxyethylene alkyl ether, poloxamer, mono Any of the preceding claims selected from glyceryl oleate, sodium docusate, cetrimide, benzyl benzoate, benzalkonium chloride, benzethonium chloride, hypromellose, nonionic emulsifying wax, anionic emulsifying wax and triethyl citrate. The composition as described.   The composition of claim 9, wherein the surfactant is SDS.   8. A composition according to any preceding claim, wherein the weight ratio of taxane to carrier is between about 0.01: 99.99 w / w and about 72:25 w / w.   12. The composition of claim 11, wherein the weight ratio of taxane to carrier is between about 0.01: 99.99 w / w and about 30:70 w / w.   A composition according to any preceding claim, wherein the weight ratio of the surfactant to the combined taxane and carrier is between about 1:99 w / w and about 50:50 w / w.   14. The composition of claim 13, wherein the weight ratio of surfactant to the combined taxane and carrier is between about 2:98 w / w and about 17:83 w / w.   A composition according to any preceding claim, wherein the substantially amorphous taxane is prepared by lyophilization.   16. The composition of claim 15, wherein the substantially amorphous taxane is prepared by lyophilization of the taxane solution in a capsule for oral administration.   A composition according to any preceding claim, further comprising one or more other pharmaceutically active ingredients.   18. The composition of claim 17, wherein the one or more other pharmaceutically active ingredients are CYP3A4 inhibitors.   19. The composition of claim 18, wherein the CYP3A4 inhibitor is ritonavir.   A composition according to any preceding claim for use in therapy.   19. A composition according to any one of claims 1 to 18 for use in the treatment of neoplastic diseases.   19. A method of treating a neoplastic disease comprising administering an effective amount of a composition according to any one of claims 1 to 18 to a subject in need of such treatment. Dissolving a taxane, a hydrophilic polymeric carrier and a surfactant in a solvent;
18. A method for preparing a composition according to any one of claims 2 to 17, comprising lyophilizing the solution to form a composition.   A pharmaceutical composition for oral administration comprising a substantially amorphous taxane and a carrier, wherein the substantially amorphous taxane is prepared by lyophilization.   A pharmaceutical composition for oral administration comprising a taxane and a CYP3A4 inhibitor together with one or more pharmaceutically acceptable excipients.   26. The composition of claim 25, wherein the CYP3A4 inhibitor is ritonavir.   27. The composition of claim 25 or claim 26, wherein the taxane is selected from docetaxel, paclitaxel, BMS-275183, functional derivatives thereof and pharmaceutically acceptable salts or esters thereof.   28. The composition of claim 27, wherein the taxane is docetaxel, functional derivatives thereof and pharmaceutically acceptable salts or esters thereof.   29. A composition according to any one of claims 25 to 28, comprising from about 0.1 mg to about 1000 mg of the taxane.   30. A composition according to any one of claims 25 to 29, intended for weekly administration, comprising from about 30 mg to about 500 mg of the taxane.   30. The composition of any one of claims 25 to 29, wherein the composition is intended for daily administration and comprises from about 0.1 mg to about 100 mg of the taxane.   32. The composition of any one of claims 26 to 31, comprising from about 0.1 mg to about 1200 mg of ritonavir.   31. A composition according to any one of claims 26 to 30, intended for weekly administration and comprising about 50 mg to about 1200 mg of ritonavir.   32. The composition of any one of claims 26-29 and claim 31, wherein the composition is intended for daily administration and comprises from about 50 mg to about 1200 mg of ritonavir.   29. A composition according to any one of claims 26 to 28, intended to be administered weekly, comprising about 100 mg of the taxane and about 100 mg of ritonavir.   36. A composition according to any one of claims 25 to 35 for use in therapy.   36. A composition according to any one of claims 25 to 35 for use in the treatment of neoplastic diseases.   38. The composition of claim 37, wherein the neoplastic disease is a solid tumor.   The solid tumor is from breast cancer, lung cancer, stomach cancer, colon cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer, endometrial cancer, ovarian cancer and NHL 40. The composition of claim 38, wherein the composition is selected.   40. The composition of claim 39, wherein the solid tumor is selected from breast cancer, ovarian cancer, prostate cancer, gastric cancer, head and neck cancer, and non-small cell lung cancer.   41. The composition of any one of claims 37 to 40, wherein the treatment comprises administration of the composition followed by administration of an additional dose of a CYP3A4 inhibitor after a predetermined period.   42. The composition of claim 41, wherein the additional dose of CYP3A4 inhibitor is ritonavir.   43. The composition of claim 42, wherein the additional dose of ritonavir is about 100 mg.   A method of treating a neoplastic disease comprising administering an effective amount of a taxane and a CYP3A4 inhibitor to a subject in need of such treatment.   45. The method of claim 44, wherein the CYP3A4 inhibitor is ritonavir.   46. The method of claim 44 or claim 45, wherein the taxane is selected from docetaxel, paclitaxel, BMS-275183, functional derivatives thereof and pharmaceutically acceptable salts or esters thereof.   47. The method of claim 46, wherein the taxane is docetaxel, a functional derivative thereof, or a pharmaceutically acceptable salt or ester thereof.   48. The method of any one of claims 44 to 47, wherein the taxane is administered substantially simultaneously with the CYP3A4 inhibitor.   48. The method of any one of claims 44 to 47, wherein the CYP3A4 inhibitor is administered about 60 minutes prior to the taxane.   50. The method of any one of claims 44 to 49, wherein the taxane is administered at a weekly interval at a dose of about 30 mg to 500 mg.   50. The method of any one of claims 44 to 49, wherein the taxane is administered daily at a dose of about 0.1 mg to 100 mg.   52. The method of any one of claims 45 to 51, wherein the ritonavir is administered at a weekly interval at a dose of about 50 mg to 1200 mg.   52. The method of any one of claims 45 to 51, wherein the ritonavir is administered daily at a dose of about 50 mg to 1200 mg.   50. The method of any one of claims 45 to 49, wherein the taxane and ritonavir are administered at weekly intervals at a dose of about 100 mg of the taxane and about 100 mg of ritonavir.   55. The method of any one of claims 44 to 54, wherein the neoplastic disease is a solid tumor.   The solid tumor is from breast cancer, lung cancer, stomach cancer, colon cancer, head and neck cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, bladder cancer, prostate cancer, testicular cancer, cervical cancer, endometrial cancer, ovarian cancer and NHL 56. The method of claim 55, wherein the method is selected.   57. The method of claim 56, wherein the solid tumor is selected from breast cancer, ovarian cancer, prostate cancer, gastric cancer, head and neck cancer, and non-small cell lung cancer.   58. The method of any one of claims 44 to 57, wherein the subject is a human.   59. The method of any one of claims 44 to 58, further comprising administration of an additional dose of the CYP3A4 inhibitor a predetermined period after administration of the initial dose of CYP3A4 inhibitor.   60. The method of claim 59, wherein the additional dose of CYP3A4 inhibitor is ritonavir.   61. The method of claim 60, wherein the additional dose of ritonavir is about 100 mg.   A method of treating a neoplastic disease, wherein a composition comprising a taxane and one or more pharmaceutically acceptable excipients is administered with a CYP3A4 inhibitor simultaneously with, or separately from, the taxane. A method comprising administering to a subject.   64. The method of claim 62, wherein the CYP3A4 inhibitor is ritonavir.   64. The method of claim 62 or 63, wherein the composition comprising a taxane is the composition of any one of claims 1-16 and 24.   A method of treating a neoplastic disease comprising administering a composition comprising a CYP3A4 inhibitor and one or more pharmaceutically acceptable excipients, simultaneously, separately or sequentially with a CYP3A4 inhibitor Administering to a treated subject.   66. The method of claim 65, wherein the CYP3A4 inhibitor is ritonavir.   68. The method of claim 65 or claim 66, wherein the taxane administered to a subject is in the form of a composition according to any one of claims 1-16 and 24.   A first pharmaceutical composition comprising a taxane and a second pharmaceutical composition comprising a CYP3A4 inhibitor, wherein the first and second pharmaceutical compositions are administered simultaneously, separately or sequentially for the treatment of neoplastic disease. Kit suitable for administration.   69. The kit of claim 68, further comprising a third pharmaceutical composition comprising a CYP3A4 inhibitor suitable for administration after the second pharmaceutical composition comprising the CYP3A4 inhibitor.   70. A kit according to claim 68 or claim 69, wherein the first pharmaceutical composition is a composition according to any one of claims 1 to 16 and 24.   Neoplastic disease treatment comprising a first pharmaceutical composition comprising a taxane and a CYP3A4 inhibitor, and a second pharmaceutical composition comprising a CYP3A4 inhibitor and suitable for administration after the first pharmaceutical composition Kit for.   72. The kit of claim 71, wherein the first pharmaceutical composition is the composition of claim 18 or claim 19.   73. The kit according to any one of claims 68 to 72, wherein the CYP3A4 inhibitor is ritonavir.   A taxane and one or more pharmaceutically acceptable excipients for use in the treatment of neoplastic disease in a subject administered a CYP3A4 inhibitor simultaneously, separately or sequentially with the taxane Composition.   75. The composition of claim 74, wherein the composition comprising a taxane is the composition of any one of claims 1-16 and 24.   A CYP3A4 inhibitor and one or more pharmaceutically acceptable excipients for use in the treatment of neoplastic disease in a subject administered with a taxane simultaneously, separately or sequentially with a CYP3A4 inhibitor A composition comprising.   77. The composition of claim 76, wherein the taxane administered to a subject is in the form of a composition according to any one of claims 1-16 and 24.   78. A composition according to any one of claims 74 to 77, wherein the CYP3A4 inhibitor is ritonavir.

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