JP2003528141A - Compositions and methods of use based on taxanes - Google Patents

Abstract

  (57) [Summary] Taxane-based compositions and methods of using the same to achieve target blood levels of taxanes in mammals, for example, for treating taxane-responsive malignant and non-malignant diseases. The compositions of the present invention provide long-term stability and overall good mouthfeel. Also disclosed are methods of using the present compositions as analytical tools for pharmacokinetic studies.

Description

Detailed Description of the Invention

(Priority) This application is filed under US provisional patent application No. 60/191 under Section 119 (e) of the US Patent Act.
, 802 (filed Mar. 24, 2000, the contents of which are hereby incorporated by reference).

TECHNICAL FIELD The present invention relates to novel compositions useful for the administration of water insoluble drugs, including drugs known to be poorly absorbed when administered orally. The invention further relates to compositions and methods of use thereof to achieve a target blood level of taxane in a mammal. Furthermore, the invention relates to methods of treatment using such compositions.

BACKGROUND OF THE INVENTION Most effective methods to solve the characteristic poor solubility of many pharmacologically useful compounds (eg, lipophilic compounds, hydrophobic compounds and amphipathic compounds). The lack is a serious drawback that hinders drug development. Kagkadis and others (PD
AJ. Pharm. Sci. 50 (5): 317-323 (1996)) and Sweetana et al. (PDA Pharm. Sci. 50 (5): 330-3.
42 (1996)) teach that poorly soluble compounds include, for example, cortisone, etoposide, cyclosporine and proleukin.
Traditionally, poorly soluble drugs due to poor or variable systemic absorption from the gastrointestinal tract (not only at additional economic cost, but also at considerable physical and psychological discomfort and Administered intravenously (with potential local trauma).

Poorly soluble chemotherapeutic and / or anti-cancer agents include taxanes such as paclitaxel, which normally do not have bioavailability when orally administered. Wani et al. Am. Chem. Soc. , 93: 2325 (1
971) is paclitaxel, which is one member of the taxane family of terpenes,
It teaches that it is a natural diterpene product isolated from Taxus brevifolia. The exact mechanism responsible for the chemotherapeutic properties of paclitaxel has not been elucidated, but Schiff et al., Proc. Natl.
Acad. Sci. USA, 77: 1561-1565 (1980); Schi
ff et al., Nature, 277: 665-667 (1979); Kumar, J.
． Biol. Chem. In some studies, such as the study of 256: 10435-10441 (1981), the ability of paclitaxel to inhibit tumorigenic growth was found to be at the N-terminal 31 amino acids of the β-tubulin subunit in microtubules. It is claimed to be derived from the ability to combine (Rao et al., J. B.
iol. Chem. 269: 3132-3134 (1994)).
Wood et al., New Eng. J. M. 332 (15): 1004 to 1014 (
1995) found that the anti-cancer properties of paclitaxel render microtubules abnormally stable and dysfunctional, thereby resulting in normal kinetics required during cell division and essential interphase processes. It is thought that this is because the destruction of microtubules, which causes cell death, is inhibited by the destruction of the.

The scientific literature is replete with papers reporting the efficacy of paclitaxel in treating a variety of unrelated conditions. For example, see: For lung and head and neck cancer, see Einzig et al., Proc. Am. Soc. Clin
． Oncol. , 20:46 (1996); for neoplasms in the skin, F.
orastire et al., Sem. Oncol. 20:56 (1990); for gastric cancer, Chang et al., Cancer, 77 (1): 14-18 (1996).
); For polycystic kidney disease, Woo et al., Nature, 368: 750 (19).
94); for malaria, see Pouvelle et al. Clin. Invests
t. 44: 413-417 (1994).

Paclitaxel and docetaxel have been approved for clinical use in treating some unrelated conditions. Markman et al., Yale J. of
Bio. & Med. 64: 583 (1991), and McGuire et al., A.
nn. Intern. Med. 111: 273 (1989) discloses the use of paclitaxel for refractory ovarian cancer in the United States; Mavrodiu.
S., ASCO, 18: 254a (1999) describe the use of docetaxel for gastric cancer; Holmes et al., J. Am. Nat. Cancer Inst
． , 83: 1797 (1991) discloses the use of paclitaxel for chemotherapy against several types of neoplasms, including breast cancer (see also package insert for taxol (paclitaxel) Mead Johnson Oncology Products); Fencel et al., ASCO, 18: 283a (
1999) teaches the use of paclitaxel and docetaxel for esophageal cancer; Vanhoefer et al., ASCO, 18: 303a (1999) describes a Phase II study using docetaxel in metastatic gastric cancer;
Kourossis et al., ASCO, 17: 226 (a) (1998) teach the use of docetaxel as salvage chemotherapy for advanced gastric cancer; X
iao et al., ASCO, 17: 306 (a) (1998) evaluates a new paclitaxel treatment method in patients with esophageal cancer previously treated with paclitaxel; Schultz et al. in patients with hormone refractory prostate cancer. Reported Phase II clinical trial of docetaxel; Ajani et al., J. Am. Nat. Can
cer Inst. , 86: 1086-1091 (1994), and Kels.
En et al., Seminars in Oncology, 21: 44-48 (19).
94) describe paclitaxel therapy for squamous cell carcinoma and adenocarcinoma as well as epidermoid carcinoma of the esophagus.

To date, various efforts have been made (i) suitable injectable and infusible taxane formulations,
And (ii) directed towards developing more water soluble analogs, derivatives and prodrugs of taxanes. Therefore, most paclitaxel formulations for IV infusion have been developed utilizing polyethoxylated castor oil, which is commercially available as CREMOPHOR EL ™, as the drug carrier. However, polyethoxylated castor oil is itself toxic, causing vasodilation, dyspnea, lethargy, hypotension and death in dogs. Polyethoxylated castor oil is also suspected to cause an allergic reaction when administered intravenously.

Alternative methods have resulted in more water soluble analogs, derivatives and prodrugs of taxanes. Thus, for example, “modified taxol IV; synthesis and biological activity of side chain modified taxols” (Magri, NF; K.
Ingston, DGI; Nat. Prod. 1988, 51, 298) teach derivatized paclitaxel analogs in which the 2'and / or 7 positions are derivatized with water-solubility enhancing groups. These efforts have resulted in prodrug compounds that are more water soluble than the original compound and that when activated show cytotoxic properties. An important group of such prodrugs is the 2'-onium salts of paclitaxel and docetaxel (eg Nicolaou et al.,
Angew. Chin. Int. Engl. 33: 1583 to 1587 (199
4)), in particular the 2'-methylpyridinium mesylate (2'-MPM) salts disclosed in PCT International Patent Application Publication WO 98/58927.
Suffness (edition) is based on Taxol (registered trademark) Science and
In Applications (CRC Press, 1995) it states that no one has progressed to clinical evaluation to date due to insufficient improvements in solubility, stability issues and low regeneration rates.

Preclinical studies suggest that paclitaxel alone is not absorbed after oral administration. Walle et al., Drug Metabo. Disp. 26 (4): 3
43-346 (1998) reported that taxol was not absorbed after oral administration, and the low oral bioavailability was attributed to the action of outward efflux pumps. Similarly, Eiseman et al., Second NCI W
orkshop on Taxol and Taxus (September 1992),
And Suffness (edition), Taxol (registered trademark) Science an
d Applications (CRC Press, 1995) teach that paclitaxel is very poorly absorbed (<1%) when administered orally. More specifically, Eiseman et al. Showed that paclitaxel had 0% bioavailability when administered orally, and Suffness (eds) considered that paclitaxel could be taken orally. I do not report. For these reasons, paclitaxel has not been administered orally to human patients. Similarly, the trade name TAXOTERE (registered trademark) (Rhone-Pou
lenc-Rorer S.M. A. Docetaxel (N-debenzoyl-N-tert-butoxycarbonyl-10-deacetylpaclitaxel) marketed under)) has been administered in parenteral form to treat breast cancer.

Poor bioavailability of paclitaxel after oral administration is due to a membrane that functions as an energy-dependent transport or efflux pump to reduce intracellular accumulation of drugs by driving xenobiotics out of cells. May be for conjugated P-glycoprotein (eg, Taxol® Science and Appli).
notes (see above)). The hypothesis has been proposed that P-glycoprotein interferes with systemic absorption by impeding the movement of small intestine through mucosal cells. A number of known agents have been shown to inhibit P-glycoprotein, such as cyclosporin A, verapamil, tamoxifen, quinidine and phenothiazines. Logically, various studies, including clinical trials, have shown that multidrug resistance (M
The effects of cyclosporine on anti-cancer drugs known to be prone to DR) are described in, for example, paclitaxel (Fisher et al., Proc, Am. Soc. Cl.
in. Oncol. 13: 143, 1994); doxorubicin (Bartle)
tt et al., J. Clin. Onc. 12: 835-842 (1994)); and etoposide (Lum et al., J. Clin. Onc. 10: 1635-1642 (1).
992)) and so on. Intravenous administration of cyclosporine with anti-cancer drugs has been shown to produce higher blood levels (probably due to reduced internal clearance), and medications with substantially reduced expected toxicity. Shown at the quantity level. For a general discussion of the pharmacological implications for clinical use of P-glycoprotein inhibitors, see Lum et al., Drug Resist. Clin. Onc. Hemat. 9: 319-33
6 (1995); Schinkel et al., Eur. J. Cancer, 31A: 1
295-1298 (1995).

PCT International Patent Application Publication WO95 / 20980 (Published August 10, 1995) (
In the following, "Benet") claims to teach methods of increasing the bioavailability of orally administered hydrophobic pharmaceutical compounds. This method uses cytochrome P4
Orally administering a biological enhancer, including an inhibitor of the 50 3A enzyme or an inhibitor of P-glycoprotein-mediated membrane transport. Benet does not reveal what bioavailability enhancer improves the availability of a particular targeted drug compound, and also specific dosages for administering the enhancer or targeted agent, It does not teach dosing schedules or methods of administration. The only combination disclosed is
Ketoconazole as a potentiator and cyclosporin A as a targeted drug.

[0012] Benet is that biological enhancers are hydrophobic compounds that generally contain two coplanar aromatic rings, a positively charged nitrogen group or a carbonyl group, ie, some impracticalities. It only illustrates a class that includes a large number of unidentified compounds, including certain embodiments. In addition, the various classes of active agents disclosed by Benet include the majority of the pharmaceutical agents listed in Physician's Desk Reference and, therefore, are safe, practical and effective for oral administration of certain agents. It's not worth it for a doctor looking for a new method. Finally, B
enet does not provide any teaching that one of ordinary skill in the art can follow to identify suitable bioenhancer / active agent combinations or to design therapeutically effective oral modalities.

PCT International Patent Application Publication WO98 / 30205 (Published July 16, 1998) (
Since then, "Quay") allegedly discloses a method of increasing the bioavailability of poorly soluble drugs. The specification discloses an emulsion of α-tocopherol containing a surfactant. PEGylated vitamin E
Are also listed. PEGylated α-tocopherol contains a polyethylene glycol subunit linked by a succinate diester at the vitamin E ring hydroxyl. Alpha-tocopherol allegedly serves as a surfactant, stabilizer and secondary solvent in the emulsion of alpha-tocopherol. Of note, this reference is particularly limited to formulations that are (a) emulsions and (b) essentially ethanol-free formulations.

[0014] Co-owned PCT International Patent Application Publication No. WO 97/15269 describes targeted agents, including taxanes, or otherwise targeted poor oral bioavailability, such as biological agents such as cyclosporine. Disclosed are novel methods and compositions that make bioavailability by co-orally administering the availability enhancer.

There is a continuing need to develop additional compositions and effective methods suitable for oral administration of taxanes. Such compositions should be able to achieve the desired therapeutic blood levels of taxanes. For obvious practical reasons, such compositions are (i) bioavailable, (ii) suitable for maintaining taxanes in solution, and (iii) chemically stable over time. Stable,
And (iv) it must exhibit long-term stability while at the same time having a good mouthfeel overall.

SUMMARY OF THE INVENTION The inventors have devised taxane-based compositions and methods of use thereof that are useful for achieving target blood levels of taxanes in mammals. The compositions of the present invention exhibit long term stability and overall good mouthfeel. As exemplified herein, such methods provide blood levels of taxanes that are comparable to those achieved by less convenient methodologies currently available, such as therapeutically effective infusion modalities. To provide the means to achieve. Accordingly, the present invention improves absorption of taxanes from the gastrointestinal tract into the bloodstream and results in target blood levels of such taxanes in mammals, including therapeutically effective blood levels. Compositions and methods useful for In some embodiments, the blood level of taxane achieved is above the blood level achieved by the composition disclosed in WO 97/15269. Moreover, the methods and compositions according to the invention are useful not only as therapeutic tools, but also as analytical tools for biochemical studies.

In a first aspect, the invention provides a pharmaceutical composition that exhibits long-term stability and overall good mouthfeel. Such compositions include poorly soluble drugs, carriers, co-solubilizers and stabilizers. In a more preferred embodiment of the invention the drug is a taxane. Preferred embodiments of the invention may provide more than one type of taxane, carrier, co-solubilizer or stabilizer. Some compositions of the present invention may include, for example, surfactants, pharmaceutical excipients, diluents, sweeteners, flavoring agents or colorants, etc., as described in further detail herein. Further comprising further ingredients. In a particularly preferred embodiment of the invention, the taxane is paclitaxel or docetaxel. When orally administered with an oral bioavailability enhancer, some of the preferred compositions of the invention produce blood levels of taxanes that are comparable to those achieved by intravenous injection. provide.

In a second aspect, the invention provides a method suitable for achieving therapeutically effective blood levels of taxanes in a mammal by orally administering the described pharmaceutical composition. To do. In a particularly preferred embodiment, the method of the present invention comprises administering a bioavailability enhancer, (eg, Wilson et al., J. Am.
Clin. Oncol. 12: 1621-1629 (1994), and Sei.
dman et al. Clin. Oncol. 16: 3353-3361 (1998)
), Which is comparable to blood levels achieved by long-term infusion, such as 96-hour infusion, which has been shown to be therapeutically effective for treating advanced metastatic breast cancer. Results in possible taxane blood levels. Pharmaceutical compositions and bioavailability enhancers useful according to this aspect are as described for the first aspect of the invention.

In a third aspect, the invention provides a method of investigating the properties of various diterpenoids. More specifically, the present invention provides a tool to study the biochemical properties of taxane components in novel formulations that can mediate a significant increase in solubility. Such studies are essential for revealing new applications, and perhaps for further optimizing already existing therapeutic outcomes, of a more comprehensive pharmacokinetic and pharmacological study of taxanes. It will bring a simple explanation.

A further aspect of the invention relates to a method of treating a mammal suffering from a taxane-responsive disease by orally administering a pharmaceutical composition as described herein. In some embodiments, the pharmaceutical compositions of this invention are orally administered with an oral bioavailability enhancer, and taxane blood levels comparable to the levels achieved by intravenous injection of taxanes. Provides a medium level. Pharmaceutical compositions and bioavailability enhancers useful according to this aspect are as described for the first aspect according to the invention.

BEST MODE FOR CARRYING OUT THE INVENTION The present inventors have developed a novel method for orally administering a water-insoluble drug, including a drug known to be poorly absorbed when orally administered. The composition and method of use thereof were devised. The invention further relates to compositions useful for achieving target blood levels of taxanes in mammals, including therapeutic blood levels, and methods of use thereof. Furthermore, the invention relates to methods of treatment using such compositions. The United States patents and other publications mentioned herein are within the knowledge of one of ordinary skill in the art and are hereby incorporated by reference in their entireties.

Technical and scientific terms used herein have the meaning commonly understood by one of skill in the art to which the present invention pertains, unless otherwise defined. To ensure a clear and complete understanding of the specification and claims, including the scope given to such terms, the following definitions are provided. It is understood that the defined terms can be presented in noun forms, verb forms, singular forms as well as plural corresponding forms.

Reference is made herein to various methodologies and materials known to those of skill in the art. Goodma as a standard reference book showing the general principles of pharmacology
n and Gilman's The Pharmacologic B
Assist of Therapeutics, 9th Edition, McGraw Hill
Companies Inc. , New York (1996).
Remington as a standard reference book showing the general principles of current therapeutic agents
's Pharmaceutical Sciences, 18th Edition, Genn
aro, Mack Publishing Co. , Easton, PA (19
90); Remington: The Science and Practi
ce of Pharmacy, Lippincott, Williams & W
ilkins (1995).

Any suitable materials and / or methods known to those of ordinary skill in the art can be utilized in carrying out the present invention. However, preferred materials and methods are described. The materials, reagents and others referred to in the following description and examples can be obtained from commercial sources unless otherwise indicated.

The present invention is intended to be used with any mammal that can benefit from the methods of the present invention. Such mammals include humans in the first place, but the invention is not so limited and is applicable for veterinary use.

In a first aspect, the present invention provides a pharmaceutical composition that exhibits long-term stability and overall good mouthfeel. Such a composition comprises a taxane, a carrier, a co-solubilizer and a stabilizer. For the purposes of the present invention, the term "carrier" is used to indicate a component that maintains (in a preferred embodiment improves) the aqueous solubility of taxanes in the pharmaceutical composition of the present invention. The carrier according to the invention comprises:
Including but not limited to components that can also function as co-dissolving agents. The carriers of the present invention feature a core structure that can be either a linear polyether or a branched glycol (eg, glycol) linked to at least one fatty acid ester. The preferred carrier used in the present invention is a nonionic surfactant or emulsifier having an HLB value of at least about 10. Such non-ionic surfactants or emulsifiers are not only compatible carriers for lipophilic taxanes (poorly soluble in water), but also the absorption of active ingredients from the gastrointestinal tract into the bloodstream. It has also been found to promote. Only such members of these detergent families with HLB values above 10 can be used as carriers in the compositions of the invention.

As a representative non-limiting example of a carrier according to the present invention, vitamin E TPGS (d
-Α-tocopheryl polyethylene glycol 1000 succinate, which is Ea
stman Chemical Co. Kingsport, available from TN); products (Gattefosse Corp. of GELUCIRE (TM) and LABRASOL (TM) containing glycerides of C ₈ -C ₁₈ fatty acids, We
CREMOPHOR ™ EL or other modified castor oils (such as modified castor oils of EL-P or RH40), including saturated polyglycolized glycerides such as Stood, NJ); Available from Olive, NJ); MYRJ ™ polyoxyethylated stearate ester (this is ICI Americas C
sold by Harlotte, NC); TWEEN ™ (IC
I Americas) and CRILLET ™ (Croda Inc.
Polyoxyethylated sorbitan ester (available from Parsippany, NJ); BRIJ ™ polyoxyethylated fatty acid ether (ICI
Americas); CROVOL ™ modified (polyethylene glycol) almond oil glycerides and corn oil glycerides, including almond oil glycerides of polyethylene glycol or corn oil glycerides (these are available from Croda Inc. Edison, NJ); EMSORB.
™ sorbitan diisostearate ester (Henkel Corp.,
Ambler, PA); SOLUTOL ™ polyoxyethylated hydroxystearate (BASF); and cyclodextrins.

A preferred pharmaceutical composition according to the invention comprises at least 30% by weight of carrier. In a particularly preferred embodiment, the carrier is present in an amount of about 30% to about 90% by weight of the composition. In a particularly preferred embodiment, the pharmaceutical composition of the invention comprises about 40% by weight Vitamin E TPGS.

The term “co-solubilizer” increases the fluidity of the composition of the invention at body temperature and / or the melting point of the composition, as is generally required for oral bioavailability. It is used to indicate the portion of viscosity reduction that lowers the temperature below body temperature. Preferred co-solubilizers according to the present invention reduce the viscosity of the vehicle at body temperature and thus increase its fluidity, and also, compared to when the carrier is used alone,
The amount of active agent that can be dissolved or dispersed in the vehicle can be increased. The co-dissolving agent according to the present invention includes a component that can also function as a carrier. Co-solubilizers according to the present invention include, but are not limited to, ingredients that may also provide increased solubility of taxanes.

As a representative non-limiting example of a viscosity reducing co-solubilizer, PHARMASOLV
E (TM) (N-methyl-2-pyrrolidone, International Sp
economic Products, Wayne, NJ); MIGLYOL ™, glycerol or propylene glycol esters of caprylic and capric acids (Huels AG, Marl, Germany); polyoxyethylated hydroxystearate esters including stearyl ether or oleyl ether ( For example, SOLUTOL ™ HS15) (BASF, Mt. Oli
ve, NJ); TWEEN ™ polyoxyethylated sorbitan ester (I
CI, Wilmington, DE); SOFTIGEN ™, polyethylene glycol esters of caprylic and capric acids (Huels AG); modified castor oils containing polyoxyethylated castor oil or hydrogenated castor oil (CREMO).
PHOR (trademark) EL, EP-P or RH40, etc.) (BASF, Mt.
ive, NJ); vegetable oils such as olive oil, polyoxyethylated fatty ethers or modified castor oil; glycerides of C ₈ -C ₁₈ fatty acids, such as certain saturated polyglycolized glycerides (LABRASOL (TM)); citric acid Tributyl, citric acid esters such as triethyl citrate and acetyltriethyl citrate, propylene glycol (alone or PHARMASOLVE ™)
In combination with), ethanol (preferably dehydrated ethanol), water, and low molecular weight polyethylene glycols (such as PEG 200, 300 and 400). In a particularly preferred embodiment, the co-dissolving agent is ethanol. In a more particularly preferred embodiment, the co-dissolving agent comprises propylene glycol and ethanol. Up to 90% by weight of the composition may be a co-dissolving agent. In some embodiments of the invention, about 10% to about 70% by weight is the co-dissolving agent. In a preferred embodiment of the invention, the co-dissolving agent is about 20% to about 60% by weight.
Present in an amount of. Thus, a preferred pharmaceutical composition may contain from about 10% to about 70% by weight propylene glycol, more preferably from about 20% to about 60%.
It may contain wt% propylene glycol. In a particularly preferred embodiment, the pharmaceutical composition of the invention comprises about 40% by weight propylene glycol.

In a particularly preferred embodiment, the pharmaceutical composition of the present invention comprises about 5% to about 50% ethanol by weight, more preferably about 10% to about 30% ethanol by weight. In the most preferred embodiment, the pharmaceutical composition of the present invention comprises about 20% by weight.
Including ethanol.

Some substances identified as carriers have also been found to be effective co-dissolving agents, either alone or in combination with other viscosity reducing agents or certain other carriers. There is. Generally, paclitaxel or other taxanes at body temperature
Alternatively, any solvent that is at least reasonably soluble by mild heating can be used as a co-solubilizer in the vehicle of the novel composition. A preferred co-dissolving agent is at least 25 mg / ml of paclitaxel or other taxane to about 20.
It can be dissolved at a temperature of from 25 ° C to 25 ° C. Some embodiments of the present invention include more than one co-dissolving agent. In some preferred embodiments, the compositions of the present invention include at least two solubilizers.

As used herein, the term “stabilizer” refers to ingredients that increase the stability of taxanes. Stabilizers according to the invention include solvolysis of taxane molecules (eg loss of ester side chains at C-13 or deacetylation at C-10) and / or (eg C compared to taxanes). Taxanes can be stabilized by reducing the rate of epimerization (at the -7 position). Stabilization of taxanes with the stabilizers according to the present invention can be achieved by one or more known degradation products (
For example, 7-epi-taxol C, 10-deacetyltaxol, 7-epi
-Taxol, 7-epi-10-deacetyltaxol, baccatin III, 1,
It can be detected by a decrease in 0-deacetylbaccatin III, cephalomannin, nitin, 7-epi-cephalomannin (eg Mil.
Ler et al., J. Org. Chem. 46: 1469-1474 (1981); V
olk et al., J. Chromatography B, 696: 99-115 (1
997)). In a particularly preferred embodiment of the invention, the stabilizing agent is ascorbic acid 6-palmitate (ie ascorbyl palmitate). Other stabilizers useful in the present invention include metal salts of acids such as α-hydroxy acids or β-hydroxy acids, metal sulfates (eg FeSO ₄ ), metal α-
Included are hydroxymethylsulfinates, and metal sulfonates. The metal salt is a co-owned US patent application No. 1 (Title of Invention: Use of a metal salt to stabilize a composition based on taxane, filed on the same date as the application; this is incorporated herein by reference. Incorporated in) is the subject.

While not wishing to be bound by any particular theory limiting the present invention, Applicants have found that some stabilizers inhibit the formation of radicals and / or are contiguous within the taxane skeleton. It is thought that the decomposition of taxane is reduced by forming a complex between the polar oxygen-containing substituents. This new conformation forms a "lock" that holds these chemical groups in place. Therefore,
Minimizing the interaction of these substituents with the surrounding medium reduces the rate of solvolysis and / or deprotonation at these sites, which in turn reduces the rate of decomposition of the parent compound. . Thus, in some embodiments of the invention, the preferred stabilizer is a radical inhibitor. Radical inhibitors are well known in the art (eg, Remington's Pharmaceut).
ical Sciences (see above)). Non-limiting, representative radical inhibitors according to the present invention include Fe ²⁺ gluconate, Cu ²⁺ gluconate, Zn ²⁺ gluconate, Ca ²⁺ ascorbate, HOCH ₂ SO ₂ Na, ascorbyl palmitate. , Β-carotene, zinc methionine and zinc citrate.

Yet another preferred stabilizer contemplated by the present invention may further help preserve the color of the pharmaceutical composition. As an example of this type of stabilizer,
Mention may be made of dl-α-tocopherol commercially available from BASF (Mt. Olive, NJ).

A preferred range for the amount of stabilizer present in the composition of the present invention is from about 0.2% to about 1.0% by total weight of the composition. Generally, the amount is from about 0.05% by weight to about 2.0.
It is in the range of% by weight. The decision is on whether a given substance functions as a stabilizer for the purposes of the present invention, and, if so, the optimal amount added to the composition is routine. Determined by experiment. For example, taxane formulations containing varying amounts of compounds are exposed to loading conditions (eg, 80 ° C. for 24 hours) and then analyzed by HPLC. Formulation (compound-free)
The percentage of unchanged taxane compared to the control is calculated from the HPLC profile. Compounds that achieve a taxane ratio of 97% are generally considered acceptable. Compounds that achieve a taxane ratio of greater than 98.5% are preferred. See also the Miller and Volk publications (supra).

The pharmaceutical composition according to the invention may comprise more than one type of carrier, co-solubilizer or stabilizer. In some embodiments, the compositions of the present invention optionally include, for example, surfactants, pharmaceutical excipients, diluents, sweeteners, as described in further detail herein. Can be formulated with additional ingredients such as flavoring agents or colorants. Conventional pharmaceutical excipients, diluents, sweeteners, flavoring agents, colorants and any other inactive ingredients routinely included in dosage forms intended for oral administration are well-known in the art. Known (Remington's P
see Pharmaceutical Sciences (above)).

A “surfactant” according to the present invention is an amphipathic component having surface-active groups which can maintain and / or promote the dispersion of hydrophobic compounds in an aqueous medium. Those skilled in the art will appreciate that suitable surfactants for the compositions of the present invention are well known in the art. Non-limiting, representative surfactants include Vitamin E (eg,
α-tocopherol) and β-carotene.

The term “taxane” is used to identify a diterpene component that has very little solubility in water. Taxanes according to the present invention include the yew (T
axus brevifolia) and various components isolated, as well as, but not limited to, derivatives, analogs, metabolites and prodrugs, and other taxanes. Preferably, the taxane of the present invention is paclitaxel,
It is selected from the group consisting of docetaxel, paclitaxel or derivatives of docetaxel, analogs, metabolites and prodrugs, and salts, polymorphs and hydrates thereof. More preferably, the taxane of the present invention comprises paclitaxel. In some embodiments of the invention, two or more taxanes are included as active ingredients.

The taxane concentration in the compositions of the present invention will vary based on the carrier, co-solubilizer and / or stabilizer selected, and based on the desired total dose of taxane administered orally to the mammal. obtain. The concentration of taxane in the pharmaceutical composition according to the present invention is in the range of about 2 mg / ml to about 100 mg / ml, preferably about 6 mg / ml to about 60 mg / ml or more, preferably about 10 mg / ml to about 50 mg / ml. obtain.

Applicants have determined that by administering an effective oral dose of a bioavailability enhancer together with the administration of a composition according to the present invention, the blood levels achieved by intravenous injection of taxane are achieved. It has been found that achieving comparable blood levels of taxanes is facilitated.
As discussed below, the bioavailability enhancer can be administered prior to, concurrently with, or shortly after the composition of the invention is administered. Thus, in some preferred embodiments of the invention, the pharmaceutical composition comprises a bioavailability enhancer.

The term “bioavailability enhancer”, also referred to as “enhancing agent” or “availability agent”, refers to an agent that can promote the absorption or bioavailability of another agent. used. Preferred bioavailability enhancers include Topicladium (Topycl)
acyclosporin and related oligopeptides, ketoconazole, dexverapamil, amiodarone, nifedipine,
Reserpine, quinidine, nicardipine, ethacrynic acid, propaphenone, serpin, amiloride, ergot alkaloid, cefoperazone, tetracycline, chloroquine, fosfomycin, ivermectin, tamoxifen VX-710, VX
-853, genistein and related isoflavonoids, calphostin, ceramides, morphine, morphine congener, other opioids and opioid antagonists. Cyclosporins are, for example, Topycladium.
inflatum games (this used to be Trichoderma pol
It was called ysporum), Topycladium terricol
It is a group of non-polar cyclic oligopeptides produced by the genus Topiculadium including a and other imperfect fungi, some of which have immunosuppressive activity. Its major component, cyclosporin A (cyclosporin or CsA), is linked to several other analogs (eg, cyclosporin B-Z), some of which show substantially less immunosuppressive activity than cyclosporin A. Have been identified together. Many synthetic and semi-synthetic analogs have also been prepared. In general, Je
gorov et al., Phytochemistry, 38: 403-407 (199
See 5). The present invention includes natural, semi-synthetic, synthetic analogs and derivatives of the cyclosporins. Cyclosporins, especially cyclosporin (Cyclosporin A), are known inhibitors of P-glycoprotein efflux pumps and other transporter pumps and certain P450-degrading enzymes, but to date,
Effective methods of clinically applying this property have not been developed to clinical and commercial feasibility or regulatory approval.

Cyclosporins that may be used in a preferred embodiment of the present invention include cyclosporins AZ, especially cyclosporin A (cyclosporin), cyclosporin F, cyclosporin D, dihydrocyclosporin A, dihydrocyclosporin C.
, Acetylcyclosporin A, PSC-833, SDZ-NIM811 (which is (Me-Ile-4) -cyclosporin), antiviral non-immunosuppressive cyclosporine, but is not limited thereto. The characteristic amino acid changes that define cyclosporin AZ are listed in Table 1 below.

[0044]

[Table 1]

In a more preferred embodiment, the present invention provides a taxane, vitamin E TPGS,
Provided is a long-term stable pharmaceutical composition for oral administration to a mammal, which comprises propylene glycol, ethanol and ascorbyl palmitate. A particularly preferred embodiment of the present invention comprises the following ingredients:

Ingredients% w / v U / mL Paclitaxel 1.20 12.0 mg Vitamin E TPGS ( ^* ) 40.00 400.00 mg Propylene glycol USP 40.00 400.00 mg Ascorbyl palmitate NF 0.50 5.0 mg dl- α-Tocopherol USP 0.50 5.0 mg Dehydrated alcohol Required amount up to 100 mL Required amount up to 1.0 mL ( ^* ) d-α-Tocopheryl polyethylene glycol 1000 Succinate

The compositions of the present invention are any conventional known to those skilled in the pharmaceutical art for preparing liquid or other flowable oral formulations containing a surface-active carrier and a lipophilic active ingredient. Can be prepared by conventional methods. Suitable, non-limiting, representative examples of preparing the compositions of the present invention include, for example, the protocols described in the Examples herein. Most of the preferred carriers are very viscous at room temperature, and in some cases retain a relatively high viscosity even when a small amount of co-dissolving agent is added, so the carrier used It is generally preferred when preparing the composition to mix the co-dissolving agent and the taxane active ingredient and heat the resulting mixture under stirring, eg to about 40 ° C. This method makes it possible to prepare a clear solution. However, some co-solubilizers (especially PHA
MASOLVE ™ lowers the viscosity of the carrier to the extent that the composition can be prepared by stirring at room temperature without heating, increasing the solubility of taxanes. The viscosity of the finished composition is 40,000 cp at body temperature (about 37 ° C)
It is preferably s or less.

The oral compositions of the present invention may be in the form of true solutions, emulsions or suspensions, although solutions of the active taxane component in the carrier or carrier / co-dissolving system are preferred.

The present invention also relates to methods of using the compositions for various purposes, including but not limited to therapeutic applications. Accordingly, in a second aspect, the present invention provides for achieving a target blood level of taxane in a mammal by orally administering an effective amount of a pharmaceutical composition as described herein. Provide a way. Such a method is suitable to provide a target blood level of taxane that is comparable to the blood level achieved by intravenous administration of taxane. Although some of the oral pharmaceutical compositions of this invention may result in target blood levels, including therapeutic blood levels of paclitaxel, when administered alone, the preferred methods of this invention are oral organisms. Administration of at least one dose of the bioavailability enhancer and at the same time administration of the oral pharmaceutical formulation of the present invention. This is because the subsequently achieved taxane levels are actually associated with the taxane's pharmacological activity. Pharmaceutical compositions and bioavailability enhancers useful according to this aspect are as described for the first aspect of the invention.

A “target blood level” according to the present invention is a blood concentration of taxane at or above a threshold concentration required to observe a particular desired activity associated with taxanes. The blood concentration of taxane. By way of non-limiting and representative example, inhibition of tubulin degradation that occurs at blood concentrations of about 0.1 μM or about 85 ng / ml, and inhibition of protein isoprenylation, which is about 0.03 μM or about 25 ng / ml. Occurs in the blood level). Furthermore, taxanes such as paclitaxel have been shown to inhibit angiogenesis and inhibit intracellular Bcl-2 phosphorylation. Some of these activities, such as direct inhibition of oncogene function or inhibition of transduction elements, are directly related to the anti-tumorigenic properties of taxanes. Thus, in some particularly preferred embodiments of the invention, the target blood level is a therapeutic blood level at which a particular pharmacological activity is observed. Target blood levels can vary widely due to a number of variables such as, for example, the drug used concurrently, liver condition, albumin levels in the mammal being treated, and variability between different pharmaceutical formulations. Target blood levels can be readily ascertained by routine methodologies such as escalating administration of the compositions of the invention while monitoring paclitaxel levels in mammals.

In a preferred embodiment of the invention, where the mammal is a human in need of a therapy that inhibits tubulin degradation, the target blood level is at least about 0. 1 μM or about 85 ng / ml. In some preferred embodiments of the invention, where the mammal is a human in need of therapy that inhibits protein isoprenylation, the target blood level is at least about 0.
03 μM or about 25 ng / ml. About 2 such target blood levels
Included, but not limited to, blood levels from 5 ng / ml to about 85 ng / ml.

In a third aspect, the present invention provides a method for examining the physical properties of diterpenoids. More specifically, the present invention provides a useful tool to study the biochemical properties of taxane components in novel formulations that can mediate greater increases in tissue distribution in vivo without increasing toxicity. I will provide a. While such tools can expand the distribution capacity of taxanes, such tools allow researchers, for example, to study tubulin and / or microtubule-binding proteins (
Various in vivo biochemical properties such as the level of overexpression of MAP), cell cycle progression, and the action of paclitaxel on nucleation of microtubule assembly in various tissues can be elucidated. Such studies are needed to reveal new applications, and perhaps to further optimize already existing therapeutic outcomes, a more comprehensive pharmacokinetic and pharmacological study of chitasans. It is expected that it will provide a clear explanation.

Finally, the methods and compositions according to the invention are useful in the treatment of taxane-responsive diseases. "Taxane responsive disease" is used to indicate any condition, including those disease conditions, which are ameliorated by oral administration of an effective amount of the pharmaceutical compositions described herein. In general, taxane-responsive diseases are characterized by uncontrolled cell proliferation, including but not limited to cancer, tumors, angiogenesis, psoriasis, and heterogeneous diseases of polycystic kidney disease. As discussed above, non-limiting, representative examples of taxane-responsive diseases include cancer, tumors, Kaposi's sarcoma, malignancy, uncontrolled tissue and cell proliferation secondary to tissue injury. To be Types of cancer that can be treated particularly effectively according to the methods of the present invention include hepatocellular carcinoma and liver metastases, gastrointestinal tract, pancreas, prostate and lung cancer, and Kaposi's sarcoma. Non-cancerous diseases that can be effectively treated according to the present invention include uncontrolled tissue and cell proliferation secondary to tissue injury, polycystic kidney disease, inflammatory diseases (eg, arthritis), and chloroquine and pyrimethamine. And malaria (Pouvelle et al., Supra), including malaria parasites resistant to.

The term “treatment” or the term “as used herein in connection with taxane-responsive diseases
"Treat" refers to preventing and ameliorating symptoms already present in an individual by altering blood levels of taxane. The treatment need not be completely effective in preventing the onset of the disease or eliminating the symptoms associated with the disease, or that the treatment is effective and does not require cure of the disease. Will also be understood by those skilled in the art. Some reduction in symptom severity, delayed onset of symptom, or delayed progression of symptom severity is possible. A person at risk of developing a taxane-responsive disease is treated prophylactically on the basis of any of a variety of factors suggestive of possible disease development, such as family history, environmental exposure, genetic markers, early symptoms, etc. obtain.

As discussed in other aspects, some of the oral pharmaceutical compositions of the present invention, when administered alone, contain target blood levels (including therapeutic blood levels) of taxanes. However, a preferred method of the present invention for treating a mammal suffering from a taxane-responsive disease is to provide an oral composition containing a taxane such as paclitaxel as an oral bioavailability enhancer. Is to be administered at the same time as the administration of. Therefore, a preferred embodiment of the method of the present invention provides for increased absorption of taxanes into the bloodstream, either simultaneously with or prior to oral administration, or both simultaneously with and prior to oral administration. , Orally administering a potentiator. Pharmaceutical compositions and bioavailability enhancers useful according to this aspect of the invention are as described for the first aspect of the invention.

Generally, the dosage range of the bioavailability enhancer co-administered with a taxane according to the present invention is from about 0.1 mg / kg patient weight to about 20 mg / kg patient weight, preferably about 3 mg / kg. kg patient weight to about 15 mg / kg patient weight, more preferably about 5 mg / kg to about 10 mg / kg. Co-administration of enhancer (Co-adm
"initration)" is substantially the same as the taxane (before 0.5 hours, 0.
Do not administer taxanes after 5 hours or at the same time, administer taxane about 0
． 5 hours to about 72 hours prior to administration, or both, ie, one or more doses of the same enhancer or different enhancers at least 0.
5 hours before, including one dose at substantially the same time (either together or immediately before or after) with the target drug. Further, "co-administration" includes administering two or more doses of taxane within 72 hours after taking the enhancer. That is,
The enhancer need not be re-administered prior to each administration of the taxane or together with each administration of the taxane, but can be administered intermittently during the treatment.

“Effective amount” is used to indicate a known amount of taxane in a pharmaceutical composition of the present invention sufficient to achieve a particular taxane blood level. The dosage range for orally administered taxanes in the compositions of the present invention will depend on a number of factors including the particular taxane, its therapeutic index, the need for the disease being treated, the age and condition of the mammal, the condition being treated. It will vary based on the nature of the disease in question, the condition of the disease, other medications the mammal is taking. The pharmacology and pharmacokinetics of taxanes, especially paclitaxel and docetaxel, are well known. This pharmacological information can be used in connection with the urgency of the mammal being treated to optimize its dosing and treatment regimens. Those skilled in the art will appreciate that the particular dosing regimen and therapeutic regimen of the compositions of the present invention may be finely adjusted to meet the needs of each patient by trial and error while monitoring patient response. For a review of treatments, see Rowinsky, Oncology, 11 (3):
7-19 (1997)).

The exact amount of each taxane contained in the oral dosage form depends on the age of the patient,
Varies depending on weight, disease and condition. For example, a paclitaxel or other taxane dosage form may comprise about 20 mg / m ^{2 to} 200 mg / m ² (based on the mammal / patient body surface area) or about 0.5 mg / kg to 30 mg / kg (mammal / patient). Sufficient amount of the targeting agent can be included to provide a daily dosage (based on patient weight) as a single daily dose or as divided (2 to 3) daily doses. The preferred dosage is long-term (eg, 8-12 hours) after each oral dose.
50 mg / m ^{2 to} 200 mg / m ² or about 2 mg / kg to maintain blood levels of taxane in the range of 50 ng / ml to 500 ng / ml over
It is 6 mg / kg. These levels are achieved with paclitaxel therapy by 96-hour IV infusion, which, unlike oral administration, causes the patient great inconvenience, discomfort, loss of valuable time, and possible infection. Level at least comparable (Wilson et al., J. Clin. Oncol. 12: 1621-1).
629 (1994)). Furthermore, such blood levels of paclitaxel inhibit its oncogenic function by inhibiting the function of oncogenes and by signaling signals that are alleged to play a crucial role in the regulation of cell proliferation. It is more than sufficient to provide the desired pharmacological activity of the targeted drug (eg, inhibition of tubulin degradation and inhibition of protein isoprenylation) that is directly related to the action.

A preferred dosing schedule for administering oral paclitaxel is (a) about 2
^{0mg / m 2 ~1000mg / m 2} ( based on body surface area), preferably about 50
1-3 result in mg / m ² ~200mg / m ² to be administered daily evenly divided doses to a patient in need thereof, continuous for 1 to 4 days in each of the 2 weeks 3 weeks Continue, (b) dosing approximately once a week, and (c) 1
Daily dosing for 2 or 3 weeks with a weekly break. The former schedule is considered by some to be the preferred IV treatment method 2
Equivalent to use of 96 hours paclitaxel infusion every week to 3 weeks.

In a particularly preferred embodiment of the invention, the pharmaceutical composition administered is about 6 by weight.
Contains 0 mg / m ² paclitaxel. In another preferred embodiment, the pharmaceutical composition comprises about 180 mg / m ² paclitaxel by weight.

Two or more different enhancers and / or two or more different taxane targeting agents,
In all of the various aspects of the methods of the present invention, they can be administered together, or alternately, or intermittently.

As discussed above, oral paclitaxel administered alone (eg, in a solid dosage form or even in a liquid vehicle without an oral absorption-promoting carrier) exhibits little bioavailability. . When the composition of the present invention is orally administered one hour after the administration of an effective oral dose of the oral bioavailability enhancer, the amount of taxane absorbed into the bloodstream is the same as that of the same dose. Paclitaxel is the standard intravenous vehicle (eg, CREMOPHOR ™ EL / Ethanol vehicle)
Is at least about 15% of the amount absorbed when administered intravenously. Relative absorption rates are plasma concentration-time curves commonly used in pharmacokinetics to quantify the rate of drug absorption and elimination measured after each AUC (oral / intravenous administration of the drug. Area under) and is determined by standard methodologies in this field, such as by comparing. A large AUC is an indication that the tested drug is more likely to be utilized to reach the target tissue or organ. The novel pharmaceutical composition of the present invention can be administered in any known pharmaceutical dosage form. For example, the composition can be encapsulated in soft or hard gelatin capsules or can be administered in the form of liquid preparations.

The oral administration of taxanes according to the present invention results in IV
In many cases toxic side effects can actually be reduced compared to therapy. I
Blood levels are slower due to absorption of the active agent through the intestinal wall (enhanced by the potentiator) rather than the sudden and sudden increase in blood levels that is typical with V infusion. And will appear at blood level. Maintaining a stable steady state for a long time at such a level within or near the ideal range is
It may be achieved more easily with oral administration than with the inconvenience and risk of infection in an already immunocompromised host.

In a further embodiment of the invention, the oral composition of the invention is adapted to the use of a carrier that is not chemically or physically compatible with the desired ancillary ingredient (eg, flavoring or coloring agent). Can be administered in a two component drug system. In such cases, the taxane can be administered to the patient as the first component of the drug in a solubilizing vehicle, and sweetening, flavoring or coloring agents can be added if desired. After the taxane has been administered, a larger volume of liquid containing at least one of the carrier or carrier / co-dissolving agent system of the present invention is administered (eg, 1 fl oz to 8 fl oz (30 ml to 240 ml)). be able to. By administering a second "chaser" formulation immediately after the taxane is administered, the precipitation of taxane that may occur when entering gastric fluid can be delayed, and when the taxane is mixed with a carrier and administered simultaneously. It has been found that oral absorption can be enhanced to a degree comparable to that observed in.

Illustrative "chaser" formulations that may be used in the two component oral taxane drug include: a) 2% to 20% (by weight) Vitamin E TPGS + the required amount of water; b) 2% to 25% Vitamin E TPGS + 2% to 25% PHARMASOL
VE ™ + required water; and c) 2% -20% Vitamin E TPGS + 2% -25% propylene glycol + required water.

According to yet another aspect of the present invention, the oral composition of the present invention contains not only one or more taxanes but also one or more bioavailability enhancers in a mixed dosage form. To do. For example, such mixed dosage forms include cyclosporine A, D, C,
About 0.1 mg / kg to about 20 mg / kg (based on average patient weight) of one or more of F and G, dihydro CsA, dihydro CsC and acetyl CsA;
About 20 mg / m ² to about 1000 mg / m ² (based on average patient body surface area)
, Preferably about 50 mg / m ² to about 200 mg / m ² of paclitaxel, docetaxel, other taxanes, or paclitaxel or docetaxel derivatives.

The compositions and methods of the present invention provide many advantages over the prior art and intravenous therapy (eg, reduced stability, reduced overall maximal mouthfeel, reduced maximum levels). Toxicity, patient convenience and comfort, ease of administration and reduced cost). Furthermore, the compositions and methods of the present invention greatly reduce the likelihood of a general allergic hypersensitivity reaction upon IV administration, thereby premedication therapy (H-1 blockers and H-2 blockers). + Steroids, etc.) or eliminate such need. The latter is particularly suitable in the treatment of diabetic cancer patients, since it is known that steroids can cause diabetes.

The present invention does not allow taxanes (eg, paclitaxel) at relatively infrequent daily doses (eg, about twice per day) and / or otherwise by the intravenous route. Or provided according to a schedule that cannot be performed. One of the bioavailability enhancers (eg cyclosporin A)
Once-a-day administration is sufficient even when two or more doses of taxane are administered during the day. So, for example, paclitaxel is a safe and effective “window area”.
On a fixed schedule (weekly, biweekly, etc.), or intermittently over a long period of time, that is, every two to four weeks for consecutive days (eg, four days) for the purpose of maintaining levels within It can be administered as a single dose.

The following examples are intended to further illustrate some preferred embodiments of the present invention and are in no way limiting. However, these examples
It is not intended to limit the invention in any way, and only those specific active ingredients, carriers, co-solubilizers, enhancers, dosage ranges, test procedures or other parameters that must be used to practice the invention. Not intended to indicate. Therefore, the use of paclitaxel to collectively exemplify various aspects of taxanes is for purely illustrative purposes and should not be construed as a limitation of the invention.

One skilled in the art can recognize or ascertain numerous equivalents to the particular materials and procedures described herein using no more than routine experimentation. Such equivalents are considered to be within the scope of this invention and are covered by the appended claims.

Example 1 Preparation of Representative Pharmaceutical Compositions Those skilled in the art will readily appreciate that a variety of protocols can be used to prepare representative compositions according to the present invention. The following is included merely to illustrate the ease with which representative compositions according to the present invention may be prepared. A representative formulation according to the present invention having the following components was prepared (hereinafter designated by the name "Formulation 1"):

Ingredients% w / v U / ml Paclitaxel 1.20 12.0 mg Vitamin E TPGS ( ^* ) 40.00 400.00 mg Propylene glycol USP 40.00 400.00 mg Ascorbyl palmitate NF 0.50 5.0 mg dl -Α-tocopherol USP 0.50 5.0 mg Dehydrated alcohol Required amount up to 100 ml Required amount up to 1.0 ml ( ^* ) d-α-tocopheryl polyethylene glycol 1000 Succinate

Paclitaxel (NaPro BioTherapeutics, Inc., B
, Ascorbyl Palmitate NF (Aldrich Ch)
electrical Co. , Milwaukee, WI) and dl-α-tocopherol USP (Roche Vitamins, Nutley, NJ), in the amount defined above, in a container of suitable volume, contained in dehydrated ethanol (F).
lorida Distillers Co. , Lake Alfred, FL
) Was dispersed in at least 2/3 of the total volume (either 1.0 ml or 100 ml). When completely dispersed, the appropriate amount of propylene glycol was added and mixed for at least 30 minutes. Vitamin E TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate, Eastman Chemical, liquefied (by separate heating to about 50 ° C.-60 ° C. or until liquefied).
Co. , Kingsport, TN). Then, the remaining amount of dehydrated alcohol was added and the final formulation was slowly cooled to about 25 ° C to 30 ° C (room temperature). When the solution reached room temperature, the solution was adjusted to final volume with ethanol with constant stirring until a bright yellow clear solution was formed.

Example 2 Stability Analysis As discussed above, one of the advantages of the composition of the present invention is its stability. The following experiment illustrates the stability of the composition according to the invention. A representative composition prepared as described in Example 1 was assayed according to ICH guidelines. 10.2-10 ml using a suitable size Eppendorf pipette
． Add 5 ml of the solution to Po / 28/400 Black Phenolic Cap.
Used with ly Seal Liner in each of 15 cc amber vials. The total weight, empty weight and net weight of each bottle was recorded. The bottle was then placed upright at 40 ° C and 75% humidity. A portion of the bottle was removed and tested according to methodologies well known in the art (
That is, the presence of known degradation products was tested by HPLC after the respective times indicated below (2 weeks and 1-6 months). As shown in Table 2 below, the composition was compared to a negative control formulation based on CREMOPHORE EL ™ (data not shown) for 7-epi-Taxol C, 10-deacetyltaxol or baccatin. It has been found that compounds, such as III, that are considered to be characteristic of paclitaxel degradation are stable as they exhibit minimal levels (expressed as% of total impurities). Furthermore, impurities were less than 3.5% after as long as 6 months of incubation (data not shown).

[0075]

[Table 2]

Example 3 Solubility Analysis To evaluate the solubility of paclitaxel in a representative composition of the present invention, prepared as in Example 1, a final paclitaxel concentration of 12 mg / ml, 15 m
The formulations at g / ml, 25 mg / ml and 50 mg / ml were diluted with water in a ratio of 1 to 11 (1 ml paclitaxel formulation and 10 ml water). afterwards,
The solution was assayed by HPLC analysis. As shown in Figure 1, paclitaxel remained in solution for at least 2 hours in all formulations except the 50 mg / ml formulation (thus showing sufficient solubility over time). Of note, preparations containing 12 mg / ml to 20 mg / ml remained in solution for the entire duration of this study.

Example 4 Pharmacokinetic Analysis The compositions and methods of the present invention are used to achieve target blood levels of taxanes in mammals, including therapeutic blood levels. To exemplify this aspect of the invention, two groups of patients (5 patients in total) were treated with Neopal®.
5 mg / kg (cyclosporin A, Novartis Pharmaceuti
cals, Inc. , Summit, New Jersey) and the like, and 30 minutes later, 60 mg / m ² (n = 2) and 180 mg of a composition prepared as described in Example 1 was administered. / M ² (n = 3) was administered as a single dose of paclitaxel. A series of blood samples were frequently taken over 30 to 48 hours and assayed for paclitaxel. The individual and average pharmacokinetic parameters for paclitaxel are shown in Table 3. These results show that Cmax and AUC after Formulation 1
Is slightly higher than that of the CREMOPHOR EL ™ formulation. With both doses, therapeutic blood levels are achieved,
And when comparing the areas under the plasma concentration versus time curves for the two doses, there was an approximately 2-fold increase in systemic exposure to paclitaxel. The latter suggests that the compositions of the present invention may provide sufficient levels of paclitaxel in plasma by ingesting lower amounts of ethanol than CREMOPHOR EL ™ based formulations.

[0078]

[Table 3]

Table 4 shows CREMOPHOR EL ™ (polyethoxylated castor oil) / E
A comparison of the pharmacokinetic parameters for the formulation based on tOH (n = 9) and the formulation 1 according to the invention (n = 4) is shown.

[0080]

[Table 4]

Example 5 Palatability Test Another property of the composition of the present invention is its control, CREMOPHOR ™ E.
Its mouthfeel when compared to L (polyethoxylated castor oil) / EtOH type blends. Formulations prepared with conventional stabilizers have an unpleasant bitter taste, probably due to castor oil. To this end, a 5 ml volume of Formulation 1 (40% Vitamin E TPGS + 40% Propylene Glycol + 20% Ethanol, see Example 1) and 75% CREMOPHOR ™ EL + 25% Ethanol was placed in 17 glass vials. Included (1 more without formulation)
1 vial was used as a negative control). I as shown in Table 5
international Flavor & Fragrances, Inc. (
Dayton, NJ), Crompton & Knowles (Charlott
e, N.N. C. ) And Virginia Dave (Brooklyn, NY)
Various flavors commercially available from S.A. were added to 16 of these vials as follows: banana (0.5%), cherry (0.2% and 0.5%), grape (0. 5%), grape mascant (0.5%), mint (0.2% and 0.
5%), peppermint (0.2% and 0.5%), herb mint (0.2% and 0.5%), pharma sweet (0.1%), pro sweet (1%), rainbow sherbet ( 0.5%), watermelon (0.5%) and wintergreen oil (0.5%)
). The preparations were given to the tester in a blindfold and tasted and scored as either (-) poor; (+) acceptable / acceptable; (++) good; or (++++) excellent. Numbers were affixed to the caps of two groups of sample vials containing placebo (Formulation 1 with different flavors or 75% Cremophor EL / 25% ethanol). A randomly selected solution was removed from these vials with a dropper. They were tested by two chemists. The results for the numbers were recorded.

As shown in Table 5, Formulation 1 in the various formulations was found to have a better mouthfeel than the corresponding formulations. Moreover, banana-flavored preparations were found to be excellent.

[0083]

[Table 5]

Example 6 Absorption Comparison Assay The purpose of the following experiments is to illustrate the ability of representative compositions and compositions of the present invention to provide absorption values greater than those observed in prior art IV methodologies. there were. For this purpose, groups of 3 male rats each were fasted for 16-18 hours prior to administration of 3H radiolabeled paclitaxel. Animals in each group were given a single oral dose of cyclosporin A (5 mg / kg) before being administered a representative pharmaceutical composition according to the invention containing paclitaxel. One hour after the administration of cyclosporine, each group was orally administered about 9 mg / kg of paclitaxel with the composition according to the present invention. Each group received a different oral formulation. Blood samples showed 1 hour after administration of paclitaxel, 1
They were collected from each animal after hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours. Blood samples were burned and assayed for total radioactivity. The total radioactivity level of blood, which corresponds to the blood level of 3H-paclitaxel, was plotted graphically against the time after administration. The data for each group of rats was summarized in the form of mean AUC, C _max and T _max . The absorption rate of 3H-paclitaxel for animals in each group was calculated by CREMOPHOR ™.
PAXENE ™ (Baker N) with EL, ethanol and citric acid
orton Pharmaceuticals, Miami, FL) 3
It was calculated by comparing the mean AUC value of the group to the corresponding mean AUC of the reference group of rats intravenously administered H-paclitaxel (9 mg / kg). Some carrier and carrier / co-dissolvant combinations formulated according to the present invention in oral compositions containing paclitaxel, as shown in Table 6, have an absorption rate greater than 15% greater than paclitaxel by IV. Was found to result in experimental animals (data not shown).

[0085]

[Table 6]

Example 7 Evaluation of Carriers The experiments described below demonstrate that a typical oral formulation was formulated with various ingredients as carriers that when administered orally gave greater absorption rates than their respective IV counterparts. 3 illustrates the ability of the composition.

Polyoxyethylated (POE) Sorbitan Fatty Acid Esters as Carriers Table 7 lists formulations containing several POE sorbitan fatty acid esters as carriers for oral paclitaxel, alone or in combination with co-dissolving agents. It In formulations where more than one component is present, the weight ratio of each of the components is indicated. Each of these formulations was tested in the animal model described above and was found to have paclitaxel absorption rates of greater than 15% when administered orally. The table shows the total dose of paclitaxel incorporated into each vehicle actually administered to the experimental animals, the concentration of paclitaxel in the composition, the HLB value of the carrier, the average AUC for the group of rats given the formulation.
Values and rates of paclitaxel absorption are shown relative to IV treated rats.

[0088]

[Table 7]

POE Alkyl Ethers as Carriers Table 8 summarizes the data for formulations containing POE alkyl ethers as carriers. The data correspond to the data listed in the table above.

[0090]

[Table 8]

POE Stearate as Carrier Table 9 summarizes the data for formulations containing POE stearate as a carrier. The data correspond to the data described in Example 7.

[0092]

[Table 9]

Ethoxylated Modified Triglycerides as Carriers Table 10 summarizes data for formulations containing ethoxylated modified triglycerides as carriers. The data shown corresponds to the data described in Example 7.

[0094]

[Table 10]

POE660 Hydroxystearate as Carrier Table 11 summarizes the data for formulations containing POE660 hydroxystearate as a carrier. The data shown corresponds to the data described in Example 7.

[0096]

[Table 11]

Saturated Polyglycolized Glycerides as Carriers Table 12 summarizes the data for formulations containing saturated polyglycolized glycerides as carriers. The data shown corresponds to the data described in Example 7.

[0098]

[Table 12]

Vitamin E TPGS System as Carrier Table 13 summarizes data for formulations containing the Vitamin E TPGS system as a carrier. The data shown corresponds to the data described in Example 7.

[0100]

[Table 13]

POE Castor Oil Derivatives and Hardened Castor Oil Derivatives as Carriers Table 14 summarizes data for formulations containing POE castor oil derivatives and hardened castor oil derivatives as carriers. The data shown corresponds to the data described in Example 7.

[0102]

[Table 14]

Polysorbate 80 Carrier Table 15 summarizes the data for formulations containing Polysorbate 80 as at least one of the carriers. The data shown corresponds to the data described in Example 7.

[0104]

[Table 15]

It has thus been shown that compositions and methods are provided which are well adapted to fulfill the various objects of the invention and to meet the requirements of practical use. Since various possible embodiments can be made from the above invention, and various changes can be made to the embodiments shown above, all matter set forth herein is to be construed as exemplary. It should be understood that it should be and should not be interpreted in a limiting sense.

As used herein, the term “about” means that the numbers and ranges disclosed herein are not fixed and that they are not included in the range or are one value. Shall indicate that the desired results are achieved by carrying out the invention using different temperatures, concentrations, amounts, etc. The term typically includes a deviation of ± 10% of any varying value.

INDUSTRIAL APPLICABILITY The present invention is useful in clinical medicine, particularly in the treatment of malignant and non-malignant diseases.

[Brief description of drawings]

FIG. 1 is a graph showing the ability of a composition of the present invention to remain in solution in a reciprocal shaking water bath for a period of 2 hours or more (12 mg / ml paclitaxel).
(●), 15 mg / ml (▽), 20 mg / ml (■), 25 mg / ml (○)
And 50 mg / ml (▼), PG / TPGS / ETOH and ascorbyl palmitate (40:40:20)).

Figure 2: Nine patients (●) orally administered a Cremophor EL-based formulation and the composition of the invention (PG / TPGS / ETOH and ascorbyl palmitate (40:40:20)). 2 is a graph showing the average plasma concentration of paclitaxel derived from the two patients (O) who were treated.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 35/00 A61P 35/00 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, G M, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ) , MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, C R, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP , KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Smith, Gregory, A .. 33168 Northwest, Florida, USA Northwest Third Avenue 14025 (72) Inventor Goocha Reis-Rocca, Jose, Si. United States, Florida 33172, Ma Iami, Northwest Satisekan de Street 9816 F-term (reference) 4C076 AA13 BB01 CC27 DD37E DD38E DD46 DD46E DD47E DD59 DD59F DD59Q DD60E EE23 EE23E EE39 EE53 EE53E FF04 FF12 FF15 FF36 FF52 FF53 FF70 4C086 AA01 AA02 BA02 MA03 MA05 MA17 MA52 NA10 ZB26

Claims (23)

[Claims] 1. A composition comprising a taxane, a carrier, a co-solubilizer and a stabilizer in a form suitable for oral administration to mammals. 2. The composition of claim 1, wherein the taxane is paclitaxel or docetaxel. 3. The composition of claim 1, wherein the taxane is present at a concentration of about 2 mg / ml to about 100 mg / ml. 4. The composition of claim 3, wherein the taxane concentration is from about 10 mg / ml to about 50 mg / ml. 5. The carrier is vitamin E TPGS, saturated polyglycolized glyceride, modified castor oil, polyoxyethylated stearate ester, polyoxyethylated sorbitan ester, polyoxyethylated fatty ether, modified almond oil glyceride and The composition of claim 1 selected from the group consisting of corn oil glyceride, sorbitan diisostearate ester, polyoxyethylated hydroxystearate, and cyclodextrin. 6. The composition of claim 1, wherein the carrier is Vitamin E TPGS. 7. The co-dissolving agent is N-methyl-2-pyrrolidone, glycerol ester or propylene glycol ester of caprylic acid and capric acid, polyoxyethylated hydroxystearate, polyoxyethylated sorbitan ester, caprylic acid and The composition according to claim 1, which is selected from the group consisting of polyethylene glycol ester of capric acid, modified castor oil, vegetable oil, saturated polyglycolized glyceride, citric acid ester, propylene glycol, ethanol, water, and low molecular weight polyethylene glycol. object. 8. The composition of claim 1, wherein the co-dissolving agent is ethanol. 9. The co-dissolving agent comprises propylene glycol and ethanol.
The composition of claim 1. 10. The composition of claim 10, wherein the ethanol is dehydrated. 11. The composition of claim 1, further comprising a surfactant. 12. The composition according to claim 11, wherein the surfactant is dl-α-tocopherol or β-carotene. 13. A weight ratio of about 2 mg / g (0.2%) to about 10 mg / g (1.0
%) Of the dl- [alpha] -tocopherol. 14. The composition of claim 1, wherein the stabilizing agent is ascorbyl palmitate. 15. The composition of claim 1, wherein the stabilizing agent is dl-α-tocopherol. 16. The composition according to claim 1, wherein the stabilizer is a radical inhibitor. 17. The composition according to claim 1, further comprising pharmaceutical excipients, diluents, sweeteners, flavoring agents and / or coloring agents. 18. The composition of claim 1, further comprising a bioavailability enhancer. 19. The composition of claim 18, wherein the bioavailability enhancer is one of cyclosporine. 20. The pharmaceutical composition according to claim 1, comprising paclitaxel, vitamin E TPGS, propylene glycol, ethanol and ascorbyl palmitate. 21. The ethanol is dehydrated ethanol and the composition is dl-
21. The composition of claim 20, further comprising alpha-tocopherol. 22. A method of achieving a target blood level of taxane in a mammal comprising orally administering to said mammal a pharmaceutical composition comprising a taxane, a carrier, a co-solubilizer and a stabilizer. . 23. A method of treating a mammalian patient suffering from a taxane responsive disease, the method comprising orally administering to said mammal a pharmaceutical composition comprising a taxane, a carrier, a co-solubilizer and a stabilizer. How to include.