CA2426956C - Pharmaceutical compositions comprising ascomycin derivatives - Google Patents

Pharmaceutical compositions comprising ascomycin derivatives Download PDF

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Publication number
CA2426956C
CA2426956C CA002426956A CA2426956A CA2426956C CA 2426956 C CA2426956 C CA 2426956C CA 002426956 A CA002426956 A CA 002426956A CA 2426956 A CA2426956 A CA 2426956A CA 2426956 C CA2426956 C CA 2426956C
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composition
ascomycin
weight
desoxy
epi
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CA2426956A1 (en
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Patrice Guitard
Barbara Haeberlin
Rainer Link
Friedrich Richter
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Novartis AG
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Novartis AG
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Priority claimed from GBGB9514397.0A external-priority patent/GB9514397D0/en
Priority claimed from GBGB9515025.6A external-priority patent/GB9515025D0/en
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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Abstract

A pharmaceutical composition for oral administration in the form of a solid dispersion comprising an ascomycin or a derivative thereof and a carrier medium.

Description

. 1 Pharmaceutical Compositions Comprising Ascomycin Derivatives This application has been divided out of Canadian Patent Application Serial No. 2,225,960, Canadian national phase of PCT/EP96/03066 filed July 16, 1996 and published as WO 97/03654 on February 6, 1997.

This invention relates to oral pharmaceutical compositions comprising a macrolide, e.g. a rapamycin or an ascomycin, in a solid dispersion.

Rapamycin is an immunosuppressive lactam macrolide produceable, for example by Streptomyces hX roscopicus. The structure of rapamycin is given in Kesseler, H., et al.; 1993;
Helv. Chim. Acta; 76: 117. Rapamycin is an extremely potent immunosuppressant and has also been shown to have antitumor and antifungal activity. Its utility as a pharmaceutical, however, is restricted by its very low and variable bioavailability. Moreover, rapamycin is highly insoluble in aqueous media, e.g. water, making it difficult to formulate stable galenic compositions. Numerous derivatives of rapamycin are known. Certain 16-0-substituted rapamycins are disclosed in WO 94/02136. 40-0-substituted rapamycins are described in, e.g., US 5 258 389 and WO 94/09010 (0-aryl and 0-alkyl rapamycins); WO 92/05179 (carboxylic acid esters), US 5 118 677 (amide esters), US 5 118 678 (carbamates), US 5 100 883 (fluorinated esters), US 5 151 413 (acetals), US 5 120 842 (silyl ethers), WO 93/11130 (methylene rapamycin and derivatives), WO 94/02136 (methoxy derivatives), WO 94/02385 and WO 95/14023 (alkenyl derivatives). 32-0-dihydro or substituted rapamycin are described, e.g., in US
5 256 790.

Further rapamycin derivatives are described in WO 96/41807, for example 32-deoxorapamycin as described in Example 1, and 16-pent-2-ynyloxy-32(S)-dihydrorapamycin as described in Examples 2 and 3.

3 0 Rapamycin and its structurally similar analogues and derivatives are termed collectively herein as "rapamycins".
EP 240 773 discloses a solid dispersion composition comprising FR-900506 substance and a water-soluble polymer.

On oral administration to humans, solid rapamycins, e.g. rapamycin, may not be absorbed to any significant extent into the bloodstream. Simple mixtures are known for rapamycins, e.g.
rapamycin, with conventional pharmaceutical excipients; however, disadvantages encountered with these compositions include unpredictable dissolution rates, irregular bioavailability profiles, and instability. To date there is no conveniently administrable oral solid formulation available for rapamycin or a derivative thereof.

The parent application provides a pharmaceutical composition in the form of a solid dispersion comprising a rapamycin and a carrier medium.

The present invention provides a pharmaceutical composition for oral administration in the form of a solid dispersion comprising 33-epi-chloro-33-desoxy-ascomycin and a carrier medium wherein the carrier medium comprises a water-soluble polymer or a cyclodextrin, and a surfa.ctant.

The compositions of this invention provide a high bioavailability of drug substance, are 2 0 convenient to administer, and are stable.

The rapamycin used in the compositions of this invention may be any rapamycin or derivative thereof, for example as disclosed above or in the above-mentioned patent applications.

Thus the rapamycin used in the solid dispersion compositions of this invention may be rapamycin or an 0-substituted derivative in which the hydroxyl group on the cyclohexyl ring of rapamycin is replaced by -OR, in which R, is hydroxyalkyl, hydroxyalkoxyalkyl, acylaminoalkyl and aminoalkyl; e.g. as described in WO94/09010, for example 40-0-(2-hydroxy)ethyl-rapamycin, 40-0-(3-hydroxy)propyl-rapamycin, 40=0-[2-(2-hydroxy)ethoxy) 3 0 ethyl-rapamycin and 40-0-(2-acetaminoethyl)-rapamycin. The rapamycin derivative may be a 26- or 28-substituted derivative.

-2a-Preferred rapamycins for use in the solid dispersion compositions of this invention include rapamycin, 40-0-(2-hydroxy)ethyl rapamycin, 32-deoxorapamycin and 16-pent-2-ynyloxy-32(S)-dihydrorapamycin. A more preferred rapamycin is 40-0-(2-hydroxy)ethyl rapamycin (hereinafter refen-ed to as compound X).

Numbering of rapamycin derivatives as used herein refers to the structure disclosed as Formula A at page 4 of published PCT application WO 96/13273.

The term solid dispersion as used herein is understood to mean a co-precipitate of the rapamycin, e.g. 40-0-(2-hydroxy)ethyl rapamycin or rapamycin, with the carrier medium. In the solid dispersion, the rapamycin is in amorphous or substantially amorphous form and is physically bound to the carrier medium.

Compositions of this invention may be administered in any convenient form, for example tablet, capsule, granule or powder form, e.g. in a sachet.

The rapamycin may be present in the composition in an amount of about 0.01 to about 30-weight-% based on the weight of the composition (% w/w), and preferably in an amount of I
to 20 % w/w based on the total weight of the composition.

The carrier medium is present in an amount of up to 99.99% by weight, for example 10 to 95 wt-%, based on the total weight of the composition.

In one embodiment the carrier medium comprises a water-soluble polymer, preferably a cellulose derivative such as hydroxypropylmethylcellulose (HPMC), hydroxy propyl-methylcellulose phthalate, or polyvinylpyrrrolidone (PVP). Good results may be obtained using HPMC with a low apparent dynamic viscosity, e.g. below 100 cps as measured at 20 C
for a 2 % by weight aqueous solution, e.g below 50 cps, preferably below 20 cps, for example HPMC 3 cps. HPMC is well-known and described, iFor example, in the Handbook of Pharmaceutical Excipients, Second Edition, pub. Pharmaceutical Society of Great Britain and Anierican Pharmaceutical Association, 1994, p. 229 to 232. HPMC, including HPMC 3cps, is available comrnercially under the trade mark Pharmacoat 603 from the Shinetsu Company.

3 0 PV-p is available, for example, under the name PovidoneTM (Handbook of Pharmaceutical Excipients), and a PVP having an average molecular weight between about 8,000 and about 50,000 Daltons is preferred.

In another embodiment the carrier medium comprises - hydroxypropylcellulose (HPC) or a derivative thereof. Examples of HPC
derivatives include those having low dynamic viscosity in aqueous media, e.g. water, e.g below about 400 cps, e.g below 150 cps as measured in a 2% aqueous solution at 25 C. Preferred HPC
derivatives have a low degree of substitution, and an average molecular weight below about 200,000 Daltons, e.g. between 50,000 and 150,000 Daltons. Examples of HPC
available TM
commercially include Klucel LF, Klucel EF and Klucel JF from the Aqualon Company; and TM
Nisso HPC-L available from Nippon Soda Ltd;

a polyethylene glycol (PEG). Examples include PEGs having an average molecular weight between 1000 and 9000 Daltons, e.g. between about 1800 and 7000, for example PEG
2000, PEG 4000 or PEG 6000 (Handbook of Pharmaceutical Excipients);

- a saturated polyglycolised glyceride, available for example under the trade mark Gelucir, e.g. Gelucir 44/14, 53/10, 50/13, 42/12, or 35/10 from the Gattefosse company; or 2 0 - a cyclodextrin, for example aP-cyclodextrin or an a-cyclodextrin.
Examples of suitable P-cyclodextrins include methyl-p-cyclodextrin; dimethyl-p-cyclodextrin;
hydroxypropyl-p-cyclodextrin; glycosyl-p-cyclodextrin; maltosyl-p-cyclodextrin; sulfo-(3-cyclodextrin; sulfo-alkylethers of 0-cyclodextrin, e.g. sulfo-C,-,-alkyl ethers. Examples of oc-cyclodextrins include glucosyl-a-cyclodextrin and maltosyl--a-cyclodextrin.

The carrier medium may further comprise a water-soluble or water-insoluble saccharose or other acceptable carrier or filler such as lactose, or microcrystalline cellulose. The filler, if present, is generally in an amount of up to about 30% by weight, e.g. 0.5 to 20 wt-%, preferably, from about 5 to about 15% by weight of the composition.
Microcrystalline 3 0 cellulose is available commercially under the trade mark Avicel, for example from FMC
Corporation.
The carrier medium may further comprise one or more surfactants, for example a non-ionic, ionic, anionic or amphoteric surfactant. Examples of suitable surfactants include polyoxyethylene-polyoxypropylene co-polymers and block co-polymers known, for example, under the trade marks Pluronic or Poloxamer, e.g. as described in Fiedler, H. P.
"Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete", Editio Cantor, D-7960 Aulendorf, 3' revised and expanded edition (1989). A preferred polyoxyetliylene-TM
polyoxypropylene block polymer is Poloxamer 188 available from the BASF
Company;
- ethoxylated cholesterins known, for example, under the trade mark Solulan, for example Solulan C24 commercially available from the Amerchol Company;

- vitamin derivatives, e.g. vitamin E derivatives such as tocopherol polyethylene glycol succinate (TPGS) available from the Eastman Company;

- sodium dodecylsulfate or sodium laurylsulfate;

a bile acid or salt thereof, for example cholic acid, glycolic acid or a salt, e.g. sodium 2 0 cholate; or lecithin.
If present in the compositions of this invention, the surfactant(s) is generally in an amount of up to about 20%, for example 1 to 15% by weight.

One or more disintegrants may be included in the compositions of this invention. Examples of TM
disintegrants include Polyplasdone (Handbook of Pharmaceutical Excipients) available commercially from the ISPCompany; sodium starch glycolate available commercially from the 3 0 Generichem Company; and crosscarmelose sodium available under the trade mark Ac-di-sol from FMC Corporation. One or more lubricants, for example magnesium stearate or colloidal _6-silicon dioxide, may further be included in the composition of this invention in an amount of up to about 5 weight %, e.g. 0.5 to 2wt-%, based on the weight of the composition.

It may be advantageous to include one or more flavouring agents in the compositions of this invention.

The present applicants have obtained good results using surfactant-free rapamycin compositions. In another aspect, therefore, this invention provides a surfactant-free solid dispersion composition comprising a rapamycin as described herein.

Antioxidants and/or stabilisers may be included in the compositions of this invention in an amount of up to about 1% by weight, for example between 0.05 and 0.5 % by weight.
Examples of antioxidants include butylated hydroxytoluene, DL-a-tocopherol, propyl gallate, ascobyl palmitate and fumaric acid. Malonic acid is an appropriate stabiliser.

In one embodiment of this invention, the composition comprises up to 30% by weight, e.g. I
to 20 wt-%, 40-0-(2-hydroxy)ethyl rapamycin, and up to 95 %, e.g. 30 to 90%, HPMC by weight.

2 0 The weight ratio of the rapamycin to carrier medium in the compositions of this invention is generally no more than 1:3, preferably less than 1:4.

In another aspect, this invention provides a process for preparing a solid dispersion composition as described herein.

In one embodiment the compositions of this invention may be obtained by dissolving or suspending the rapamycin and carrier medium in a solvent or solvent mixture.
The solvent may be a single solvent or mixture of solvents, and the order of dissolution and suspension of the rapamycin with the carrier medium in the solvent may be varied. Solvents suitable for use in 3 0 preparing solid dispersion compositions of this invention may be organic solvents such as an alcohol, for example methanol, ethanol, or isopropanol; an ester, e.g.
ethylacetate; an ether, e.g. diethyl ether; a ketone, e.g. acetone; or a halogenated hydrocarbon, e.g.
dichloroethane.
A convenient solvent mixture is an ethanol/acetone mixture having a weight ratio of ethanol to acetone of between about 1:10 to about 10:1, for example 1:5 to 5:1.

Typically the rapamycin and carrier medium are present in a ratio by weight with the solvent of 1:0.1 to 1:20. The solvent may be evaporated and the rapamycin co-precipitated with carrier medium. The resulting residue may be dried, for example under reduced pressure, sieved and milled. The milled dispersion may be combined with other excipients and, for example, compressed as a tablet, or filled into sachets or gelatin capsules.

In another embodiment, the solid dispersion compositions may be prepared by melting the carrier medium to form a melt, and combining the melt with the rapamycin, e.g.
by stirring, optionally in the presence of a solvent or solvent mixture as described herein.

Alternatively the solid dispersions of this invention may be prepared by spray drying techniques as described, for example, in Theory and Practice of Industrial Pharmacy, Lachrriann et al., 1986. A suspension as formed above is dispersed through a nozzle into a chamber maintained at, for example, 20 to 80 C. The solvent is evaporated on passing through the nozzle, and finely dispersed particles are collected.

The compositions of this invention, after milling, typically have a mean particle size of less than about 0.5mm, for example less than about 350 }am, e.g. about 100 to about 300 rn.

The oral compositions of this invention are useful for the known indications of the rapamycin, e.g. the following conditions:

a) Treatment and prevention of organ or tissue allo- or xeno=-transplant rejection, e.g. for the treatment of recipients of e.g. heart, lung, combined heart-lung, liver, kidney, pancreatic, skin or comeal transplants. They are also indicated for the prevention of graft-versus-host disease, such as following bone marrow transplantation.

3 0 b) Treatment and prevention of autoimmune disease and of inflammatory conditions, in particular inflammatory conditions with an etiology including an autoimmune component such as arthritis (for example rheumatoid arthritis, arthritis chronica progrediente and arthritis deformans) and rheumatic diseases. Specific autoimmune diseases for which the compounds of the invention may be employed include, autoimmune hematological disorders (including e.g. hemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia), systemic lupus erythematosus, polychondritis, scierodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (including e.g. ulcerative colitis and Crohn's disease) endocrine ophthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primary billiary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minimal change nephropathy) and juvenile dermatomyositis.
c) Treatment and prevention of asthma.

d) Treatment of multi-drug resistance (MDR). MDR is particularly problematic in cancer patients and AIDS patients who will not respond to conventional chemotherapy because the medication is pumped out of the cells by Pgp. The compositions are therefore useful for enhancing the efficacy of other chemotherapeutic agents in the treatment and control of multidrug resistant conditions such as multidrug resistant cancer or multidrug resistant AIDS.

e) Treatment of proliferative disorders, e.g. tumors, hyperproliferative skin disorder and the like.

f) Treatment of fungal infections.

g) Treatment and prevention of inflammation, especially in potentiating the action of steroids.

h) Treatment and prevention of infection, especially infection by pathogens having Mip or Mip-like factors.
TM
i) Treatment of overdoses of FK-506 and other macrophilin binding immunosuppressants.

3 0 Where the pharmaceutical composition of this invention is in unit dosage form, e.g. as a tablet, capsule, granules or powder, each unit dosage will suitably contain between 1mg and 100 mg of the drug substance, more preferably between 10 and 50 mg; for example 15, 20, 25, or 50 mg. Such unit dosage forms are suitable for administration I to 5 times daily depending upon the particular purpose of therapy, the phase of therapy and the like.

The exact amount of the compositions to be administered depends on several factors, for example the desired duration of treatment and the rate of release of the rapamycin.

The utility of the pharmaceutical compositions can be observed in standard clinical tests in, for example, known indications of active agent dosages giving equivalent blood levels of active agent; for example using dosages in the range of I mg to 1000 mg, e.g. 5mg to 100mg, of active agent per day for a 75 kilogram adult and in standard animal models.
The increased bioavailability of the drug substance provided by the compositions can be observed in standard animal tests and in clinical trials.

The dosage form used, e.g. a tablet, may be coated, for example using an enteric coating.
Suitable coatings may comprise cellulose acetate phthalate;
hydroxypropylmethylcellulose TM
phthalate; a polymethyacrylic acid copolymer, e.g. Eudragit L, S; or hydroxypropylmethyl cellulose succinate.

The rapamycin used in the compositions of this invention, e.g. 40-0-(2-hydroxy)ethyl rapamycin or rapamycin, may be in crystalline or amorphous form prior to formation of the solid dispersion. An advantage, therefore, of this invention is that the rapamycin need not be crystalline. Thus the rapamycin may be used directly in combination, for example with a solvent, and does not have to be isolated in advance. Another advantage of the invention is that dissolution rates of the solid dispersion are higher than dissolution rates found for a crystalline rapamycin or an amorphous rapamycin in a simple mixture.

This invention provides a pharmaceutical composition for oral administration in the form of a solid dispersion comprising 33-epi-chloro-33-desoxy-ascomycin and a carrier medium.
Examples of suitable ascomycins for use in the solid dispersion compositions of this invention include ascomycin or a derivative thereof, e.g. 33-epi-chloro-33-desoxy-ascomycin.

To date there is no conveniently administrable oral solid formulation available for 33-epi-chloro-33-desoxy-ascomycin. In another aspect, therefore, this invention provides a pharmaceutical composition in the form of a solid dispersion comprising 33-epi-chloro-33-desoxy-ascomycin and a carrier medium.

The compound 33-epi-chloro-33-desoxy-ascomycin is described in published European application EP 427 680 under Example 66a.

33-epi-chloro-33-desoxy-ascomycin will be referred to hereinafter as Compound Y.

The ascomycin, e.g. compound Y, compositions of this invention provide a high bioavailability of drug substance, are convenient to administer, and are stable.

The ascomycin, e.g. compound Y, may be present in the composition in an amount of about 0.01 to about 30% w/w, and preferably in an amount of 1 to 20 % w/w.

The carrier medium may comprise any of the aforementioned components in amounts by wt-%
2 0 as described above. Suitable water-soluble polymers, cyclodextrins and other excipients, e.g.
surfactants, for use in the 33-epi-chloro-33-desoxy-ascomycin compositions of this invention are as described above.

In a preferred aspect, this invention provides a surfactant-containing composition comprising 2 5 an ascomycin, e.g. compound Y, in the form of a solid dispersion as described herein.

The weight ratio of the ascomycin, e.g. compound Y, to carrier medium is generally no more than 1:3, preferably less than 1:4.

3 0 The ascomycin, e.g. compound Y, solid dispersion compositions may be prepared in analogous manner to the processes described above.

The oral compositions of compound Y disclosed herein are useful, for example, in the treatment of inflammatory and hyperproliferative skin diseases and of cutaneous manifestations of inununologically-mediated diseases. More specifically, the compositions of this invention are useful as antiinflammatory and as immunosuppressant and antiproliferative agents for use in the prevention and treatment of inflammatory conditions and of conditions requiring immunosuppression, such as a) the prevention and treatment of - rejection of organ or tissue transplantation, e.g. of heart, kidney, liver, bone marrow and skin, - graft-versus-host disease, such as following bone marrow grafts, - autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroidis, multiple sclerosis, Myasthenia gravis, diabetes type I
and uveitis, - cutaneous manifestations of immunologically-mediated illnesses;

b) the treatment of inflammatory and hyperproliferative skin diseases, such as psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrhoeic dermatitis, Lichen planus, Pemphigus, bullous Pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus 2 0 erythematosus and acne; and c) Alopecia areata.

Where the pharmaceutical composition of this invention is in unit dosage form, e.g. as a tablet, capsule or powder, each unit dosage will suitably contain between 1 mg and 100 mg of the drug substance, more preferably between 10 and 50 mg; for example 15, 20, 25, or 50 mg. Such unit dosage forms are suitable for administration 1 to 5 times daily depending upon the particular purpose of therapy, the phase of therapy and the like.

In one embodiment of this invention, the composition comprises 30% by weight compound Y
3 0 and 70 % by weight HPMC in a dosage of e.g. 10 to 50mg per day for use in, e.g. psoriasis, atopical dermatitis or contact dermatitis.

The exact amount of the compositions to be administered depends on several factors, for example the desired duration of treatment and the rate of reflease of compound Y.

The utility of the pharmaceutical compositions containing compound Y can be observed in standard clinical tests in, for example, known indications of active agent dosages giving equivalent blood levels of active agent; for example using dosages in the range of 1 mg to 1000 mg of active agent per day for a 75 kilogram adult and in standard animal models. The increased bioavailability of the drug substance provided by the compositions can be observed in standard animal tests and in clinical trials.

Following is a description by way of example only of solid dispersion compositions of this invention.

Example I
A solid dispersion composition is prepared containing the following ingredients (in parts by weight):
Compound X 9.1 HPMC 3 cps 81.8 2 0 Lactose 200 mesh 9.1 The composition (Form A) is prepared by dissolving the rapamycin and carrier medium in an ethanol/acetone mixture. Absolute ethanol is used in a 1:1 ratio by weight with the acetone.
The solvents are then evaporated, and the resulting dry residue milled to a fine powder with mean particle size < 0.5 mm.

Example 2 A solid dispersion composition is prepared containing the following ingredients (in parts by weight):
Compound X 16.7 3 0 HPMC 3 cps 66.7 Poloxamer 188 (from BASF) 16.7 The composition (Form B) is prepared in analogous manner to that in Example 1.
Example 3 A solid dispersion composition is prepared containing the following ingredients (in parts by weight):

Compound X 16.7 HPMC 3 cps 66.7 TPGS* 16.7 The composition (Form C) is prepared in analogous manner to that in Example 1.
* tocopherol polyethylene glycol succinate Example 4 A solid dispersion composition is prepared containing the following ingredients (in parts by weight):
Compound X 10 HPMC 3 cps 80 Solulan C24 (from Amerchol) 10 The composition (Form D) is prepared in analogous manner to that in Example 1.

2 0 The above compositions Forms A to D may be formed into tablets, filled into capsules, or powdered and packaged in sachets.

Pharmacokinetics after administration of 40-0-(2-hydroxy)ethyl rapamycin to rats a) Drug administration 0.5 ml aqueous dispersions of the Compound X compositions (corresponding to 4.0 mg active ingredientlrat) were administered by gastric intubation during a short inhalation anaesthesia with a I mi syringe, attached to a polyethylene tube. Six animals were used for each composition Forms A, B, C and D.

3 0 b) Blood sampling The animals received a permanent cannula into a vena jugularis one day prior to this experiment. 0.5 ml venous blood (vena jugularis) was collected from each rat and stored in 2.5 mi EDTA tubes. The blood samples of 2 animals (1 and 2, 3 and 4, 5 and 6) were pooled and stored at -80 C until drug analysis. Samples were taken before administration and 10 minutes (m), 30m, 60m, 120m, 300m, 480m and 1440m after drug administration.

c) Bioanalytics The blood samples were analysed using reversed phase HPLC.

Table I shows the pharmacokinetic data collected after adrr.iinistration of Compound X to rats.
Table 1 Summary Profiles (averages of 2-3 pools) blood concentration (ng/ml) time (h) Form A Form B Form C Form D

0.17 118 117 85 68 0.5 422 131 125 74 Cmax (ng/ml) 573 135 131 81 Tmax (hr) 5.00 0.50 0.50 0.50 AUC 0-8h 3502 720 565 376 [(ng/ml).h]

AUC 0-24h 8213 1487 1192 886 [(ng/ml).h]

Form A resulted in blood levels higher than those after administration of surfactant-containing compositions.

Dog Study Following the above promising results, a relative bioavailability study was performed in fasted beagle dogs using a dose of 1 mg/kg body weight. Hard gelatin capsules each containing 10mg compound X were administered to 8 dogs in a 4-way latin square design; the dogs were fed 6 hours post administration of the capsules, and blood levels of compound X were determined over 48 hours. Similar blood concentration profiles of compound X were observed for all the dogs, with a terminal halflife of compound X in blood between 10 and 40 hours.
Median peak levels of 140 ng/ml and median AUC levels of 0-48 hr ca. 1600 ng.h/ml were observed.

Example 5 A solid dispersion composition is prepared containing the following ingredients (in parts by weight):
Compound Y 20 HPMC 3 cps 80 The composition (Form E) is prepared by dissolving compound Y and carrier medium in an ethanol/acetone mixture. The solvents are then evaporated, and the resulting dry residue milled.
Example 6 A solid dispersion composition is prepared containing the following ingredients (in parts by weight):

2 0 Compound Y 20 HPMC 3 cps 70 Poloxamer 188 10 The composition (Form F) is prepared in analogous manner to that in Example 5.
Example 7 2 5 A solid dispersion composition is prepared containing the f'ollowing ingredients (in parts by weight):

Compound Y 20 HPMC 3 cps 75 Sodium laurylsulfate 5 3 0 The composition (Form G) is prepared in analogous manner to that in Example 5.

The above compositions Forms E to G may be formed into tablets, filled into capsules, or powdered and packaged in sachets.

Pharmacokinetics after administration of 33-epi-chloro-33-desoxy-ascomycin to rats a) Drug administration 0.5 ml aqueous dispersions of the drug compositions (corresponding to 4.0 mg active ingredientlrat) were administered by gastric intubation during a short inhalation anaesthesia with a 1 ml syringe, attached to a polyethylene tube. Six animals were used for each composition Forms E, F, and G.

b) Blood sampling The animals received a permanent cannula into a vena jugularis one day prior to this experiment. 0.5 ml venous blood (venajugularis) was collected from each rat and stored in 2.5 n-d EDTA tubes. The blood samples of 2 animals (1 and 2, 3 and 4, 5 and 6) were pooled and stored at -80 C until drug analysis. Samples were taken before administration and 10 minutes (m), 30m, 60m, 120m, 300m, 480m and 1440m after drug administration.
c) Bioanalytics The blood samples were analysed using reversed phase HPLC.

The results are plotted in Figures 1 and 2, in which ng/ml (vertical axis) is plotted against time in hours (horizontal axis). Figure 1 shows that Form F resulted in blood levels substantially 2 0 higher than blood levels observed after administration of Form E or Form G. Figure 2 shows that Form F resulted in high blood levels when administered with food.

Compound Y is in amorphous form in the compositions E, F and G on formation and after 6 months storage as determined by X-ray diffraction.

Forms E, F and G are tested for respective dissolution rates. On stirring in a solution of 0.2 wt% sodium dodecylsulfate in water at 37 C, it is found that over 80%
available compound Y
is released and dissolved from each milled composition containing 10mg compound Y after 30 minutes. 92% available compound Y is released from Form E. This compares with 3 0 approximately 5% release after 30 minutes from an equivalent amount of crystalline compound Y.

Claims (24)

Claims
1. A pharmaceutical composition for oral administration in the form of a solid dispersion comprising 33-epi-chloro-33-desoxy-ascomycin and a carrier medium, wherein the carrier medium comprises a water-soluble polymer or a cyclodextrin, and a surfactant.
2. A composition as claimed in claim 1, wherein the water-soluble polymer is hydroxypropylmethylcellulose.
3. A composition as claimed in claim 1 or 2, wherein the water-soluble polymer is hydroxypropylmethylcellulose in an amount of up to about 95% by weight, based on the total weight of the composition.
4. A composition as claimed in claim 1, wherein the water-soluble polymer is polyvinylpyrrolidone.
5. A composition as claimed in any one of claims 1 to 4, wherein the composition comprises 1 to 20% by weight of 33-epi-chloro-33-desoxy-ascomycin, based on the total weight of the composition.
6. A composition as claimed in any one of claims 1 to 5, wherein the surfactant is a polyoxyethylene-polyoxypropylene co-polymer.
7. A composition as claimed in any one of claims 1 to 5, wherein the surfactant is sodium lauryl sulfate.
8. A composition as claimed in any one of claims 1 to 3, wherein the composition comprises up to 20% by weight of surfactant, based on the total weight of the composition.
9. A composition as claimed in any one of claims 1 to 8, further comprising an antioxidant.
10. A composition as claimed in claim 9, wherein the antioxidant is selected from the group consisting of butylated hydroxytoluene, DL-alpha-tocopherol propyl gallate, ascorbyl palmitate and fumaric acid.
11. A composition as claimed in any one of claims 1 to 10, wherein the composition further comprises a disintegrant.
12. A composition as claimed in any one of claims 1 to 11, wherein the composition further comprises a lubricant.
13. A composition as claimed in any one of claims 1 to 12, further comprising a water-soluble saccharose.
14. A composition as claimed in any one of claims 1 to 13, wherein the composition further comprises a lactose.
15. A composition as claimed in any one of claims 1 to 14, further comprising a microcrystalline cellulose.
16. A composition as claimed in any one of claims 1 to 15, wherein the weight ratio of 33-epi-chloro-33-desoxy-ascomycin to carrier is less than 1:4.
17. A composition as claimed in any one of claims 1 to 16, wherein the 33-epi-chloro-33-desoxy-ascomycin is in amorphous or substantially amorphous form or a substantial portion is in amorphous form.
18. A composition as claimed in any one of claims 1 to 17 in unit dosage form.
19. A composition as claimed in claim 18 in capsule or tablet form.
20. A composition as claimed in claim 18 or 19, further comprising an enteric coating.
21. Use of a composition as claimed in any one of claims 1 to 20 for the manufacture of a drug for treating or preventing inflammatory or hyperproliferative skin diseases.
22. A method of forming a pharmaceutical composition comprising 33-epi-chloro-33-desoxy-ascomycin and a carrier medium, which carrier medium comprises a water-soluble polymer or a cyclodextrin and a surfactant, wherein the method comprises:
(a) suspending 33-epi-chloro-33-desoxy-ascomycin in a solvent to form a suspension, (b) combining a water-soluble polymer or a cyclodextrin and a surfactant and optionally further components with the solvent, and (c) spray drying the suspension to form the pharmaceutical composition.
23. A method according to any claim 22, wherein the pharmaceutical composition is subsequently formed into a unit dosage form.
24. A method according to claim 23, wherein the pharmaceutical composition is subsequently formed into a tablet or filled into a capsule.
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Families Citing this family (152)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH686761A5 (en) 1993-05-27 1996-06-28 Sandoz Ag Pharmaceutical formulations.
BE1009856A5 (en) * 1995-07-14 1997-10-07 Sandoz Sa Pharmaceutical composition in the form of a solid release including macrolide and a vehicle.
CA2230748C (en) * 1997-03-14 2010-08-03 American Home Products Corporation Rapamycin formulations for oral administration
SI1064942T1 (en) * 1998-03-26 2004-12-31 Fujisawa Pharmaceutical Co., Ltd. Sustained release preparation of a macrolide
JP3718341B2 (en) 1998-05-12 2005-11-24 信越化学工業株式会社 Low substituted hydroxypropylcellulose and process for producing the same
US20060240070A1 (en) * 1998-09-24 2006-10-26 Cromack Keith R Delivery of highly lipophilic agents via medical devices
GB9826882D0 (en) * 1998-12-07 1999-01-27 Novartis Ag Organic compounds
AU2003200370B2 (en) * 1998-12-07 2005-10-27 Novartis Ag Stabilization of macrolides
EP1181034B1 (en) 1999-05-10 2010-07-21 Paolo Brenner Combinations of immunosuppressive agents for the treatment or prevention of graft rejections
EP1054019A1 (en) * 1999-05-18 2000-11-22 Shin-Etsu Chemical Co., Ltd. Low-substituted hydroxypropyl cellulose
WO2001013957A2 (en) 1999-08-24 2001-03-01 Cellgate, Inc. Enhancing drug delivery across and into epithelial tissues using oligo arginine moieties
US20070032853A1 (en) 2002-03-27 2007-02-08 Hossainy Syed F 40-O-(2-hydroxy)ethyl-rapamycin coated stent
US6680069B1 (en) 1999-11-09 2004-01-20 Shin-Etsu Chemical Co., Ltd. Low-substituted hydroxypropyl cellulose and process for manufacturing the same
WO2001034119A2 (en) 1999-11-12 2001-05-17 Abbott Laboratories Inhibitors of crystallization in a solid dispersion
US7364752B1 (en) 1999-11-12 2008-04-29 Abbott Laboratories Solid dispersion pharamaceutical formulations
JP3552160B2 (en) 2000-01-14 2004-08-11 信越化学工業株式会社 Method for forming low-substituted hydroxypropylcellulose particles
IL134701A0 (en) * 2000-02-23 2001-04-30 J P M E D Ltd Homogeneous solid matrix containing vegetable proteins
DE10026698A1 (en) * 2000-05-30 2001-12-06 Basf Ag Self-emulsifying active ingredient formulation and use of this formulation
US20040018228A1 (en) * 2000-11-06 2004-01-29 Afmedica, Inc. Compositions and methods for reducing scar tissue formation
EP1389108A2 (en) * 2001-05-09 2004-02-18 Novartis AG Methods for selective immunomodulation using pimecrolimus
US20040137066A1 (en) * 2001-11-26 2004-07-15 Swaminathan Jayaraman Rationally designed therapeutic intravascular implant coating
US6641611B2 (en) 2001-11-26 2003-11-04 Swaminathan Jayaraman Therapeutic coating for an intravascular implant
GB0123400D0 (en) * 2001-09-28 2001-11-21 Novartis Ag Organic compounds
AU2006218279B2 (en) * 2001-09-28 2009-12-10 Novartis Ag Pharmaceutical compositions comprising colloidal silicon dioxide
US6939376B2 (en) 2001-11-05 2005-09-06 Sun Biomedical, Ltd. Drug-delivery endovascular stent and method for treating restenosis
US7682387B2 (en) 2002-04-24 2010-03-23 Biosensors International Group, Ltd. Drug-delivery endovascular stent and method for treating restenosis
IL162734A0 (en) 2002-02-01 2005-11-20 Ariad Gene Therapeutics Inc Phosphorus-containing compounds & uses thereof
CN1688291A (en) * 2002-02-01 2005-10-26 辉瑞产品公司 Immediate release dosage forms containing solid drug dispersions
JP2005523262A (en) * 2002-02-01 2005-08-04 ファイザー・プロダクツ・インク Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming substances
JP3956114B2 (en) * 2002-06-28 2007-08-08 インターナショナル・ビジネス・マシーンズ・コーポレーション Display control method, program using the same, information processing apparatus, and optical character reader
EP1585738A2 (en) * 2002-11-15 2005-10-19 Novartis AG Drug delivery system
AR043504A1 (en) * 2003-03-17 2005-08-03 Novartis Ag PHARMACEUTICAL COMPOSITIONS THAT INCLUDE RAPAMYCIN FOR THE TREATMENT OF INFLAMMATORY DISEASES
US7160867B2 (en) * 2003-05-16 2007-01-09 Isotechnika, Inc. Rapamycin carbohydrate derivatives
US20050118344A1 (en) 2003-12-01 2005-06-02 Pacetti Stephen D. Temperature controlled crimping
US20060177500A1 (en) * 2003-07-09 2006-08-10 Hee-Jong Shin Solid dispersion of tacrolimus
ATE540671T1 (en) 2003-08-04 2012-01-15 Bend Res Inc PHARMACEUTICAL COMPOSITIONS OF AMORPHOUS DRUG ADSORBATES AND LIPOPHILIC MICROPHASE-FORMING MATERIALS
US8377952B2 (en) * 2003-08-28 2013-02-19 Abbott Laboratories Solid pharmaceutical dosage formulation
US8025899B2 (en) * 2003-08-28 2011-09-27 Abbott Laboratories Solid pharmaceutical dosage form
AU2004270154A1 (en) * 2003-09-03 2005-03-17 Wyeth Amorphous rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid and its pharmaceutical compositions containing the same
US7585517B2 (en) 2003-09-18 2009-09-08 Macusight, Inc. Transscleral delivery
US7780973B2 (en) * 2003-12-15 2010-08-24 Ethicon Endo-Surgery, Inc. Method and device for minimally invasive implantation of biomaterial
US20050142161A1 (en) * 2003-12-30 2005-06-30 Freeman Lynetta J. Collagen matrix for soft tissue augmentation
DE602004011398T2 (en) * 2004-01-08 2009-01-15 Wyeth DIRECT COMPRESSIBLE PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION OF CCI-779
AU2005207786B2 (en) * 2004-01-29 2010-11-25 Eisai R & D Management Co., Ltd Method of stabilizing macrolide compound
HUE042304T2 (en) 2004-04-23 2019-06-28 Cydex Pharmaceuticals Inc DPI Formulation Containing Sulfoalkyl Ether Cyclodextrin
WO2006026531A1 (en) * 2004-08-27 2006-03-09 Cordis Corporation Solvent free amorphous rapamycin
US20060094744A1 (en) * 2004-09-29 2006-05-04 Maryanoff Cynthia A Pharmaceutical dosage forms of stable amorphous rapamycin like compounds
US20060088591A1 (en) * 2004-10-22 2006-04-27 Jinghua Yuan Tablets from a poorly compressible substance
KR100678824B1 (en) * 2005-02-04 2007-02-05 한미약품 주식회사 Amorphous taclolimus solid dispersion having an enhanced solubility and pharmaceutical composition comprising same
SI1848431T1 (en) 2005-02-09 2016-05-31 Santen Pharmaceutical Co., Ltd. Liquid formulations for treatment of diseases or conditions
US8663639B2 (en) 2005-02-09 2014-03-04 Santen Pharmaceutical Co., Ltd. Formulations for treating ocular diseases and conditions
WO2006094507A1 (en) * 2005-03-08 2006-09-14 Lifecycle Pharma A/S Pharmaceutical compositions comprising sirolimus and/or an analogue thereof
EP1868663B1 (en) * 2005-03-23 2011-11-16 Abbott Laboratories Delivery of highly lipophilic agents via medical devices
US20060240108A1 (en) * 2005-04-26 2006-10-26 Bernard Bobby L Cellulosic films incorporating a pharmaceutically acceptable plasticizer with enhanced wettability
DE102005026755A1 (en) * 2005-06-09 2006-12-14 Basf Ag Production of solid solutions of sparingly soluble active ingredients by short-term overheating and rapid drying
US7629331B2 (en) 2005-10-26 2009-12-08 Cydex Pharmaceuticals, Inc. Sulfoalkyl ether cyclodextrin compositions and methods of preparation thereof
CN102579467A (en) 2005-11-14 2012-07-18 阿里亚德医药股份有限公司 Administration of mntor inhibitor to treat patients with cancer
US7700614B2 (en) 2005-12-14 2010-04-20 Abbott Laboratories One pot synthesis of tetrazole derivatives of rapamycin
JP5528708B2 (en) 2006-02-09 2014-06-25 参天製薬株式会社 Stable formulations and methods for preparing and using them
US8222271B2 (en) 2006-03-23 2012-07-17 Santen Pharmaceutical Co., Ltd. Formulations and methods for vascular permeability-related diseases or conditions
US7883855B2 (en) 2006-07-21 2011-02-08 Abbott Laboratories Immunosuppressant drug extraction reagent for immunoassays
EP1938800A1 (en) 2006-12-06 2008-07-02 Ranbaxy Laboratories Limited Sirolimus nanodispersion
US7914999B2 (en) 2006-12-29 2011-03-29 Abbott Laboratories Non-denaturing lysis reagent
WO2008082982A1 (en) 2006-12-29 2008-07-10 Abbott Laboratories Improved assay for immunosuppressant drugs
WO2008082984A2 (en) 2006-12-29 2008-07-10 Abbott Laboratories Non-denaturing lysis reagent for use with capture-in-solution immunoassay
EP2118654B1 (en) 2006-12-29 2013-03-27 Abbott Laboratories Diagnostic test for the detection of a molecule or drug in whole blood
EP1952807A1 (en) * 2007-01-24 2008-08-06 LEK Pharmaceuticals D.D. Sirolimus formulation
EP2268160B1 (en) 2008-03-20 2012-12-05 Virun, Inc. Emulsions including a peg-derivative of tocopherol
SA109300195B1 (en) 2008-03-28 2013-04-20 Astrazeneca Ab A Novel Anti-Cancer Pharmaceutical Composition
US20120064143A1 (en) 2008-11-11 2012-03-15 The Board Of Regents Of The University Of Texas System Inhibition of mammalian target of rapamycin
FR2943539B1 (en) 2009-03-31 2011-07-22 Ethypharm Sa PHARMACEUTICAL COMPOSITION COMPRISING A IMMUNOSUPPRESSIVE MACROLIDE OF THE LIMUS FAMILY.
US8728516B2 (en) * 2009-04-30 2014-05-20 Abbvie Inc. Stabilized lipid formulation of apoptosis promoter
TWI540132B (en) 2009-06-08 2016-07-01 亞培公司 Pharmaceutical dosage form for oral administration of a bcl-2 family inhibitor
TWI532484B (en) * 2009-06-08 2016-05-11 艾伯維有限公司 Solid dispersions containing an apoptosis-promoting agent
WO2015103447A1 (en) 2013-12-31 2015-07-09 Rapamycin Holdings, Llc Oral rapamycin nanoparticle preparations and use
US9283211B1 (en) 2009-11-11 2016-03-15 Rapamycin Holdings, Llc Oral rapamycin preparation and use for stomatitis
AU2010336518B2 (en) * 2009-12-22 2014-03-06 Abbvie Inc. ABT-263 capsule
CN103037708B (en) 2010-03-23 2015-05-20 维尔恩公司 Nanoemulsion including sucrose fatty acid ester
CA2795544A1 (en) 2010-04-27 2011-11-03 Roche Glycart Ag Combination therapy of an afucosylated cd20 antibody with a mtor inhibitor
IT1400977B1 (en) * 2010-07-01 2013-07-05 Euticals Spa NEW COMPLEXES OF PHARMACEUTICAL, SOLID, SOLUBLE IN WATER AND THEIR WATER SOLUTIONS FOR ORAL, OPHTHALMIC, TOPICAL OR PARENTERAL USE, CONTAINING A MACROLIDE AND SOME CYCLODEXTRINES.
CA2811805A1 (en) 2010-10-29 2012-05-03 Abbvie Inc. Solid dispersions containing an apoptosis-inducing agent
UA113500C2 (en) 2010-10-29 2017-02-10 MEL EXTRUSION SOLID DISPERSIONS CONTAINING AN APOPTOSIS-INDUCING AGENT
RU2593231C2 (en) 2010-11-23 2016-08-10 ЭббВи Айэленд Анлимитед Компани Methods for treatment using selective bcl-2 inhibitors
CN107266435A (en) 2010-11-23 2017-10-20 Abbvie 公司 The salt and crystalline form of cell death inducer
WO2012092421A2 (en) 2010-12-30 2012-07-05 Surmodics, Inc. Composition for intravascular delivery of therapeutic composition
EP2702173A1 (en) 2011-04-25 2014-03-05 OSI Pharmaceuticals, LLC Use of emt gene signatures in cancer drug discovery, diagnostics, and treatment
US20120303115A1 (en) * 2011-05-25 2012-11-29 Dadino Ronald C Expandable devices coated with a rapamycin composition
CA2838387A1 (en) 2011-06-06 2012-12-13 Chevron Phillips Chemical Company Lp Use of metallocene compounds for cancer treatment
KR101151890B1 (en) * 2011-08-11 2012-05-31 동아제약주식회사 Method of preparing a stabilized and solubilized formulation of sirolimus derivatives
WO2013022201A1 (en) * 2011-08-11 2013-02-14 Dong-A Pharm. Co., Ltd. Process of preparing a stabilized and solubilized formulation of sirolimus derivatives
PE20141649A1 (en) 2011-10-06 2014-11-14 Novartis Ag PHARMACEUTICAL COMPOSITIONS INCLUDING 40-O- (2-HYDROXY) ETHYL-RAPAMYCIN
EP2594260A1 (en) * 2011-11-18 2013-05-22 LEK Pharmaceuticals d.d. Solid preparations comprising sirolimus with desired bioavailability and method for its preparation
US8912215B2 (en) * 2011-12-13 2014-12-16 Everon Biosciences, Inc. Rapamycin composition
KR200477251Y1 (en) * 2011-12-30 2015-05-22 엘에스산전 주식회사 Main contact position indicating mechanism for molded case circuit breaker
CN103585122B (en) * 2012-08-17 2017-12-05 山东新时代药业有限公司 A kind of tablet containing everolimus and preparation method thereof
EP2906214A1 (en) 2012-10-12 2015-08-19 The Board of Regents of The University of Texas System Use of mtor inhibitors to treat vascular cognitive impairment
US9610385B2 (en) 2013-03-07 2017-04-04 Abbott Cardiovascular Systems Inc. Method of fabricating an implantable medical device comprising a rapamycin derivative
DK2968281T3 (en) 2013-03-13 2020-11-02 Univ Texas MTOR INHIBITORS FOR PREVENTING THE GROWTH OF THE INTESTINAL POLYPH
US20140275082A1 (en) 2013-03-14 2014-09-18 Abbvie Inc. Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases
TW201503912A (en) 2013-03-19 2015-02-01 Novartis Ag Pharmaceutical compositions comprising everolimus
US10682415B2 (en) 2013-07-22 2020-06-16 Wisconsin Alumni Research Foundation Thermogel formulation for combination drug delivery
RU2707285C2 (en) 2013-10-08 2019-11-26 ЭйАй ТЕРАПЬЮТИКС, ИНК. Rapamycin for treating lymphangioleiomyomatosis
JP2016537345A (en) 2013-11-13 2016-12-01 ノバルティス アーゲー MTOR inhibitors for enhancing immune responses
CN103610646B (en) * 2013-12-05 2015-07-15 江苏奥赛康药业股份有限公司 Composition containing everolimus and preparation method thereof, and pharmaceutical preparation containing composition
EP3083964B1 (en) 2013-12-19 2022-01-26 Novartis AG Human mesothelin chimeric antigen receptors and uses thereof
EP3087101A4 (en) 2013-12-20 2017-12-06 Novartis AG Regulatable chimeric antigen receptor
CN104721158B (en) * 2013-12-24 2018-01-30 正大天晴药业集团股份有限公司 A kind of everolimus tablet of stabilization
US9700544B2 (en) 2013-12-31 2017-07-11 Neal K Vail Oral rapamycin nanoparticle preparations
JP2017505789A (en) 2014-02-11 2017-02-23 ラム・セラピューティクス，インコーポレーテッド Rapamycin for the treatment of lymphangioleiomyomatosis
US10307371B2 (en) 2014-02-11 2019-06-04 AI Therapeutics, Inc. Rapamycin for the treatment of lymphangioleiomyomatosis
ES2939760T3 (en) 2014-03-15 2023-04-26 Novartis Ag Cancer treatment using a chimeric receptor for antigens
US10300070B2 (en) 2014-03-27 2019-05-28 The Brigham And Women's Hospital, Inc. Metabolically-activated drug conjugates to overcome resistance in cancer therapy
MX2016012712A (en) 2014-04-04 2017-03-31 Lam Therapeutics Inc An inhalable rapamycin formulation for treating age-related conditions.
KR102487608B1 (en) 2014-04-07 2023-01-12 노파르티스 아게 Treatment of cancer using anti-cd19 chimeric antigen receptor
CA2968049A1 (en) 2014-04-16 2015-10-22 Rapamycin Holdings, Llc Oral rapamycin preparation and use for stomatitis
US10456445B2 (en) 2014-06-02 2019-10-29 Children's Medical Center Corporation Methods and compositions for immunomodulation
JP2017528433A (en) 2014-07-21 2017-09-28 ノバルティス アーゲー Low immunoenhancing dose of mTOR inhibitor and CAR combination
TWI719942B (en) 2014-07-21 2021-03-01 瑞士商諾華公司 Treatment of cancer using a cd33 chimeric antigen receptor
WO2016014553A1 (en) 2014-07-21 2016-01-28 Novartis Ag Sortase synthesized chimeric antigen receptors
EP3660042B1 (en) 2014-07-31 2023-01-11 Novartis AG Subset-optimized chimeric antigen receptor-containing t-cells
WO2016025880A1 (en) 2014-08-14 2016-02-18 Novartis Ag Treatment of cancer using gfr alpha-4 chimeric antigen receptor
CN112410363A (en) 2014-08-19 2021-02-26 诺华股份有限公司 anti-CD 123 Chimeric Antigen Receptor (CAR) for cancer therapy
ES2891332T3 (en) 2014-09-17 2022-01-27 Novartis Ag Targeting cytotoxic cells with chimeric receptors for adoptive immunotherapy
EP3209330B1 (en) 2014-10-07 2022-02-23 AI Therapeutics, Inc. An inhalable sirolimus formulation for the treatment of pulmonary hypertension
EP3204777A1 (en) 2014-10-08 2017-08-16 Novartis AG Biomarkers predictive of therapeutic responsiveness to chimeric antigen receptor therapy and uses thereof
MA40910A (en) 2014-11-07 2017-09-12 Civitas Therapeutics Inc RAPAMYCIN POWDERS FOR PULMONARY ADMINISTRATION
WO2016130645A1 (en) 2015-02-10 2016-08-18 Lam Therapeutics, Inc. Rapamycin for the treatment of lymphangioleiomyomatosis
WO2016135740A1 (en) 2015-02-23 2016-09-01 Natco Pharma Limited Process for preparing stable oral compositions of everolimus
EP3280795B1 (en) 2015-04-07 2021-03-24 Novartis AG Combination of chimeric antigen receptor therapy and amino pyrimidine derivatives
ES2948133T3 (en) 2015-04-17 2023-08-31 Novartis Ag Methods to improve the efficiency and expansion of cells expressing a chimeric antigen receptor
US20180298068A1 (en) 2015-04-23 2018-10-18 Novartis Ag Treatment of cancer using chimeric antigen receptor and protein kinase a blocker
EP3297629A1 (en) 2015-05-20 2018-03-28 Novartis AG Pharmaceutical combination of everolimus with dactolisib
US10383860B2 (en) 2015-07-28 2019-08-20 Nippon Kayaku Kabushiki Kaisha Pharmaceutical composition comprising rapamycin or derivative thereof, and method for producing the same
US20190015513A1 (en) * 2015-08-28 2019-01-17 Nippon Kayaku Kabushiki Kaisha Pharmaceutical composition comprising rapamycin or derivative thereof
US20190022073A1 (en) * 2015-09-03 2019-01-24 Nippon Kayaku Kabushiki Kaisha Pharmaceutical composition comprising rapamycin or derivative thereof
WO2017204215A1 (en) 2016-05-27 2017-11-30 日本化薬株式会社 Pharmaceutical composition containing rapamycin or derivative thereof
CA3031542A1 (en) 2016-07-20 2018-01-25 University Of Utah Research Foundation Cd229 car t cells and methods of use thereof
US20190231755A1 (en) * 2016-10-04 2019-08-01 Nippon Kayaku Kabushiki Kaisha Method for producing solid dispersion comprising rapamycin derivative
EP3523331A1 (en) 2016-10-07 2019-08-14 Novartis AG Chimeric antigen receptors for the treatment of cancer
AU2017363970A1 (en) 2016-11-23 2019-06-20 Novartis Ag Methods of enhancing immune response with everolimus, dactolisib or both
CN107080738A (en) * 2017-04-26 2017-08-22 四川制药制剂有限公司 The preparation method of acetylspiramycin tablet
US20200055948A1 (en) 2017-04-28 2020-02-20 Novartis Ag Cells expressing a bcma-targeting chimeric antigen receptor, and combination therapy with a gamma secretase inhibitor
WO2018213352A1 (en) 2017-05-15 2018-11-22 C.R. Bard, Inc. Medical device with drug-eluting coating and intermediate layer
US10596165B2 (en) 2018-02-12 2020-03-24 resTORbio, Inc. Combination therapies
WO2019210153A1 (en) 2018-04-27 2019-10-31 Novartis Ag Car t cell therapies with enhanced efficacy
EP3788369A1 (en) 2018-05-01 2021-03-10 Novartis Ag Biomarkers for evaluating car-t cells to predict clinical outcome
EP3880266A1 (en) 2018-11-14 2021-09-22 Lutonix, Inc. Medical device with drug-eluting coating on modified device surface
CN113939324A (en) 2019-04-08 2022-01-14 巴德外周血管股份有限公司 Medical devices having drug eluting coatings on modified device surfaces
EP3741367A1 (en) 2019-05-21 2020-11-25 Premark Pharma GmbH Treatment of ocular disease
KR20220024756A (en) * 2019-06-26 2022-03-03 가부시키가이샤 리코 pharmaceutical composition
US20220401421A1 (en) * 2019-12-19 2022-12-22 Triviumvet Dac Veterinary formulations comprising rapamycin and methods of using the same for treating animal disease
WO2023288046A1 (en) 2021-07-15 2023-01-19 President And Fellows Of Harvard College Compositions and methods relating to cells with adhered particles

Family Cites Families (76)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3852421A (en) 1970-03-23 1974-12-03 Shinetsu Chemical Co Excipient and shaped medicaments prepared therewith
ZA737247B (en) 1972-09-29 1975-04-30 Ayerst Mckenna & Harrison Rapamycin and process of preparation
US4127647A (en) * 1975-04-08 1978-11-28 Meiji Seika Kaisha, Ltd. Process for preparation of stable amorphous macrolide antibiotic solids
US4248856A (en) 1979-07-10 1981-02-03 American Home Products Corporation Sustained release pharmaceutical compositions
JPS5620513A (en) 1979-07-31 1981-02-26 Eisai Co Ltd Sugar-coated tablet containing fat-soluble drug
US4309404A (en) 1979-08-09 1982-01-05 American Home Products Corporation Sustained release pharmaceutical compositions
US4309405A (en) 1979-08-09 1982-01-05 American Home Products Corporation Sustained release pharmaceutical compositions
AU543727B2 (en) 1980-06-02 1985-05-02 Ayerst Mckenna & Harrison Inc. Injectable composition of rapamycin
FR2525108B1 (en) * 1982-04-19 1989-05-12 Elan Corp Ltd HIGH-SOLUBILITY MEDICINES AND PROCESS FOR OBTAINING THEM
US4415547A (en) 1982-06-14 1983-11-15 Sterling Drug Inc. Sustained-release pharmaceutical tablet and process for preparation thereof
US4650666A (en) 1983-11-30 1987-03-17 Dainippon Pharmaceutical Co., Ltd. Pullulan and sugar coated pharmaceutical composition
US4753801A (en) 1985-10-25 1988-06-28 Eli Lilly And Company Sustained release tablets
US4659336A (en) 1986-03-28 1987-04-21 Texaco Inc. Motor fuel composition
GB8608080D0 (en) * 1986-04-02 1986-05-08 Fujisawa Pharmaceutical Co Solid dispersion composition
US5026560A (en) 1987-01-29 1991-06-25 Takeda Chemical Industries, Ltd. Spherical granules having core and their production
DE3823702A1 (en) 1988-07-13 1990-01-25 Bayer Ag PROCESS FOR PREPARING POLYESTERS CONTAINING ACRYLOYL GROUPS AND THEIR USE AS PAINT BINDERS
GB2222683B (en) 1988-08-17 1992-04-15 Hydramotion Ltd Device for moisture measurement of particulate material
PT93772A (en) * 1989-04-17 1991-01-08 Searle & Co PROCESS FOR THE PREPARATION OF COMPOSITIONS FOR THE TREATMENT OF NEOPLASMS, CONTAINING AN ANTI-NEOPLASTIC AGENT, FOR EXAMPLE DOXORUBICIN AND A PROTEIN AGENT TO REDUCE THE SIDE EFFECTS, FOR EXAMPLE CARBETIMER
US5100899A (en) 1989-06-06 1992-03-31 Roy Calne Methods of inhibiting transplant rejection in mammals using rapamycin and derivatives and prodrugs thereof
DK0427680T3 (en) * 1989-11-09 1995-12-18 Sandoz Ltd Heteroatom-containing cyclic compounds
US5352671A (en) * 1989-11-09 1994-10-04 Sandoz Ltd. Heteroatoms-containing tricyclic compounds
JPH03240726A (en) * 1990-02-15 1991-10-28 Fujisawa Pharmaceut Co Ltd Chemotherapeutic effect enhancer
US5260301A (en) 1990-03-01 1993-11-09 Fujisawa Pharmaceutical Co., Ltd. Pharmaceutical solution containing FK-506
JP2542122B2 (en) 1990-04-18 1996-10-09 旭化成工業株式会社 Spherical nucleus, spherical granule and method for producing the same
CA2081474A1 (en) 1990-05-08 1991-11-09 Manzer Durrani Direct spray-dried drug/lipid powder composition
US5135934A (en) 1990-07-06 1992-08-04 Du Pont Merck Pharmaceutical Company 3-phenyl-5,6-dihydrobenz(c) acridine-7-carboxylic acids and related compounds as immunosuppressive agents
AU658577B2 (en) 1990-08-10 1995-04-27 Smithkline Beecham Corporation Immunosuppressive compositions
US5145684A (en) 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
US5078999A (en) * 1991-02-22 1992-01-07 American Home Products Corporation Method of treating systemic lupus erythematosus
IL101353A0 (en) 1991-04-03 1992-11-15 American Home Prod Pharmaceutical compositions for treating diabetes
US5100883A (en) 1991-04-08 1992-03-31 American Home Products Corporation Fluorinated esters of rapamycin
EP0580860B2 (en) * 1991-04-16 2004-12-15 Nippon Shinyaku Company, Limited Method of manufacturing solid dispersion
DK0581959T3 (en) * 1991-04-26 2001-01-29 Fujisawa Pharmaceutical Co Use of macrolide compounds for eye diseases
EP0525960B1 (en) 1991-06-18 1996-03-20 American Home Products Corporation Use of rapamycin for the treatment of adult T-cell leukemia/lymphoma
ZA924953B (en) * 1991-07-25 1993-04-28 Univ Louisville Res Found Method of treating ocular inflammation
US5457111A (en) 1991-09-05 1995-10-10 Abbott Laboratories Macrocyclic immunomodulators
US5286730A (en) 1991-09-17 1994-02-15 American Home Products Corporation Method of treating immunoinflammatory disease
US5817333A (en) 1991-10-31 1998-10-06 Fujisawa Pharmaceutical Co., Ltd. Liposome preparation containing a tricyclic compound
PT633783E (en) 1992-03-30 2000-11-30 American Home Prod RAPAMICINE FORMULATION FOR INTRAVENOUS INJECTION
AU670937B2 (en) 1992-04-28 1996-08-08 Wyeth Method of treating hyperproliferative vascular disease
US5472954A (en) * 1992-07-14 1995-12-05 Cyclops H.F. Cyclodextrin complexation
US5315246A (en) 1992-08-19 1994-05-24 Eastman Kodak Company Rotating source for generating a magnetic field for use with a currency detector
GB9221220D0 (en) * 1992-10-09 1992-11-25 Sandoz Ag Organic componds
US5457194A (en) 1993-03-17 1995-10-10 Abbott Laboratories Substituted aliphatic amine-containing macrocyclic immunomodulators
GB2278780B (en) 1993-05-27 1998-10-14 Sandoz Ltd Macrolide formulations
CH686761A5 (en) 1993-05-27 1996-06-28 Sandoz Ag Pharmaceutical formulations.
GB2279006A (en) * 1993-06-03 1994-12-21 Fujisawa Pharmaceutical Co Treatment of amyotrophic lateral sclerosis
US5352783A (en) 1993-06-09 1994-10-04 Merck & Co., Inc. Microbial transformation product having immunosuppressive activity
DE4322826A1 (en) 1993-07-08 1995-01-12 Galenik Labor Freiburg Gmbh Pharmaceutical preparation
IL110787A0 (en) 1993-08-27 1994-11-11 Sandoz Ag Biodegradable polymer, its preparation and pharmaceutical composition containing it
DE4329503A1 (en) 1993-09-01 1995-03-02 Galenik Labor Freiburg Gmbh Pharmaceutical preparations for the targeted treatment of Crohn's disease and ulcerative colitis
IL111004A (en) 1993-09-30 1998-06-15 American Home Prod Oral rapamycin formulations
US5516770A (en) 1993-09-30 1996-05-14 American Home Products Corporation Rapamycin formulation for IV injection
AU688782B2 (en) 1993-09-30 1998-03-19 Wyeth Rapamycin formulations for oral administration
US5616588A (en) 1993-09-30 1997-04-01 American Home Products Corporation Rapamycin formulation for IV injection
US5536729A (en) 1993-09-30 1996-07-16 American Home Products Corporation Rapamycin formulations for oral administration
IL111003A0 (en) * 1993-09-30 1994-11-28 American Home Prod Multi-component oral rapamycin formulation
GB9326284D0 (en) 1993-12-23 1994-02-23 Erba Carlo Spa Pyrrolydenemethyl-derivatives and process for their preparation
AU2826495A (en) 1994-06-02 1996-01-04 Enzon, Inc. Method of solubilizing substantially water insoluble materials
FR2722984B1 (en) 1994-07-26 1996-10-18 Effik Lab PROCESS FOR THE PREPARATION OF DRY PHARMACEUTICAL FORMS AND THE PHARMACEUTICAL COMPOSITIONS THUS PRODUCED
SE9403846D0 (en) * 1994-11-09 1994-11-09 Univ Ohio State Res Found Small particle formation
US5585115A (en) 1995-01-09 1996-12-17 Edward H. Mendell Co., Inc. Pharmaceutical excipient having improved compressability
US5547948A (en) 1995-01-17 1996-08-20 American Home Products Corporation Controlled release of steroids from sugar coatings
US5759577A (en) 1995-01-17 1998-06-02 American Home Products Corporation Controlled release of steroids from sugar coatings
EP0808154B1 (en) 1995-02-06 2000-12-20 Elan Pharma International Limited Formulations of compounds as nanoparticulate dispersions in digestible oils or fatty acids
US5573783A (en) 1995-02-13 1996-11-12 Nano Systems L.L.C. Redispersible nanoparticulate film matrices with protective overcoats
JP3934705B2 (en) * 1995-05-26 2007-06-20 ノバルティス ファーマ株式会社 Cyclodextrin composition
US5616595A (en) * 1995-06-07 1997-04-01 Abbott Laboratories Process for recovering water insoluble compounds from a fermentation broth
DE69624247T2 (en) * 1995-06-07 2003-09-11 Conoco Inc Spinning process for carbon fibers from solvated pitches
KR100400620B1 (en) 1995-06-09 2004-02-18 노파르티스 아게 Rapamycin Derivatives
IE80467B1 (en) * 1995-07-03 1998-07-29 Elan Corp Plc Controlled release formulations for poorly soluble drugs
BE1009856A5 (en) 1995-07-14 1997-10-07 Sandoz Sa Pharmaceutical composition in the form of a solid release including macrolide and a vehicle.
US5766623A (en) 1996-03-25 1998-06-16 State Of Oregon Acting By And Through The Oregon State Board Of Higher Education On Behalf Of Oregon State University Compactable self-sealing drug delivery agents
DE19635999A1 (en) 1996-09-05 1998-03-12 Dystar Textilfarben Gmbh & Co Dye mixtures of fiber-reactive azo dyes and their use for dyeing fiber material containing hydroxyl and / or carbonamide groups
US5989591A (en) 1997-03-14 1999-11-23 American Home Products Corporation Rapamycin formulations for oral administration
US5985325A (en) 1997-06-13 1999-11-16 American Home Products Corporation Rapamycin formulations for oral administration

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