MX336100B

Cyclosporine emulsion.

Abstract

The present invention relates to a cyclosporin emulsion containing: i) a cyclosporin; ii) a natural oil (long chain triglyceride); iii) a phosphatidylcholine; iv) glycerol; y) a pharmaceutically tolerable alkali salt of a free fatty acid, vi) a medium chain triglyceride oil; vii) optionally, hydrochloric acid or sodium hydroxide to adjust the pH; viii) water.

MX336100B, drawing sheet 1 — Sheet 1 of 87

Term

5 yearsleft in the term

Expires 30 September 2031.

4 claims: 3 independent, 1 dependent

1
CLAIMS JdlitUÍO REIVINDICACIONES jdlitUÍO Mexican d © to Property Mexicano d© to Propiedad 1. An oil-in-water cyclosporine emulsion comprises:1. Una emulsión de ciclosporina aceite-en-agua comprende: 5 i) 5 g / 1 of cyclosporin, ii) 100 g / 1 of soybean oil, iii) 12 g / 1 of egg lecithin, iv) 25 g / 1 of glycerol without water, 5 i) 5 g/1 de ciclosporina, ii) 100 g/1 de aceite de soya, iii) 12 g/1 de lecitina de huevo, iv) 25 g/1 de glicerol sin agua, v) 0.3 g / 1 sodium oleate, v) 0.3 g/1 de oleato de sodio, 10 vi) 100 g / 1 medium chain triglyceride oil selected from the group consisting of coconut oil, palm oil, and combinations thereof, and vii) water for injection, wherein the emulsion is isoosmolar and has a 10 vi) 100 g/1 de aceite de triglicérido de cadena media seleccionado del grupo que consiste de aceite de coco, aceite de palma, y combinaciones de los mismos, y vii) agua para inyección, en donde la emulsión es isoosmolar y tiene una 15 osmolaridad de 280 a 305 mOsm/1, y en donde la composición no contiene aceite de ricino polietoxilado. fifteen osmolarity from 280 to 305 mOsm / 1, and where the composition does not contain polyethoxylated castor oil.
3
The emulsion according to claim 3. La emulsión de conformidad con la reivindicación 1, en donde el pH de la emulsión es de aproximadamente 6 a aproximadamente 8.8. 1, where the pH of the emulsion is from about 6 to about 8.8.
4
La emulsión de ciclosporina de conformidad con Four. The cyclosporine emulsion in accordance with 25 claim 1, further comprising:hydrochloric acid or sodium hydroxide to adjust the pH. 25 la reivindicación 1, que además comprende: ácido clorhídrico o hidróxido de sodio para ajustar el pH. La presente invención se refiere a una emulsi órMusíriu' The present invention relates to an orMusíriu 'emulsion RESUMEN ciclosporina que contiene: i) una ciclosporina;ii) un aceite natural (triglicérido de cadena larga);iii) una fosfatidilcolina;iv) glicerol;v) una sal alcalina farmacéuticamente tolerable de un ácido graso libre, vi) un aceite de triglicérido de cadena media;vii) opcionalmente, ácido clorhídrico o hidróxido de sodio para ajustar el pH;viii) agua. SUMMARY cyclosporine containing: i) a cyclosporine;ii) a natural oil (long chain triglyceride);iii) a phosphatidylcholine;iv) glycerol;v) a pharmaceutically tolerable alkali salt of a free fatty acid, vi) a medium chain triglyceride oil;vii) optionally, hydrochloric acid or sodium hydroxide to adjust the pH;viii) water.

Independent claims3

763 paragraphs in 20 sections, as filed

(51) Int. Cl:

(22) Filing date (21) Application number:

27/03/2013

2013003578

A61K 9/107 (2006·01)

A61K 38/13 <2006 01>

(86) PCT application number: EP 11/67117 (87) PCT publication number: WO 2012/042023 (04/05/2012) (30) Priority (s): 10/01/2010 US 61 / 388,633

10/01/2010 DK PA 2010 00891 (71) Applicant: <

NEUROVIVE PHARMACEUTICAL AB Biomedical Center D10 S-221 84 Lund SE (72) Inventor (s):

ESKIL ELMÉR

Thomanders v. 2C Lund S-224 65 SE (74) Representative:

JOSE F. HINOJOSA CUELLAR. *

Paseo de los Tamarindos No. 400-A, Piso 9 CUAJIMALPA DE MORELOS Distrito Federal 05120 MX (54) Title: EMULSION DE CICLOSPORINA. (54) Title: CYCLOSPORINE EMULSION.

(57) Summary

(57) Abstract

The present invention relates to a cyclosporine emulsion containing: i) a cyclosporine ii) a natural oil (long Chain triglyceride) iii) a phosphatidylchol ine, iv) glycerol, v) a pharmaceutically tolerable alkali salt of a free fatty acid, vi) a medium Chain triglyceride-oil vii) optionally, hydrochloric acid or sodium hydroxide for pH adjustment viii) water.

Institute

Mexican Property

Industrial

_I KNOW_

HOtHMtfe Wt KMWmU

PATENT TITLE NO. 336100

Owner (s): NEUROVIVE PHARMACEUTICAL AB

Address: Biomedical Center D10, S-221 84, Lund, SWEDEN

Name: CYCLOSPORIN EMULSION.

Classification:

In lnt.CI.8: A61K38 / 13; A61K9 / 107 ESKIL ELMÉR

i reference patent e «torga with indamenti vited from the date of conformity with article 23 of the present law.

1st, 2nd fraction V, 6 * fraction III, and 59 gives the Law of Property inAistriai.

holy patent has a validity of twenty «unenforceable parties, and will be subject to the payment of the taris to keep vig ites the i with fundamen

7 bis 2 of 12/26/1997, 17 i / 2012); Articles 1, 3 'f ___ (DOF 12/14/1999, referring to the

09/2007); Articles 1, 3, 4, 5 section V subsection a), 16 sections I and III and 30 of the Organic Statute); 1st. 3rd and 5th subsection a) of the Agreement that delegates powers to the Deputy General Directors, Coordinator, Divisional Directors, Heads of Regional Offices, Divisional Deputy Directors, Departmental Coordinators and other subordinates of the Mexican Institute of Industrial Property. (DOF 12/15/1999, amended on 02/04/2000, 07/29/2004, 08/04/2004 and 09/13/2007).

who subscribes to the present Industrial Opportunity (Diarli title lo h

Official of the Federation (D. l / 01/2004r 06/16/2005, 2 * 1/2006, (105 / 2009,06 / 01/2010, 18, Biso a), 4 * and 12 ° fraction, s I and III <I Institute Regulation 707/2002, 15 / 07/2004, 2 * 7/2004 and property i and 5/1999, colon V

Issue Date: Janua ry 8, 2016

TO DIVISIONAL DIRECTOR OF PATENTS

NAHANNY CANAL REYES

Arenal No 550. Floor 1,

Coi. Santa María Tepepan Town, Xochimilco Delegation,

CP 16020, México, DF Tel. £ 55) 53 34 07 00 www.impigob.mx

CYCLOSPORIN EMULSION

2¿ / 3 / ξ & 7 &

Field of the Invention The present invention relates to a novel cyclosporin composition in the form of an emulsion with a content of medium chain triglycerides. The emulsion is an oil-in-water emulsion, it is bioequivalent to the commercially available Sandimmune® product, but has an improved tolerability profile compared to Sandimmune®.

Background of the invention

Cyclosporine is an immunosuppressant widely used in organ and tissue transplants. Cyclosporine has low solubility in water, and a Sandimmune® product marketed for infusion has been formulated as a concentrate containing 50 mg / ml of cyclosporine and polyoxylated castor oil (Cremophor EL®) in ethanol and must be diluted with an isotonic solution. of sodium chloride or a 5% glucose solution before administration. However, intravenous administration of the cyclosporine composition containing Cremophor EL® has been associated with hypersensitivity reactions, with responses ranging from mild skin reactions to anaphylaxis and cardiac collapse. Therefore, there is a need for Cremophor®-free cyclosporin compositions, as well as ready-to-use compositions.

Institute be usedM © ácano

Cremophor EL is the trademark for its version of polyethoxylated castor oil. It is prepared by reacting 35 moles of ethylene oxide with each mole of castor oil. The resulting product is a mixture (CAS number 61791-12-6): the main component is the material in which the hydroxyl groups of the castor oil triglyceride have been ethoxylated with ethylene oxide to form polyethylene glycol ethers. Minor components are polyethylene glycol and ricinoleic acid esters, polyethylene glycols, and polyethylene glycol ethers of glycerol. Cremophor EL is a synthetic, non-ionic surfactant.

Its usefulness comes from its ability to stabilize emulsions of nonpolar materials in aqueous systems.

A number of Cremophor products are available from BASF (Cremophor RH 40 (Polyoxyl-40 hydrogenated castor oil), Cremophor EL (polyocyl-35 castor oil), Cremophor ELP (extra pure EL grade), which are all grades of castor oil, polyoxyl, and Cremophor A 6 (macrogol-6-cetostearyl ether) and Cremophor A 25 (macrogol25-cetostearyl ether), which are the grades of macrogol-cetostearyl ether. To the best of our knowledge, currently only Cremophor EL® has been associated with hypersensitivity reactions. However, it is likely that all Cremophor® products in the oil series

Polyoxyl castor beans have the same side effect if they are administered to a subject.

Description of the invention

Ready-to-use cyclosporin compositions for parenteral administration have been described, inter alia, in EP-B-0 570 829. However, further developments of such compositions have been necessary in order to obtain compositions that are bioequivalent to the product. Sandimmune® and in order to guarantee adequate shelf life.

Other developments are aimed at ensuring formulations that can have sufficient stability and shelf life to meet marketing and distribution requirements in commercial pharmaceutical activities, while being bioequivalent and through the use of ingredients that are beneficial for therapeutic goals such as metabolism. mitochondrial and are not toxic.

In clinical practice, this also means that the goal of e.g. Sandimmune® can be better achieved and thus ensure that in clinical practice it is possible to avoid the adverse effect of Cremophor® and ethanol, and avoid having to premedicate with corticosteroids and / or antihistamines in cases where the pretreatment or multi-pharmacy approach is contraindicated.

The present invention provides a composition (teSÍitUÍC

Mexican

cyclosporine without Cremophor for industrial administration especially intravenous administration.

A composition of the present invention contains:

A cyclosporine

A natural oil (long chain triglyceride) (eg, soybean oil)

A phosphatidylcholine (eg, egg lecithin)

Glycerol

A pharmaceutically tolerable alkaline salt of a free fatty acid (e.g., sodium oleate)

Medium chain triglyceride-oil (e.g., coconut oil and / or palm oil)

Optionally, hydrochloric acid or sodium hydroxide to adjust the pH

Water.

A composition of the present invention has an osmolality in the isoosmolar range, that is, the osmolarity is in the range of about 280 mOsm / 1 to about 305 mOsm / 1, preferably about 295-300 mOsm / 1, which corresponds to the plasma value, that is, the isoosmolar value. The use of a composition containing cyclosporin with an isoosmolar osmolality is important in order to ensure good biocompatibility. Many of the known emulsions of

SnájStUi '1 cyclosporine are hyperosmolar in order to achieve good penetration through the blood-cell barrier ^ Sá ^ fí ^ P1® ^ ® 'Industrie when such compositions are used, eg, in the treatment of cerebrovascular accident. However, the cyclosporin emulsions of the invention can also be used in other important therapeutic areas such as, e.g., in relation to cardiac reperfusion injury and immunosuppression, where the use of a hyperosmolar composition can lead to entry unwanted in the brain from specific metabolites, substances, blood components, etc., which in turn can lead to toxic or adverse effects, all of which are unwanted.

The terms osmolarity, osmolality, and tonicity are often used interchangeably. For specific definitions, see Remington's Pharmaceutical Sciences, 18to edition, Mack Publishing Company 1990, pages 1481-1498, which is incorporated herein by reference.

A composition of the present invention can also be used in the treatment of traumatic brain injury, where the composition crosses the blood-brain barrier due to ruptures therein caused by brain damage itself and where, therefore, there is no need for a hyperosmolar composition to break the blood-brain barrier. An isoosmolar composition is highly preferable to a hyperosmolar composition in such indications.

Cyclosporine therapeutically active cyclosporine. Cyclosporine may have immunosuppressive or non-immunosuppressive properties (NICAMs), or it may have any other known or unknown effect (eg, for cardioprotection or neuroprotection for the treatment of cardiovascular diseases such as myocardial infarction, reperfusion, or in neurodegenerative diseases, brain damage, ischemia, trauma, etc. Cyclosporins are known to have protective effects on mitochondria. Preferred are cyclosporins that are suitable for use in immunosuppression. The cyclosporin can be a natural or synthetic cyclosporin. As is clear from the following, several chiral carbon atoms are present. Therefore, any of these forms - either alone or in any combination - that have therapeutic activity are encompassed by the term cyclosporine.

In the examples, the following cyclosporine has been used:

INN: Cyclosporine Chemical Names:

a) Cyclo [[(2S, 3R, 4R, 6E) -3-hydroxy-4-methyl-2 (methylamino) -oct-6-enoyl] -L-2-aminobutanoyl-N-methylglycyl-N-methyl-L-leucyl -Lvalyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N7 methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl];

Cyclo [[(E) - (2S, 3R, 4R) -3-hydroxy-4-methyl- ^ i, j ^ jr (methylamino) -6-octenoyl] -L-2-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-Lvalyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl -L-leucyl-N-methyl-L-valyl];

c) [R- [R *, R * - (E)]] - (L-alanyl-D-alanyl-N-methyl-Lleucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3 -hydroxy-N, 4-dimethyl-L-2-amino-6-octenoyl-La-aminobutyryl-N-methylglycyl N-methyl-Lleucyl-L-valyl-N-methyl-L-leucyl) cyclic.

Other names: Cyclosporine (INN)

Cyclosporine (INN - E)

Digest Names: Ciclosporin (Ciclosporinum) (Ph

Eur.)

Cyclosporine (USP)

CAS Number: 59865-13-3

Structural formula (see figure 1)

Molecular Formula: C62H111N11O12

Molecular mass, relative (Mr): 1202.61

Chirality: Cyclosporine is a naturally occurring molecule that has several chiral carbon atoms.

General properties

Physical form: White or almost white powder.

Solubility: soluble in acetone, ethanol, methanol, ether, chloroform and methylene chloride, slightly soluble in saturated hydrocarbons;

practically insoluble in water.

Specific Optical Rotation: -185 ° to -193 °

(methanol)

Phosphatidylcholine

Egg lecithin and / or soy lecithin, egg lecithin in particular, are preferred as phosphatidylcholine suppliers, in particular 3-sn-phosphatidylcholine or hydrogenated 3-phosphatidylcholine. Lecithins with a content of more than 60% of partially hydrogenated 3-sn-phosphatidylcholine and / or 3-snphosphatidylcholine and / or hydrogenated 3-snphosphatidylcholine are particularly suitable.

Pharmaceutically tolerable salts of fatty acids

An alkaline salt of a free fatty acid with 6 to 26 carbon atoms can be added to adjust the pH value or to facilitate the emulsification and homogenization process. The sodium and potassium salts of palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid and linolenic acid are especially preferred. In a preferred embodiment, sodium acetate is used.

Isotonically isoosmolar adjustable substance / de

aju Ü'C to Propase. ' indueW:

As seen from the examples herein, glycerol has been used to adjust the osmolarity of the composition to isoosmolar. However, other substances such as sorbitol, xylitol, sodium chloride, glucose may also be suitable.

Natural oils (long chain triglyceride) Soybean oil or safflower oil or combinations thereof can be used as natural oils. In a preferred embodiment, soybean oil is used.

TCM oils (medium chain triglycerides)

<td>How I know</td><td>deduce from</td><td>the next,</td><td>it seems that</td><td>the</td>

<td>presence of a</td><td>TCM oil</td><td>It is important</td><td>to achieve</td><td>the</td>

<td colspan="2">desired stability of</td><td>emulsion in</td><td>particular</td><td>with</td>

<td>according to the</td><td>stability</td><td>physics of the</td><td>emulsion.</td><td>The</td>

<td colspan="3">cyclosporine has a very good solubility</td><td colspan="2">in TCM oil and</td>

<td>TCM oil,</td><td colspan="2">therefore, it contributes</td><td>to avoid</td><td>the</td>

<td>precipitation no</td><td>desired of</td><td colspan="2">cyclosporine during</td><td>the</td>

<td>storage.</td><td></td><td></td><td></td><td></td>

<td>What's more,</td><td>the oils</td><td>from TCM seem</td><td colspan="2">have an effect</td>

beneficial in the brain, eg, there are indications that it may be beneficial in the treatment of Alzheimer's disease and ah?

other conditions where protection of stabilization and support of mitochondrial function is important / necessary.

Mitochondria are present and produce energy in almost every cell in the body. Mitochondrial collapse can be associated with a variety of acute injuries, such as myocardial infarctions and traumatic brain injury, and chronic diseases such as amyotrophic lateral sclerosis, multiple sclerosis, and other neurological disorders. In myocardial infarctions, reperfusion of the blocked artery can cause reperfusion injury and additional damage and disability to the heart muscle, as well as increased mortality. · Mitochondrial protection in heart muscle tissue can moderate the long-term impact of heart attacks.

A suitable TCM oil is coconut oil, palm oil, or a combination thereof.

Water

The water used must be of an appropriate quality for parenteral products, such as water for injections (standard pharmacopoeia).

Manufacturing method

A suitable method for the manufacture of a composition of the invention appears in figure 2 and in the 'r -—----- iOF 1 8', fiH!·· ^ · di fruaeonJ Us examples of this.

toiííut © ^ © ^ canc privacy

Industrie!

Examples of compositions according to the invention

In all of the compositions mentioned herein, the osmolarity is set to the isoosmolar value of about 285 to about 305 mOsm / 1, preferably set to about 295 to about 300 mOsm / 1.

More specifically, a composition according to the invention contains:

a cyclosporin in a concentration range of 1 to 15 g / 1, a phosphatidylcholine (eg, egg lecithin) in a concentration range of 5 to 25 g / 1, a pharmaceutically tolerable alkaline salt of a free fatty acid (eg, sodium oleate) in a concentration range of 0.1 to 1 g / 1, optionally by adjusting the pH, eg, 1 M sodium hydroxide in an amount sufficient to achieve a final pH of the composition from about 6 to about 8.8, glycerol in a concentration range of 10 to 50 g / 1, a natural oil (long chain triglyceride) (e.g. soybean oil) in a concentration range of 50 to

medium chain triglyceride oil in a concentration range of 50 to 150 g / l, and water up to 1 liter.

In particular embodiments, a composition according to the invention contains:

a cyclosporin in a concentration range of 1 to 15 g / 1, egg lecithin in a concentration range of 5 to 25 g / 1, a pharmaceutically tolerable alkaline salt of a free fatty acid (e.g., oleate of sodium) in a concentration range of 0.1 to 1 g / 1, optionally pH adjustment, e.g., 1 M sodium hydroxide in an amount sufficient to achieve a final pH value of the composition of about 8 to about 8.8, glycerol in a concentration range of 10 to 50 g / 1 / a natural oil (long-chain triglyceride) (e.g. soybean oil) in a concentration range of 50 to 150 g / 1, triglyceride oil of medium chain in a concentration range of 50 to 150 g / 1, and water up to 1 liter.

A cyclosporine in a concentration range of 1 to 15 g / 1,

It instituted a phosphatidylcholine (eg, egg lecithin) d ©? @Frop! @Dac a concentration range of 5 to 25 sodium oleate g / 1, in JíKJusTFiC a concentration range of 0.1 to 1 g / 1, optionally , pH adjustment, eg, 1 M sodium hydroxide in an amount sufficient to achieve a final pH value of the composition of about 8 to about 8.8, glycerol in a concentration range of 10 to 50 g / i.

a natural oil (long chain triglyceride) (e.g. soybean oil) in a concentration range of 50 to 150 g / 1, medium chain triglyceride oil in a concentration range of 50 to 150 g / 1 , and water up to 1 liter.

A cyclosporin in a concentration range of 1 to 15 g / 1, egg lecithin in a concentration range of 5 to 25 g / 1, sodium oleate in a concentration range of 0.1 to 1 g / 1, optionally, adjustment pH, e.g., 1 M sodium hydroxide in an amount sufficient to achieve a final pH value of the composition of about 8 to about 8.8, glycerol in a concentration range of 10 to 50

g/ i, feásorac ta Freiste 'a natural oil (long-chain triglyceride ^ CaUSlFtet' (e.g., soybean oil) in a concentration range of 50 to 150 g / 1, medium-chain triglyceride oil in a range concentration of 50 to 150 g / 1, and water up to 1 liter.

A cyclosporin in a concentration range of 1 to 15 g / 1, a phosphatidylcholine (eg, egg lecithin) in a concentration range of 5 to 25 g / 1, a pharmaceutically tolerable alkaline salt of a free fatty acid (e.g., sodium oleate) in a concentration range of 0.1 to 1 g / 1, optionally pH adjustment, e.g., 1 M sodium hydroxide in an amount sufficient to reach a final pH value of the composition from about 8 to about 8.8, glycerol in a concentration range of 10 to 50 g / i, soybean oil in a concentration range of 50 to

150 g / 1, medium chain triglyceride oil in a concentration range of 50 to 150 g / 1, and water up to 1 liter.

One cyclosporin in a concentration range of 1 to 15 g / 1 to 25 g / 1, egg lecithin

a pharmaceutically tolerable alkaline salt of a free fatty acid (e.g., sodium oleate) in a concentration range of 0.1 to 1 g / 1, optionally pH adjustment, e.g., 1 M sodium hydroxide in an amount sufficient to reach a final pH value of the composition of approximately 8 to approximately 8.8, glycerol in a concentration range of 10 to 50 g / i, soybean oil in a concentration range of 50 to

150 g / 1, medium chain triglyceride oil in a concentration range of 50 to 150 g / 1, and water up to 1 liter.

A cyclosporin in a concentration range of 1 to 15 g / 1, a phosphatidylcholine (eg, egg lecithin) in a concentration range of 5 to 25 sodium oleate g / 1, in a concentration range of 0.1 at 1 g / 1, optionally, pH adjustment, e.g., 1 M sodium hydroxide in an amount sufficient to achieve a final pH value of the composition of about 8 to about 8.8, glycerol in a concentration range of 10

BridusWr g / i,

soybean oil in a concentration range of 50 to

150 g / 1, medium chain triglyceride oil in a concentration range of 50 to 150 g / 1, and water up to 1 liter.

Furthermore, the invention relates to compositions having the following compositions:

a cyclosporine at a concentration of 5 g / 1, a phosphatidylcholine (eg, egg lecithin) at a concentration of 12 g / 1, a pharmaceutically tolerable alkaline salt of a free fatty acid (eg. , sodium oieate) at a concentration of 0.3 g / 1, optionally, pH adjustment, e.g., 1 M sodium hydroxide in an amount sufficient to achieve a final pH value of the composition of from about 8 to about 8.8 , glycerol in a concentration of 25 g / 1, a natural oil (long chain triglyceride) (eg, soybean oil) in a concentration of 100 g / 1, medium chain oil triglycerides in a concentration range of 100 g / 1, water up to 1 liter.

A cyclosporin at a concentration of 5 g / 1, egg lecithin at a concentration of 12 g / 1, a pharmaceutically tolerable alkaline salt of a free fatty acid (e.g., sodium acetate) at a concentration of 0.3 g / 1, optionally, pH adjustment, e.g., 1M sodium hydroxide in an amount sufficient to achieve a final pH value of the composition of from about 8 to about 8.8, ri, M'] v' and glycerol in a concentration of 25 g / 1,

Efedsanc tí © So Prapidtfat a natural oil (long chain triglyceride) (e.g. soybean oil) in a concentration of 100 g / 1, medium chain triglycerides of oil in a concentration range of 100 g / 1, water up to 1 liter.

A cyclosporin in a concentration of 5 g / 1, a phosphatidylcholine (eg, egg lecithin) in a concentration of 12 g / 1, sodium oleate in a concentration of 0.3 g / 1, optionally, pH adjustment, e.g., 1 M sodium hydroxide in an amount sufficient to reach a final pH value of the composition of about 8 to about 8.8, glycerol in a concentration of 25 g / 1, a natural oil (long chain triglyceride) (eg, soybean oil) in a concentration of 100 g / 1, medium chain triglycerides of oil in a concentration range of 100 g / 1, water up to 1 liter.

A cyclosporin in a concentration of 5 g / 1, egg lecithin in a concentration of 12 g / 1, sodium oleate in a concentration of 0.3 g / 1, optionally, pH adjustment, e.g., sodium hydroxide 1 M in an amount sufficient to reach a value

Institution

Mercan © of final pH of the composition of approximately g ^ g Property, IndusTrtaí approximately] 8.8, glycerol in a concentration of 25 g / 1, a natural oil (long chain triglyceride) *

(eg, soybean oil) in a concentration of 100 g / 1, medium chain oil triglycerides in a concentration range of 100 g / 1, water up to 1 liter.

A cyclosporin in a concentration of 5 g / 1, a phosphatidylcholine (e.g., egg lecithin) in a concentration of 12 g / 1, a pharmaceutically tolerable alkaline salt of a free fatty acid (e.g., oleate of sodium) at a concentration of 0.3 g / 1, optionally pH adjustment, e.g., 1 M sodium hydroxide in an amount sufficient to achieve a final pH value of the composition of about 8 to about 8.8, glycerol in a concentration of 25 g / 1, soybean oil in a concentration of 100 g / 1,

Medium chain triglyceride oil in a concentration range of 100 g / 1, water up to 1 liter.

A cyclosporin in a concentration of 5 g / 1, egg lecithin in a concentration of 12 g / 1,

a pharmaceutically tolerable alkaline salt of free fatty acid (eg, sodium oleate) in a! concentration of 0.3 g / 1, optionally pH adjustment, e.g., 1 M sodium hydroxide in an amount sufficient to achieve a final pH value of the composition of about 8 to about 8.8, glycerol in a concentration of 25 g / 1, soybean oil in a concentration of 100 g / 1, medium chain triglyceride oil in a concentration range of 100 g / 1, h ^ ista water 1 liter.

A cyclosporin in a concentration of 5 g / 1, a phosphatidylcholine (eg, egg lecithin) in a concentration of 12 g / 1, sodium oleate in a concentration of 0.3 g / 1, optionally, pH adjustment, e.g., 1 M sodium hydroxide in an amount sufficient to achieve a final pH value of the composition of about 8 to about 8.8, glycerol in a concentration of 25 g / 1, soybean oil in a concentration of 100 g /1, medium chain triglyceride oil in a concentration range of 100 g / 1, water up to 1 liter.

A cyclosporin in a concentration of 5 g / 1, »egg lecithin in a concentration of 12 g / 1, and sodium oleate in a concentration of 0.3 g / 1, optionally, pH adjustment, eg, 1 M sodium hydroxide in an amount sufficient to achieve a final pH value of the composition of approximately 8 to approximately 8.8, glycerol in a concentration of 25 g / 1, soybean oil in a concentration of 100 g / 1, medium chain triglyceride oil in a concentration range of 100 g / 1, water up to 1 liter.

In all the compositions mentioned above, the medium chain triglycerides can be coconut oil, palm oil, or combinations thereof.

The composition of the emulsion that has been tested in a clinical study was produced according to the following formula (300 L batch size):

<td>Ingredient</td><td>Quantity (kg)</td><td>Quality standard</td>

<td>Cyclosporine</td><td> 1.50</td><td>Rl-CEP 1999-034 Rev 02</td>

<td>Egg lecithin</td><td> 3.60</td><td></td>

<td>Glycerol (without water)</td><td> 7.50</td><td>Ph. Eur.</td>

<td>Sodium oleate</td><td> 0.09</td><td></td>

<td>1M sodium hydroxide</td><td>cs</td><td>Ph. Eur.</td>

<td>Soybean oil (long chain triglyceride)</td><td> 30.00</td><td>Ph. Eur.</td>

<td>TCM (Medium Chain Triglyceride) Oil</td><td> 30.00</td><td>Ph. Eur.</td>

<td>Water for injection</td><td>Add 300 L</td><td>Ph. Eur.</td>

<td>Nitrogen gas</td><td>As required</td><td>Ph. Eur./USP</td>

Therefore, a preferred composition

Indusfr'-i invention is as follows:

<td>Ingredient </td><td>Concentration g / L</td>

<td>Cyclosporine</td><td> 5</td>

<td>Egg lecithin</td><td> 12</td>

<td>Glycerol (without water)</td><td> 25</td>

<td>Sodium oleate</td><td> 0.3</td>

<td>1M sodium hydroxide</td><td>cs</td>

<td>Soybean oil (long chain triglyceride)</td><td> 100</td>

<td>TCM (Medium Chain Triglyceride) Oil</td><td> 100</td>

<td>Water for injection</td><td>Add 1 L</td>

<td>Nitrogen gas</td><td>As required (for production purposes)</td>

TCM oil is coconut oil, palm oil, or a combination thereof.

As is clear from the experimental section of a composition according to the invention, in particular, the aforementioned composition is bioequivalent to the Sandimmune® product, that is, the concentrate is diluted to a ready-to-use composition. The bioequivalence study has been carried out according to well-established guidelines (EMEA - European Medicines Agency, London, January 2010 Guidelines on the

Bioequivalence Research, or U.S. Department of Health and Human Services, Food and Drug Administration, March 2003, from Guia para la Industria, Bioavailability and Bioequivalence Studies for

Pharmaceutical products

General considerations).

Managed

Orally

The study also reveals that a composition

According to the invention it has a much better se profile than the Sandimmune® product. Thus, without premedication with corticosteroids, in 19 subjects two severe anaphylactic reactions were observed after administration with Sandimmune®, while no reactions were observed after administration in 33 subjects with a composition according to the invention. To summarize the clinical study, the table below shows the observed side effects. Two serious adverse events (SAEs) were reported. These were anaphylactic and anaphylactoid reactions that occurred after administration of Sandimmune® Injection (injectable). The proportion of general adverse effects was significantly higher in Sandimmune® Injection compared to the composition according to the invention.

<td></td><td>Proportion</td><td>Proportion</td><td></td><td></td><td></td>

<td></td><td>Sandimmune Injection</td><td>CicloMulsion (according to the invention)</td><td>Average of the ratio. <%></td><td>Confidence interval of 95% of the ratio (%)</td><td>d ^ McN ^</td>

<td>In general</td><td> 0.800</td><td> 0.350</td><td> -0.450</td><td> -0.668 ; 0.232</td><td> 0.0027</td>

<td>Disorders eyepieces</td><td> 0.050</td><td> 0.000</td><td> -0 .050</td><td> -0.146 ; 0.046</td><td>N / C</td>

<td>Disorders gastro- intestinal</td><td> 0.150</td><td> 0.150</td><td> 0.000</td><td> -0.139; 0.139</td><td> 1.0000</td>

<td>Disorders of the system immunological</td><td> 0.200</td><td> 0.050</td><td> -0.150</td><td> -0.306 ; 0.006</td><td> 0.0833</td>

<td>Reaction anaphylactic</td><td> 0.050</td><td> 0.000</td><td> -0.050</td><td> -0.146 ; 0.046</td><td>N / C</td>

<td>Reaction anaphylactoid</td><td> 0.050</td><td> 0.000</td><td> -0 .050</td><td> -0.146 ; 0.046</td><td>N / C</td>

<td>Hypersensitivity</td><td> 0.100</td><td> 0.050</td><td> -0 .050</td><td> -0.146 ; 0.046</td><td> 0.3173</td>

<td>Nervous system disorders</td><td> 0.500</td><td> 0.250</td><td> -0.250</td><td> -0.485 ; 0.015</td><td> 0.0588</td>

<td>Disorders psychiatric</td><td> 0.050</td><td> 0.000</td><td> -0.050</td><td> -0 .146 ; 0.046</td><td>N / C</td>

<td>System disorders player and breast</td><td> 0.050</td><td> 0.000</td><td> -0.050</td><td> -0.146 ; 0.046</td><td>N / C</td>

<td>Respiratory, thoracic, and midstinal disorders</td><td> 0.050</td><td> 0.050</td><td> 0000</td><td> 0000 ; 0.000</td><td>N / C</td>

<td>Disorders vascular</td><td> 0.400</td><td> 0.100</td><td> -0.300</td><td> -0.511 ; 0.056</td><td> 0.0339</td>

Another advantage of a composition of the invention (in addition to bioequivalence with Sandimmune® Injection and better safety profile of Sandimmune® Injection) is the excellent stability of the composition. The presence of medium chain triglycerides is currently believed to play an important role in this regard. Therefore, based on the stability studies carried out according to the ICH guidelines and reported in the examples, the general conclusion is that a shelf life of 30-36 months when stored below 25 ° C and protected from light is reasonable.

Other advantages are:

'1. Ready to use solution. Sandimmúne Injection is marketed · as a 50 mg / ml infusion concentrate that has to be withdrawn with a syringe and then injected into a larger volume of saline or 5% glucose. The concentrate solution is highly viscous, especially at or below room temperature, making it more difficult to extract and empty to the correct amount than with a ready-to-use composition. In addition, after injection of the saline infusion concentrate, careful mixing is required to avoid the injection of large lumps of Cremophor ® containing cyclosporine into the circulation, which also affects the concentration of cyclosporine given early and late. in a treatment.

two. There is no non-physiological emulsifier. The content of a composition of the invention are physiological fats and phospholipids that can be metabolized by the human body.

3. There is no risk of serious solvent-related hypersensitivity reactions, including anaphylactic reactions and death.

Four. There is no risk of solvent related cytotoxicity, nephrotoxicity or cardiotoxicity.

5. Eliminates the need for IV tubes

required for products that contain you © the Property

Cremophor® (to avoid leaching of plasticizers).

6. Premedication with antihistamine corticosteroids is not necessary.

7. There is no risk of unwanted substance penetrating the blood-brain barrier.

The emulsions of the invention are suitable for use in the treatment of disease in which cyclosporine is indicated. Examples are immunosuppressive disorders, reperfusion injury (organ damage), cardiac reperfusion injury (cardioprotection), renal reperfusion injury (nephroprotection), reperfusion injury of the liver (hepatoprotection), prevention of brain damage (neuroprotection).

Brief description of the figures

Figure 1 shows the structure of cyclosporin

Figure 2 shows a method for the manufacture of an emulsion according to the invention

Figure 3. shows the arithmetic mean with one standard deviation of the concentration of cyclosporine in the blood in the participants administered

CicloMulsion or Sandimmune. n = 52

Figure 4 shows the mean concentration of

cyclosporine in blood with standard deviation in Property participants given CicloMuision (A) Sandimmune (B), either with or without premedication consisting of 50 mg diphenhydramine orally, 10 mg dexamethasone intravenously, and 50 mg ranitidine intravenously.

Figure 5 shows the pharmacokinetics of Sandimmune® and CicloMuision®. This shows the results of Example 4. The figure shows the individual plots of concentrations in whole blood after the infusion of 5 mg / kg of cyclosporine sampled for 48 hours in 52 healthy individuals. Left - Sandimmune Injection, right CicloMuision.

Figure 6 shows the results of Example 4.

This shows the confidence interval (90%) for the means of the ratios (% CicloMulsion / Sandimmune) and intra-individual coefficient of variation (CV) of the pharmacokinetic variables of cyclosporine in whole blood.

The invention is further illustrated in the following non-limiting examples.

Examples Example 1

Manufacture of a composition according to the invention

Preparation of the emulsion Preparation of the aqueous suspension:

A mixing tank is provided with the appropriate amount of hot water for injection. All raw materials except oil components are ground and dispersed in water for injection at 55-70 ° C. The suspension

Instituto Mexicano d® Industrial Property is dispersed through intense mixing

Pre-emulsion preparation:

A solution of preheated oil components (50-60 ° C), containing dissolved cyclosporin, is added. Aqueous suspension and the oil phase are mixed at 55-70 ° C. If necessary, adjust the pH.

Homogenization:

The preparation of the final emulsion is carried out by several homogenization steps. Pressures of 400 ± 30 bar (stage 1) and 100 ± 30 bar (stage 2) are applied. The temperature of the emulsion is between 55 ° C and 90 ° C. Between the homogenization steps, the emulsion is stored in intermediate storage tanks.

Final emulsion:

Depending on the capacity of the equipment used (homogenizers and containers) the emulsion has to be diluted under stirring with the appropriate amount of water for injection. The resulting emulsion is cooled to a temperature of 15-25 ° C. A sample of the final concentration is taken for in-process control and a pH adjustment can be carried out.

Filtration of the emulsion:

The emulsion is filtered through a 10 µm absolute pore size filter.

Filling and closing:

The emulsion is filled under a nitrogen atmosphere into suitable infusion bottles. The filled ones are closed with rubber stoppers and stoppers with transparent hinged covers.

Sterilization:

The filled containers are sterilized in a rotary autoclave.

Example 2

Composition according to the invention The composition of the emulsion that has been tested in a clinical study was produced according to the following formula (300 L batch size):

<td>Ingredient</td><td>Quantity (kg)</td><td>Quality standard</td>

<td>Cyclosporine</td><td> 1.50</td><td>Rl-CEP 1999-034 Rev 02</td>

<td>Egg lecithin</td><td> 3.60</td><td></td>

<td>Glycerol · (without water)</td><td> 7.50</td><td>Ph. Eur</td>

<td>Sodium oleate</td><td> 0.09</td><td></td>

<td>1M sodium hydroxide</td><td>cs</td><td>Ph. Eur.</td>

<td>Soybean oil (long chain triglyceride)</td><td> 30.00</td><td>Ph. Eur.</td>

<td>TCM (Medium Chain Triglyceride) Oil</td><td> 30.00</td><td>Ph. Eur.</td>

<td>Water for injection</td><td>Add 300 L</td><td>Ph. Eur.</td>

<td>Nitrogen gas</td><td>As required</td><td>Ph. Eur./USP</td>

Example 3

Stability of a composition according to the invention

The composition of Example 2 was subjected to stability studies in accordance with ICH guidelines.

$% ία topiedoc '

WUitíte;

The 5 mg / ml cyclosporine emulsion for injection batch PP0915013 is put into stability at 25 ° C / 60% of and 40 ° C / 75% RH according to ICH requirements. Currently, 12-month data is available.

All results, at both temperatures, are within specification. Cyclosporine appears very stable with no tendency to decline. Only small amounts of degradation products are found. The following tables summarize the results.

25 ° C / 60% RH

<td>Test object</td><td colspan="5">Storage time (months)</td>

<td>Appearance White homogeneous emulsion</td><td>Conformed</td><td>conformed</td><td>conformed</td><td>conformed</td><td>conformed</td>

<td>Particle size distribution> bpm 100% £ 5pm 98% £ 1.5pm</td><td> 100/100</td><td> 100/98.6</td><td> 100/99.2</td><td> 100/99</td><td> 100/98</td>

<td>Particle size distribution> mean bpm z £ 350nm Polydispersity £ 0.25</td><td> 240 0.09</td><td> 243 0.06</td><td> 239 0.08</td><td> 239 0.09</td><td> 239 0.08</td>

<td>Peroxide value £ 2.5mEq / L</td><td> 0.02</td><td> 0.04</td><td> 0.05</td><td> 0.10</td><td> 0.0</td>

<td>Cyclosporine test 95.0 - 105.0%</td><td> 97.6</td><td> 100.6</td><td> 100.2</td><td> 100.2</td><td> 101.4</td>

<td>Degradation products Cyclosporin H (£ 1.4%) Dihydrocyclosporin, A (£ 1.4%) Isocyclosporin A (£ 1.4%) Unknown individual (£ 0.2%) Total (£ 2.0%)</td><td><DL 0.1 0.1 0.1. <0.4</td><td> 0.1 0.1 0.2 0.1 <0.5</td><td> 0.3 0.3 0.1 0.1 <0.8</td><td>0.2 0.2 0.2 <DL <0.7</td><td> 0.3 0.2 0.1 0.1 <0.8</td>

<td>Free fatty acids £ 12mEg / L</td><td> 2</td><td> 2</td><td> 3</td><td> 3</td><td> 4</td>

<td>Lysophosphatidylcholine</td><td> 3</td><td> 6</td><td> 7</td><td> 7</td><td> 8</td>

<td>Sterility Sterile</td><td>sterile</td><td> -</td><td> -</td><td> -</td><td> -</td>

& Pifa

40 ° C / 75% RH

Mexican Institute of Industrial Property

<td>Test object</td><td colspan="3">Storage time (months)</td>

<td>Appearance White homogeneous emulsion</td><td>conformed</td><td>conformed</td><td>conformed</td>

<td>Particle size distribution> bpm 100% ¿5pm 98% ¿1.5 pm</td><td> 100/100</td><td> 100/99.6</td><td> 100/99.6</td>

<td>Particle size distribution> average bpm z ¿350nm Polydispersity ¿0.25</td><td> 240 0.09</td><td> 242 0.05</td><td> 240 0.05</td>

<td>Peroxide value ¿2.5mEq / L</td><td> 0.02</td><td> 0.06</td><td> 0.08</td>

<td>Cyclosporine test 95.0 - 105.0%</td><td> 97.6</td><td> 101.2</td><td> 99.6</td>

<td>Degradation products Cyclosporin H (<1.4%) Dihydrocyclosporin A (¿1.4%) Isocyclosporin A (¿1.4%) Unknown individual (<0.2i) Total (¿2.0%)</td><td><DL 0.1 0.1 0.1 <0.4</td><td> 0.4 0.1 0.2 0.1 <0.7</td><td> 0.9 0.3 0.1 0.1 <1.3</td>

<td>Free fatty acids <12mEg / i</td><td> 2</td><td> 4</td><td> 6</td>

<td>Lysophosphatidylcholine ¿16. 7%</td><td> 3</td><td> 9</td><td> 12</td>

<td>Sterility Sterile</td><td>sterile</td><td> -</td><td></td>

Example 4

A clinical study to compare the bioavailability and pharmacokinetics of cyclosporine

Summary

Background

Cyclosporine is an immunosuppressant widely used in organ and tissue transplants. Cyclosporin has poor water solubility, and the concentrate for solution for infusion has therefore been formulated in polyoxyethylated castor oil (Cremophor EL®). However, intravenous administration of drug preparations

Cyclosporine containing cremophor has been associated with hypersensitivity reactions, with responses ranging from d ^^ to g ^. mild skin conditions up to anaphylaxis and heart collapse. A ready-to-use, cremophor-free cyclosporine lipid emulsion (CicloMulsion, cyclosporine 5 mg / ml) for intravenous use has been developed. The objectives of the present study were to compare the pharmacokinetics and the tolerability profile of CicloMulsion with the reference product Sandimmune Injection.

Method

Healthy Caucasian and non-Caucasian male and female volunteers (n = 52) were investigated according to an open-label, laboratory-blinded, subject-blinded, randomized, single-dose, two-period crossover design. . Five kg mg of each of the two formulations was infused intravenously over 4 hours. Cyclosporine concentrations in blood by validated LC-MS / MS analysis, standard pharmacokinetics in accordance with performed by analysis of variance. Point and 90% confidence intervals of the geometric least squares relationships of the relevant test / reference variables were calculated. Tolerability and safety were assessed by 'follow-up of were determined

FDA and EMA comparisons are

Estimates for averages

adverse effects, complete blood count, vital signs measurements, electrocardiogram and post-test physical examination <j¿jgygjjfc $ |

Results

The pharmacokinetics of Sandimmune® and CicloMulsion® are shown in Figure 5. Combined individual plots of concentrations in whole blood after infusion of 5 mg / kg of cyclosporine sampled for 48 hours in 52 healthy individuals. Left - Sandimmune Injection, right

- CicloMulsion.

Confidence intervals of pharmacokinetic variables of cyclosporine in whole blood.

<td>Variable</td><td>Ratio mean (%)</td><td>90% confidence interval of the relationship</td><td>Intra-individual CV (%)</td><td>Power</td>

<td>AüC (0-tlastJ (hr * ng / mL)</td><td> 89.88</td><td> (87.92:91.88)</td><td> 6.71</td><td> >99%</td>

Table 1 and Figure 6. Confidence interval ^^ Qi for the CycloMulsion / Sandimmune means) and intra-individual of the

the relationships (% coefficient of variation (CV) pharmacokinetic variables of cyclosporine in whole blood.

Proportional analysis of adverse events

<td></td><td colspan="2">Proportion</td><td rowspan="2">Ratio mean (%)</td><td rowspan="2">Confidence interval of 95% of the ratio (%)</td><td rowspan="2">McNemar's p-value</td>

<td></td><td>Sandimmune Injection</td><td>CycleMulsion</td>

<td>In general</td><td> 0.800</td><td> 0.350</td><td> -0.450</td><td> -0.668 ; -0.232</td><td> 0.0027</td>

<td>Eye disorders</td><td> 0.050</td><td> 0.000</td><td> -0.050</td><td> -0.146 ; 0.046</td><td>N / C</td>

<td>Gastrointestinal disorders</td><td> 0.150</td><td> 0.150</td><td> 0.000</td><td> -0.139; 0.139</td><td> 1.0000</td>

<td>Immune system disorders</td><td> 0.200</td><td> 0.050</td><td> -0.150</td><td> -0.306 ; 0.006</td><td> 0.0833</td>

<td>Reaction anaphylactic</td><td> 0.050</td><td> 0.000</td><td> -0.050</td><td> -0.146 ; 0.046</td><td>N / C</td>

<td>Reaction anaphylactoid</td><td> 0.050</td><td> 0.000</td><td> -0.050</td><td> -0.146 ; 0.046</td><td>N / C</td>

<td>Hypersensitivity</td><td> 0.100</td><td> 0.050</td><td> -0.050</td><td> -0.146 ; 0.046</td><td> 0.3173</td>

<td>Nervous system disorders</td><td> 0.500</td><td> 0.250</td><td> -0.250</td><td> -0.485 ; -0.015</td><td> 0.0588</td>

<td>Disorders psychiatric</td><td> 0.050</td><td> 0.000</td><td> -0.050</td><td> -0 .146 ; 0.046</td><td>N / C</td>

<td>Reproductive system and breast disorders</td><td> 0.050</td><td> 0.000</td><td> -0.050</td><td> -0.146 ; 0.046</td><td>N / C</td>

<td>Respiratory, thoracic and midstinal disorders</td><td> 0.050</td><td> 0.050</td><td> 0.000</td><td> 0000 ; 0.000</td><td>Irtch</td>

<td>Disorders vascular</td><td> 0.400</td><td> 0.100</td><td> -0.300</td><td> -0.544 ; -0.056</td><td> 0.0339</td>

to.

S'O icon ítíoc

Table 2. Two serious adverse events (SAE) were reported. These were the anaphylactic reaction and the anaphylactoid reaction that occurred after the administration of Sandimmune Injection. The proportion of global adverse events was significantly higher in

Sandimmune Injection compared to CicloMulsion.

CicloMulsion has the following advantages over

Sandimmune Injection iv:

1. Ready to use solution

two. Physiological emulsifier. The content of 15 CicloMulsion are fats and phospholipids that can be metabolized by the human body.

3. There is no risk of serious cremophor-related hypersensitivity reactions, including anaphylactic reactions and death.

Four. There is no risk of cytotoxicity, nephrotoxicity or cardiotoxicity related to cremophor.

5. Eliminates the need for IV tubes

required for products containing cremophor (to avoid leaching of plasticizers).

Conclusions

CicloMulsion, a ready-to-use cremophor-free intravenous cyclosporine formulation, is bioequivalent to Sandimmune Injection.

CicloMulsion shows an improved safety and tolerability profile. Serious hypersensitivity reactions related to Cremophor, including anaphylactic reactions and death, can therefore be avoided in patients requiring intravenous cyclosporine treatment.

Details regarding the clinical study

Introduction

Cyclosporine is widely used to prevent graft rejection after transplantation. The intravenous formulation currently on the market, Sandimmune® Injection (Sandimmune), uses Cremophor® EL (CrEL) as the emulsifying excipient. CrEL is known to cause hypersensitivity reactions in some patients, ranging from skin reactions to anaphylactic shock and death. The present inventors have evaluated the pharmacokinetics and tolerability of a new CREL lipid-free cyclosporine emulsion, CicloMulsion®, compared to Sandimmune. Fifty-two healthy subjects were treated with 5 mg / kg of each of the two cyclosporine formulations as

Evaluations were madej ^ vj ^^ Q reSledad

with the Geometrica btricrt actu media guidelines for intravenous infusion of 4 hr.

bioequivalence of conformity

The relationships of the

CycloMulsion / Sandimmune (90% confidence interval) were 0.90 (0.88-0.92) for the Area Under the Curve (0 hr at the last quantifiable concentration) and 0.95 (0.92 to 0.97) for the maximum concentration of cyclosporine in blood. For all other variables analyzed, the 90% confidence intervals were also within the accepted range of bioequivalence of 0.80-1.25. An anaphylactoid reaction and an anaphylactic reaction, both classified as serious adverse reactions, were reported after treatment with Sandimmun. No serious adverse events were recorded after treatment with CicloMulsion. The proportion of total adverse events was significantly higher for Sandimmuhe. The present inventors concluded that CicloMulsion is bioequivalent to Sandimmúne and exhibits fewer adverse reactions.

List of abbreviations

AE Adverse Events

ANOVA Analysis of variance

AUC Area Under the Curve

Area Under the Curve for a time from 0 to 4

AUCq-4

HtU hours M © XÍca¡l¿>

i. Property

AUCo-t Area Under the Curve for a time 0 to the last quantifiable concentration

AUCo-oo Area Under the Curve for a time 0 hours extrapolated to infinity

AUC4-t Area Under the Curve for a 4 hour time to the last quantifiable concentration

AUC4- «> Area Under the Curve for a time of 4 hours extrapolated to infinity

CI

CL

Cmax

CycleMulsion

Cremophor EL

CrEL

CsA

CV

ECG

EDTA

EMA

FDA

IV

LC-MS / MS

LLOQ

Confidence interval

Clearing

Maximum concentration in the blood

Cyclosporine lipid emulsion without

Cremophor EL

Ciclosporin, Ciclosporin, Ciclosporin A Coefficient of Variation

Electrocardiogram

Ethylenediaminetetraacetic acid

European Medicines Agency

Food and Drug Administration intravenous

Liquid Chromatography-Mass Spectrometry / Mass Spectrometry

Low level of quantification

MedDRA

Medical Dictionary for

Regulatory's

MRT

Average residence time

Ph Eur

European Pharmacopoeia

PVC

Polyvinyl chloride

SA'E

Serious Adverse Event

Sandimmune Sandimmune ® Injection

SpO2 tlí. two

USP

Peripheral Blood Oxygen Saturation

Apparent terminal half-life

United States Pharmacopeia

Cyclosporine (CsA) is a powerful immunosuppressant first registered in 1983 that acts by reducing the function of T lymphocytes through the inhibition of calcineurin. CsA is widely used to prevent organ rejection and graft-versus-host disease after solid organ or bone marrow transplantation, and for the treatment of autoimmune diseases such as psoriasis, atopic dermatitis, pyoderma gangrenosum, ulcerative colitis, idiopathic nephrotic syndrome. and inflammatory uveitis (1-7). The molecule is highly hydrophobic and requires a lipophilic solvent for delivery. The intravenous (IV) form of CsA currently on the market, Sandimmune® Injection (Novartis Pharma Stein AG, Switzerland) (Sandimmune), is a preparation with ethanol and polyoxyethylated castor oil, Cremophor® EL (CREL).

CrEL is not inert (8), and there have been a number of reports of serious adverse effects after intravenous CsA administration due to reactions to this vehicle medium (9-16). Hypersensitivity reactions to CrEL have also been reported when used for other intravenous drug preparations such as diazepam and Althesin® (17-21). In rodents, neurotoxicity, cardiotoxicity, and nephrotoxicity due to IV CsA dissolved in CrEL have been demonstrated (22-25) and, in a canine model, CrEL has been shown to reduce cardiac output and hepatic blood flow in a non-dependent manner. dose (26). The effects of CrEL include complement activation, histamine release, and severe hypersensitivity reactions (8, 17, 19, 21).

CsA in CrEL requires a dilution step prior to administration. Incorrect preparation of formulations containing CrEL has been reported to cause anaphylactoid reactions (27, 28). An additional concern with the use of ethanol and CrEL is the leaching of plasticizers from polyvinyl chloride (PVC) bags and infusion sets used in routine clinical practice. Consequently, preparation and administration should be done using glass or other non-PVC infusion sets (29, 30).

Concern for the safety of CrEL as a

Carrier medium for intravenous drugs has been numerous times and various drugs that had previously been produced in CrEL preparations are now available only with other carrier medium such as lipid emulsions. Known examples are propofol (17, 31) and diazepam (32). Others, such as the chemotherapeutic agent paclitaxel, are available with and without CrEL as a solvent (33), and the CrEL-containing anesthetic drug Althesin® is no longer marketed for use in humans (17, 21, 34).

In this study, the objective was to evaluate the pharmacokinetics of a ready-to-use CsA preparation without CrEL-ethanol for IV administration, CicloMulsion® (NeuroVive Pharmaceutical AB, Lund, Sweden), relative to the CrEL-containing product currently on the market. (Sandimmune® Injection) and evaluate if the two formulations are bioequivalent. A ready-to-use preparation without CrEL potentially offers greater patient safety with fewer adverse events due to improper handling or immunological reactions to CrEL.

Study design

<td>East</td><td>It was</td><td colspan="4">a single center crossover study,</td><td>from</td>

<td colspan="2">open label,</td><td>blind</td><td>for him</td><td>subject, blind</td><td>in order to</td><td>the</td>

<td>laboratory,</td><td>from</td><td>dose</td><td>only,</td><td>randomized,</td><td>from</td><td>two</td>

Insmuw Mexicano treatments, two periods, two sequences, pf & M | $ c! A £ pharmacokinetics of two formulations of CsA IV. The goal ^5^^ The primary objective was to evaluate the pharmacokinetics, and the secondary objective was to compare the tolerability profiles of the two preparations.

The study protocol, including amendments, subject information sheets and informed consent documents, were examined by the Ethics Committee of the Faculty of Health Sciences of the State University.

Free (reference number ETOVS 65/09), and by the South African Medicines Control Council (reference number BE 2009009), and written approval was obtained. The study was conducted in accordance with the statement of

Helsinki and in the Guidelines for Good Clinical Practice issued by the International Conference on Harmonization.

It was designed to comply with the Guidance for Industry Statistical Approaches to Establishing Bioequivalence issued by the U.S. Department of Health and Human Services, Food and Drug Administration (FDA) (35), and Guidance Note on Research of Bioavailability and Bioequivalence by the European Medicines Agency (EMA) (36).

Cyclosporine formulations

The reference formulation of CsA used was i

Sandimmune ® Injection (Novartis Pharma Stein AG, CsA mg / ml, United States Pharmacopeia

contains Cremophor® EL (each 1 ml infusion concentrate was diluted in 20 ml of 0.9% saline before use). The test product used was CicloMulsion® (NeuroVive Pharmaceutical AB, Lund, Sweden), 5 mg / ml cyclosporine without Cremophor and ready-to-use ethanol, Ph Eur / USP lipid emulsion. Each ml of the lipid emulsion contains 100 mg of refined soybean oil, 100 mg of medium chain triglycerides, 12 mg of egg lecithin, 25 mg of glycerol, water, and sodium oleate and sodium hydroxide to adjust the pH .

Participants

Healthy, healthy, non-pregnant and non-lactating male volunteers and female volunteers between 18 and 55 years of age with a body mass index in the range of 19-33 kg / m2 they were eligible. Other inclusion criteria were: 60-100 kg of body mass, normal 12-lead electrocardiogram (ECG) and vital signs, clinically acceptable results in the medical history and physical examination, laboratory results within the reference ranges (unless that the deviation was deemed irrelevant for the purpose of the study), willingness to submit to physical examinations and laboratory investigations

prior, intermediate, and post-study understanding and willingness to sign the informed consent, and abstinence from tobacco for three months prior to the study. Participating women of childbearing age underwent a pregnancy test before each dose of CsA and, if positive, were excluded from the study. During the study period, reliable non-hormonal methods of contraception had to be used.

Exclusion criteria included evidence of psychiatric disorder, history of or current drug abuse (including alcohol), use of any medication within two weeks prior to first administration of study medication, participation in another study with an experimental drug with administration within twelve weeks prior to the current study, severe illness within the past three months, blood donation or blood loss greater than 500 mL during the eight weeks prior to the first study drug administration, positive test for hepatitis B or C or HIV, positive urine drug test, vaccination of any kind within four weeks of the first dose or vaccination planning within three months of the last dose, close family member receiving the live vaccine during the study or within three months after the study, and hypotension or hypertension during the screening period. ÍÍíUikSJÍO

The history of any of the sií

sñcíissFrlní diseases was also the criterion for exclusion from the study: any type of neoplasm, immunodeficiency, tendency to recurrent infections, known untreated parasitic infection, allergy to any compound in the reference and test product, or to egg or soy , any bronchospastic disease, epilepsy, porphyria, psoriasis, atopic dermatitis, hypercholesterolemia, gout, rheumatoid arthritis, or kidney disease.

Care was taken to include both female and male participants, both Caucasian and non-Caucasian. Written informed consent was obtained from all participants prior to enrollment in the study.

Sampling period

The subjects were randomized into two treatment sequences: the test product followed by the reference product or vice versa. There was a washout period adjusted to 14-21 days between the first and second treatment periods. Participants came to the clinic the night before treatment for laboratory tests, including blood samples, pregnancy test and urine drug test. The subjects were instructed not to ingest any citrusM® ^, OH · '' and / or apple or pineapple '72 hr before the start of the infusion and lntíusí?: C.

within 24 hr, no alcohol or products containing caffeine were allowed. On the clinical day, the only food served prior to drug administration was a normal breakfast. Through an IV cannula, subjects received either 5 mg / kg CicloMulsion (test) or 5 mg / kg Sandimmune (reference), infused at a constant rate for 4 hr with a syringe pump. The recommended dose for the induction of immunosuppression with Sandimmune in clinical practice is 3-6 mg / kg / day.

The same arm was used for administration during both treatment periods. All infusion set was compatible with the reference and the test product. Through an IV cannula in the contra-lateral arm, a total of 22 blood samples for CsA analysis were obtained before the dose and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4 , 4.5, 5, 6, 7, 8, 10, 14, 18, 24, 30, 36 and 48 hr after the start of the infusion. All samples were collected in flasks containing ethylenediaminetetraacetic acid (EDTA), labeled and stored at -70 ° C until analysis. The concentration of CsA in whole blood was tested with liquid chromatography mass spectrometry / mass spectrometry (LC-MS / MS). The method was validated in accordance with current

Mfuí © FDA guidelines (37). The lower limit of quantification pyelidity (LLOQ) was 39.39 ng / ml and the mean CV ffeL5USl?! L3t 3.5% for CsA. Complete sets of calibration standards and quality controls were included within each series.

Twenty-four hours after the start of study medication administration, subjects were allowed to leave the clinic, provided they returned for 1½ subsequent blood sampling. Vital signs were monitored during the infusion and measured 2 hr after the completion of the infusion and after the last blood sample had been drawn. Food and beverages during the clinic days were standardized.

Water was left ad libitum before and after infusion of study medication. Alcohol, caffeine, citrus fruits, apple and pineapple were not allowed until the last blood sample had been drawn in each treatment period.

Tolerability assessment

Each subject was carefully monitored for adverse events (AEs) during the infusion, and was questioned on the day of the study for any symptoms of these events. AEs were classified as mild, moderate, or severe according to the following definitions:

habitual activities; subject may I experienced! ®

I felt slight discomfort.

Moderate: They cause some limitation of habitual activities; the subject may experience discomfort.

Severe: They cause the inability to carry out normal activities; the subject may experience excruciating pain or discomfort.

The investigator considers each AE in causal relationship with the administered medical product as safe, probable, possible, unlikely, unrelated, or not evaluable. Each AE was encoded with the Dictionary

Physician for Regulatory Activities (MedDRA) and is reported according to strict criteria.

the proportions of total adverse events and adverse events by organ class were compared between CicloMulsion and Sandimmune by means of a 95% confidence interval (Cl) for the difference of paired proportions and p-values of the McNemar test.

Pharmacokinetics and Bioequivalence Assessment Pharmacokinetic variables for CsA were calculated using non-compartmental methods using WinNonlin® Professional Version 5.2 (Pharsight

Corporation, Mountain View CA, USA). The statistic was performed with SAS® Software version

Institute, Cary, NC, USA). All values by

LLOQ before the first positive sample were replaced 5 by zero. For the pharmacokinetic evaluation, the final values below the LLOQ were ignored.

CycloMulsion was compared to Sandimmune with respect to a number of the pharmacokinetic variables using analysis of variance (ANOVA) with sequence, subject within sequence effects, products, and log-transformed data period. The parameters compared were the area under the time-concentration curves of CsA for time 0 to the time of the last quantifiable concentration (AUCo-t) f time 0 hr extrapolated to infinity (AUCo-oo), time of 4 hr extrapolated to the infinity (AUC4-00), time from 0 to 4 hr (AUC0-4) and time 4 to the last quantifiable concentration (AUC4_t), the maximum concentration of CsA in blood (CmtoX), apparent CsA terminal half-life (tis.z), blood CsA clearance (CL) and mean residence time (MRT). Cmax, AUCo-oo, AUCo-t, AUC4-00, were considered primary variables and the rest secondary. The estimates and the 90% Cls for the geometric mean of the CycloMulsion / Sandimmune relationships of all variables were calculated. The two products were considered bioequivalent if the 90% Cl for the primary variables was within the limits of 0.8 and 1.25.

Based on the FDA and EMA recommended bioequivalence range of 1.25 for Cmax, AUCo-t and

IncSusTric an estimate within the subject's coefficient of variation (CV) of 35%, and a mean test / reference ratio between 0.95 and 1.05, 52 subjects were required to reach a power of 80% at an alpha level of 0.05 to show bioequivalence (38).

Modifications in study design

The initial study design did not include any premedication but, due to an unexpectedly high incidence of serious adverse events (SAE) for the reference product, the remainder of the study was premedicated.

An amendment to the study protocol was prepared and approved by the ethics committees mentioned above. For consistency purposes, premedication was used before CicloMulsion and Sandimmune although triggering of AEs, restoration of premedication were observed after administration of Sandimmune. Thirteen subjects completed both treatment periods without premedication. Eighteen subjects received the test product in the first treatment period without premedication, and received the reference product with premedication in the second treatment period. The rest (21 subjects) received premedication during both treatment periods, and therefore with the y i.1

test and reference product.

Premedication consisted of one 50 diphenhydramine capsule orally 1 hr before the start of the test or reference drug infusion, 10 mg dexamethasone by slow IV injection, and 50 mg IV infusion of ranitidine over approximately 5 minutes at 30 minutes before each study drug dose. The study was put on hold due to protocol modifications to be <

approved. This caused the washout period for the 18 subjects who received the test product in the first treatment period, without premedication, and the reference product with premedication in the second treatment period, to be extended to more than six weeks. Neither premedication is known to change the pharmacokinetic properties of CsA or affect the bioanalytical test.

Results

Sixty-five volunteers were enrolled in the study and were randomized to a sequence of treatment. Two subjects withdrew before the first dosing due to illness, and eleven more withdrew before completing the study. Of these eleven, three were due to withdrawal of consent, two due to investigator / sponsor decision (uncertainty of the dose received due to infusion problems), and six due to ESAs. None

bioequivalence. Fifty-two participants completed the study and were included in the pharmacokinetic evaluation.

The demographic data of the subjects who completed the study are presented in Table 1.

Table 1: Demographic data of the subjects included in the pharmacokinetic study

<td>Gender male Female</td><td> 33/19</td>

<td>Age (years) mean (range)</td><td> 24.4 (18-46)</td>

<td>Race Caucasian / African / Mixed</td><td> 35/16/1</td>

<td>Body mass (kg) mean (range)</td><td> 70.4 (60.0-99.8)</td>

<td>BMI (kg / m2) mean (range)</td><td> 23.3 (18.8-28.3)</td>

Sixty-three participants received at least one dose of study medication and were included in the overall tolerability assessment. Due to an unexpectedly high number of severe adverse reactions to Sandimmune, the study protocol was changed and premedication was introduced as described above.

Statistical analysis of the incidence of ESAs was performed only including the thirteen participants who received the test drug and the reference drug, without premedication.

η ..

I Π Μ Y /? / ί

Pharmacokinetics and Bioequivalence Assessment For each time point, arithmetic lag @ ifl§ with standard deviation were calculated for whole blood CsA concentrations for the test drug CicloMulsion and the reference drug Sandimmúne. A graphical presentation of CsA concentrations over time is provided in Figure 1. In Figures 4A and 4B, time-concentration curves are presented separately for subjects who received and those who did not receive concomitant premedication. The pharmacokinetic parameters are presented in Table 2.

BfagQftO

Table 2: Pharmacokinetic parameters of cyclosporine in subjects treated with CicloMulsion or

Sandimmúne as a single intravenous infusion over 4 hr at the dose of 5 mg / kg. Arithmetic means, standard deviation (SD) and coefficient of variation (CV).

<td rowspan="3">Parameter (unit)</td><td colspan="3">CicloMulsion® (n = 52)</td><td colspan="3" rowspan="2">Sandimmúne® Injection (n = 52)</td>

<td>Extrapolation(%)</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Trnax (h)</td><td> 3.7</td><td> 0.4</td><td> 11.4</td><td> 3.7</td><td> 0.4</td><td> 10.1</td>

The part of the AUC0- «that was extrapolated was tí © fe Ownership of approximately 5% for both study drugs, j ^ usííiGt which indicates that a reliable estimate was obtained from the AUCo-» ·

There were no values below LLOQ among the positive samples.

The statistical analysis of bioequivalence after dosing with either CicloMulsion or Sandimmune are presented in table 3. The point estimates of the geometric means of the CicloMulsion / Sandimmune ratios (90% CI) of the primary variables of Cmax and AUCo-t for CsA were 0.95 (0.92-0.97) and 0.90 (0.88-0.92), respectively, and AUCo- »and AUC4_a> for CsA were 0.90 (0.880.92) and 0.87 (0.84-0.90), respectively. Therefore, the

90% CI of all primary variables were within the acceptable range for bioequivalence of 0.80 to 1.25.

90% of the CI for all secondary variables also met the criteria for bioequivalence.

Table 3: Bioequivalence evaluation of cyclosporine exposure in whole blood after dosing with a single dose of CicloMulsion (test) and Sandimmune Inyect-ion (reference). The geometric means of the log-transformed data, standard deviation (SD), the point estimates and the 90% confidence interval (CI) of the CycloMulsion / Sandimmune Injection relationship and the within-subject coefficient of variation (CV).

Paxameter / unit?

Geometric mean and Standard Deviation_

CicloMulsion® Sandimmune® Injection

Mean SD Mean SD Ratio

90% Cl

Tolerability

Of the 63 subjects, 55 reported one or more adverse events (AE). The AEs rated at least possibly related to study medication were reported primarily from the MedDRA-encoded organ classes of nervous system disorders and vascular disorders (Table 4). Nervous system disorders included headache, burning sensation, paraesthesia, dizziness, and sensory loss. Vascular disorders included hot flash events and orthostatic hypotension. When subjects received Sandimmune without premedication, 84% (16/19) experienced adverse events assessed as at least possibly related to the study medication, compared to 64% (21/33) when they received CicloMulsion. With premedication, the figures were 76% (31/41) for Sandimmune and 67% (16/24) for CicloMulsion. The proportional analysis of AEs was performed for

overall (p subjects treated with both CicloMulsion Sandimmune and without premedication. A significantly higher number of adverse events was found at = 0.003) and vascular disorders (p = 0.03) when subjects were treated with Sandimmun. There were no other significantly different proportions between the two formulations.

Table 4: Summary of all adverse events at least 10 possibly related to study medication. Number of patients (n) who reported adverse events and incidence in%. Presented with and withou t premedication for CicloMulsion and Sandimmune Injection.

Without premedication _._ With premedication_

All subjects Sandimmune Inyection CicloMuision Sandimmune Inyection CicloMuision dP ti dP

Γ *

IT

CM »d

LO r * o rm oo ro m fd i — I ¡Muta c @ feWap¡Ísü3d feiebSÍFfW

CM h oj ro co en lo rm 'sr m r- oh r- n κ i oo r- i — i

CM cm mil

Γ0 Γ0 «d cm, i

CO CO l I CO III

I Ir-I III <30 CO CO II «tT | | | I co r-ι r- r * oo

LO m CM · «d ΓΗ ri 00 LO U0 lf) CO CM CM

<td></td><td></td><td>you</td><td>"or</td><td>Φ</td><td></td><td>to</td><td></td><td> <0</td><td></td><td></td><td>you</td><td>Φ</td><td>υ</td><td>CO</td><td></td><td>• d</td><td>• d</td><td></td><td>former</td><td></td><td>CO</td><td></td><td>CO</td><td>g</td><td>• d</td><td> 0</td><td></td><td>Φ</td><td>'you</td>

<td>g</td><td>to</td><td></td><td>c</td><td> <0</td><td>C0</td><td>neither</td><td>P</td><td> <0</td><td>you</td><td>CO</td><td>you</td><td>P</td><td>you</td><td>you</td><td>AND</td><td>you</td><td>you</td><td>g</td><td>you</td><td>m</td><td>you</td><td>• d</td><td>you</td><td>(X</td><td>you</td><td> (0</td><td>c</td><td>you</td><td>you</td>

phytoiuto

Two serious adverse events were recorded.

it first affected a 21-year-old male, who was randomly assigned during the treatment period to receive the reference drug, Sandimmune. Directly after starting the infusion, she had experienced shortness of breath and a feeling of suffocation. The infusion treatment was interrupted with 40% oxygen through the Hudson mask was started, and she received 25 mg of promethazine and hydrocortisone 200 mg IV. Due to continued dyspnea, inhalation with nebulized salbutamol was started. Thirty-seven minutes after the start of the infusion, the event was considered resolved and oxygen therapy was discontinued. The day after he left the clinic, but he felt tired for another three days. The event was diagnosed as an anaphylactoid reaction.

The second of the two SAEs reported involved a 42-year-old male, who also received the reference drug Sandimmune in the first treatment period. Eleven minutes after the infusion of the medication began, she developed a cough, facial flushing, and dyspnea. Auscultation of the chest revealed wheezing sounds and peripheral blood oxygen saturation (SpO2) measured by pulse oximeter was 95%. His condition deteriorated rapidly, he became pale and sweaty, and a systolic / diastolic blood pressure of 75/42 was recorded.

mmHg. The infusion was stopped and treatment with Mexican oxygen was started through the Hudson mask, and intravenous infusion with Ringer's lactate was started. Blood pressure did not increase and SpO2 was reduced to 91% after a couple of minutes, he was treated with 0.5 mg of adrenaline and 25 mg of promethazine intramuscularly and 5 mg of salbutamol as nebulized inhalation. A 200 mg hydrocortisone infusion was also started. Five minutes after the first medical intervention, his blood pressure returned to normal; within an hour all drug treatment could be interrupted. After 24 hours, the intravenous fluid treatment was stopped and the subject was able to leave the clinic. He reported feeling fatigued for another five days, but was able to carry out all normal activities. The event was diagnosed as an anaphylactic reaction. Both subjects were excluded from the rest of the study.

Due to the events described above, as well as an allergic reaction considered moderate and possibly related to Sandimmune that also led to the withdrawal of the subject, the study was pending and a modification was made to the study protocol with the addition of premedication as described above. .

Other t ^ es subjects did not complete the study due to adverse events. These were all moderate and

possibly or probably related to corr ^ * “study medication. Of these, two of the participants received the test product with a premedication and one the reference product with premedication. None of the subjects who received the test drug CicloMulsion without premedication withdrew due to adverse events.

A summary of all adverse reactions at least possibly related to the study medication is presented in Table 4. No clinically significant or consistent changes in laboratory values or ECG findings were observed due to the administration of CsA. Vital signs and clinical findings were essentially unchanged during the study for all participants except for the two SAEs described above.

Discussion

After a single intravenous dose of 5 mg / kg, CicloMulsion and Sandimmune met the conventional criteria for bioequivalence. CicloMulsion was the best tolerated of the two CsA formulations.

Three patients had to be excluded from the study due to adverse reactions to Sandimmune, so the study design was changed after a decision by local authorities. Due to this high incidence of

received severe adverse reactions in subjects that Sandimmune, premedication was introduced. The pharmacokinetics calculated between subjects who did not receive premedication were similar, and bioequivalence could be established with a low within-subject CV (for most variables below 10%), including premedicated and non-premedicated subjects. Therefore, changes in the protocol and the introduction of premedication did not affect the pharmacokinetic profile of CsA. In clinical practice, most CrEL-containing IV drugs (such as the anti-cancer agent paclitaxel) are given with premedication due to the known risk of hypersensitivity reactions to CrEL or, in the case of Sandimmune, given to often as part of a combination regimen with corticosteroids. It is feasible to assume that · the true incidence of adverse reactions to Sandimmune is obscured by the protective effect of corticosteroids. A number of the reports of CrEL reactions have been explained by incorrect dilution of concentrate of «

Sandimmune Injection. CrEL has a higher specific gravity than water and a high viscosity and, unless mixed properly, it will not be divided evenly in the infusion bottle. CREL and CsA concentrations up to nine times the desired dose have been reported during the first 10 minutes of infusion when mixed.

incorrectly (15, 27, 28). With a ready-to-use proprietary ready-to-use preparation without dilution, this will not be a problem.

. When Althesin® was withdrawn in the late 1980s due to serious side effects due to CrEL, some authors argued that CrEL should not be used as a solvent for future drugs (39). Until now, CsA for IV administration has not been available with any other emulsifiable excipient, which is surprising considering the extensive literature reporting serious or even fatal CrEL-related reactions (27, 40).

There are several previous studies comparing the pharmacokinetics of CsA formulations administered orally, but few for IV administration. In its oral form, CsA has often been found to have great variation in bioavailability between individuals (41—

45) due to a number of factors, such as gastric emptying rate, biliary, pancreatic, and intestinal secretion rate, polymorphism in cytochrome P4503A enzymes, and different P-glycoprotein haplotypes expressed in the mucosa of the intestinal wall. Intra-individual differences are usually explained by dietary factors and clinical condition (42-44, 46, 47).

There are examples of intravenous drugs in which the pharmacokinetic profiles have been significantly

altered when a lipid emulsion an emulsifier; known examples are (17. 48-50). Taking this into account.

the intra-individual coefficient of variation (CV) was estimated to be 35% when the study was designed. It was found to be less than 10% for all primary variables, supporting the view that most of the intra-individual variation in bioavailability is mainly due to factors relevant to orally administered CsA formulations. The% inter-individual CV in this study was between 10% and 20% for Cmax AUCo-t AND AUCo-οο, consistent with previous reports of CsA IV (41, 51, 52). The ongoing debate about switching from orally administered brand and generic CsA formulations, for reasons of variability, should therefore not be extrapolated to IV drug formulations.

From the study, it is concluded that CicloMulsion is bioequivalent to Sandimmune and that the CsA IV CicloMulsion formulation without ethanol and CrEI, ready to use, is better tolerated.

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176 members in 21 offices

This recordMember, by publication datePriority claim11 more offices are in the list below

Priority claims14

Priority claims
Document	Office	Kind	Date
38863310	United States of America	P	2010-10-01
38863310	United States of America	P	2010-10-01
61388633	United States of America	–	2010-10-01
PA201000891	Denmark	–	2010-10-01
PA201000891	Denmark	A	2010-10-01
PA201000891	Denmark	A	2010-10-01
2011067117	European Patent Office (EPO)	W	2011-09-30
2011067117	European Patent Office (EPO)	W	2011-09-30
61388633	–	–	–
DKPA201000891	–	–	–
EP1167117	–	–	–
PA201000891	–	–	–
US20100388633P	–	–	–
WO2011EP67117	–	–	–

Members176

Family members, oldest first
Document	Office	Kind
US2009088336A1	United States of America	A1	2009-04-02
AU2008308686A1	Australia	A1	2009-04-09
CA2934220A1	Canada	A1	2009-04-09
CA3138078A1	Canada	A1	2009-04-09
CA3170924A1	Canada	A1	2009-04-09
WO2009046227A1	World Intellectual Property Organization (WIPO)	A1	2009-04-09
CA2701794A1	Canada	A1	2009-04-16
CA3042430A1	Canada	A1	2009-04-16
MX2010003578A	Mexico	A	2010-06-09
EP2205968A1	European Patent Office (EPO)	A1	2010-07-14
KR20100097103A	Republic of Korea	A	2010-09-02
EP2205968A4	European Patent Office (EPO)	A4	2010-09-29
CN101874205A	China	A	2010-10-27
IL204877D0	Israel	D0	2010-11-30
JP2010540971A	Japan	A	2010-12-24
HK1150175A1	Hong Kong, China	A1	2011-11-04
RU2010117267A	Russian Federation	A	2011-11-10
US8088593B2	United States of America	B2	2012-01-03
CA2812901A1	Canada	A1	2012-04-05
WO2012042023A2	World Intellectual Property Organization (WIPO)	A2	2012-04-05
US2012149035A1	United States of America	A1	2012-06-14
WO2012042023A3	World Intellectual Property Organization (WIPO)	A3	2012-06-21
NZ584963A	New Zealand	A	2012-11-30
IL223599D0	Israel	D0	2013-02-03
IL223600D0	Israel	D0	2013-02-03
IL223601D0	Israel	D0	2013-02-03
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SG188082A1	Singapore	A1	2013-03-28
AU2011310111A1	Australia	A1	2013-04-04
AU2013205047A1	Australia	A1	2013-05-16
AU2013205052A1	Australia	A1	2013-05-16
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AU2013205047A8	Australia	A8	2013-05-30
AU2013205052A8	Australia	A8	2013-06-13
IL225300D0	Israel	D0	2013-06-27
JP2013145247A	Japan	A	2013-07-25
EP2621469A2	European Patent Office (EPO)	A2	2013-08-07
EA201390507A1	Eurasian Patent Organization (EAPO)	A1	2013-08-30
US2013244898A1	United States of America	A1	2013-09-19
CN103323610A	China	A	2013-09-25
US2013252320A1	United States of America	A1	2013-09-26
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MX2013003578A	Mexico	A	2013-10-25
EP2657699A1	European Patent Office (EPO)	A1	2013-10-30
KR20130119006A	Republic of Korea	A	2013-10-30
KR20130124944A	Republic of Korea	A	2013-11-15
EP2205968B1	European Patent Office (EPO)	B1	2013-11-20
US2013323270A1	United States of America	A1	2013-12-05
DK2205968T3	Denmark	T3	2014-02-17
ES2447875T3	Spain	T3	2014-03-13
CL2013000865A1	Chile	A1	2014-03-28
US8697377B2	United States of America	B2	2014-04-15
JP5511669B2	Japan	B2	2014-06-04
AU2011310111B2	Australia	B2	2014-08-14
IL204877A	Israel	A	2014-08-31
US8822167B2	United States of America	B2	2014-09-02
CN101874205B	China	B	2014-10-01
JP2014186038A	Japan	A	2014-10-02
US2014335506A1	United States of America	A1	2014-11-13
IL223599A	Israel	A	2014-11-30
RU2013127796A	Russian Federation	A	2014-12-27
CN104297506A	China	A	2015-01-21
CN104297507A	China	A	2015-01-21
AU2008308686B2	Australia	B2	2015-01-22
AU2013205047B2	Australia	B2	2015-01-22
RU2540424C2	Russian Federation	C2	2015-02-10
CN104502579A	China	A	2015-04-08
AU2013205052B2	Australia	B2	2015-04-16
AU2015201617A1	Australia	A1	2015-04-16
US9012163B2	United States of America	B2	2015-04-21
CN104548064A	China	A	2015-04-29
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US9040487B2	United States of America	B2	2015-05-26
KR20150063603A	Republic of Korea	A	2015-06-09
US2015198588A1	United States of America	A1	2015-07-16
US2015238563A1	United States of America	A1	2015-08-27
IL223600A	Israel	A	2015-08-31
IL223603A	Israel	A	2015-08-31
US9121851B2	United States of America	B2	2015-09-01
CN103118664B	China	B	2015-11-25
IL223602A	Israel	A	2015-11-30
US2015355169A1	United States of America	A1	2015-12-10
KR101579327B1	Republic of Korea	B1	2015-12-21
US2015377871A1	United States of America	A1	2015-12-31
US2015377914A1	United States of America	A1	2015-12-31
HK1206422A1	Hong Kong, China	A1	2016-01-08
HK1206424A1	Hong Kong, China	A1	2016-01-08
MX336100BThis record	Mexico	B	2016-01-08
US2016025721A1	United States of America	A1	2016-01-28
JP5860468B2	Japan	B2	2016-02-16
HK1208357A1	Hong Kong, China	A1	2016-03-04
US9285366B2	United States of America	B2	2016-03-15
HK1209185A1	Hong Kong, China	A1	2016-03-24
US2016139138A1	United States of America	A1	2016-05-19
US2016161513A1	United States of America	A1	2016-06-09
EP2621469B1	European Patent Office (EPO)	B1	2016-07-20
MX340897B	Mexico	B	2016-07-29

Showing 100 of 176

Cyclosporine emulsion.

Abstract

Term

PATENT TITLE NO. 336100

TO DIVISIONAL DIRECTOR OF PATENTS

NAHANNY CANAL REYES

CYCLOSPORIN EMULSION

CI

CL

CV

ECG

EDTA

EMA

FDA

IV

LC-MS / MS

LLOQ

MRT

PVC

SA'E

USP

IT

USES. 2001

Priority claims14

Members176

Numbers

Titles2

Classification