Pharmaceutical compositions for oral administration containing long-chain triglycerides and lipophilic surfactants

 

(57) Abstract:

The pharmaceutical composition contains undecanoate testosterone as a medicinal substance. Undecanoate testosterone dissolved in the liquid carrier. Carrier liquid comprises glycerides of long chain fatty acids having from 14 to 22 carbon atoms, preferably long-chain triglyceride, and lipophilic surfactant with HLB less than 10, preferably neuroglial. The specified carrier liquid does not contain free fatty acids. A new composition for oral administration provides increased solubility of the sex hormone - testosterone undecanoate and is characterized by improved stability during storage. Composition with undecanoate testosterone can be successfully used in capsule formulations with soft gel and hard shell. 6 C. and 12 C.p. f-crystals.

This invention relates to pharmaceutical compositions intended for oral administration. In particular, this invention relates to liquid pharmaceutical compositions suitable for encapsulation in soft gel.

It is known that some drugs is necessary in order for both the acid. For example, long-chain fatty acids may be prone to absorption into the lymphatic system and, therefore, may be useful in pharmaceutical compositions, in which the lymphatic system is a desirable target for the active ingredient. One of the problems associated with compositions containing fatty acid, is the increase of the chemical instability due to the acidic nature of fatty acids and the presence of reactive carboxyl groups. Molecules of medicinal preparations containing alcohol groups can be subjected to esterification or in the case of molecules, representing esters, interesterification.

In the past this problem was solved through the use of free fatty acids in the compositions, which were concluded in the capsule soft gel, and storage of capsules in the cooling conditions to reduce the speed of interaction between drugs and fatty acids. However, if the drug in the composition is not sufficiently soluble, storage at low temperatures leads to crystallization, which in turn requires trim capsules at room temperature, in order to ensure the dissolution of the crystal plumage the presses storage.

Lacy et al. in PCT application WO 95/24893, published on September 21, 1995 , discloses a system carriers for hydrophobic drugs, which includes easily digestible oil and a pharmaceutically acceptable surfactant for dispersion of oil in vivo for the introduction of carrier, and this surfactant comprises a hydrophilic component, a surfactant that is not inhibited significantly lipolysis easily digestible oil and a lipophilic component, a surfactant, which significantly reduces the inhibitory effect of the hydrophilic component surfactants. Suitable digestible oils represent a full or partial esters of medium chain (C8-C22) or long-chain (C14-C22) fatty acids and low molecular weight (up TO6) mono-, di - or polynuclear alcohols. Especially preferred are triglycerides of medium chain length or a mixture of long-chain tri - and diglycerides, which may contain monoglycerides. The preferred oil is fractionated coconut oil.

Used lipophilic surfactants include jantarnoy, lactic, citric and/or tartaric acids; mono - and/or diesters of propylene glycol and fatty acids; polyglyceryl esters of fatty acids; castor oil ethoxylates; ethoxylates of fatty acids and esters; fatty acid esters and sorbitol.

Used hydrophilic surfactants have the value of the hydrophilic/lipophilic balance (HLB) above 10 and includes phospholipids; fatty acid derivatives of polyoxyethylenesorbitan; ethoxylates of castor oil or hydrogenated castor oil; ethoxylates of fatty acids, ethoxylates of alcohols; copolymers and block copolymers of polyoxyethylene and polyoxypropylene; anionic surfactants and alkylphenol surfactants.

The composition may contain ethanol as co-solvent, and disclosed compositions containing up to 15 wt.% of ethanol.

Perry et al. in PCT application WO 97/40823 published on 6 November 1997, disclose a pharmaceutical composition comprising a hydrophobic drug; easily digestible oil chosen from esters of glycerol (triglycerides), or esters of propylene glycol and medium chain (C8-C12) or long-chain (C14-C22) fatty acids; monolaurate propylene who/SUB> fatty acids; and a hydrophilic surfactant, which is polyoxyethylene gidrirovannoe castor oil, where the digestible oil is present in a quantity in the range from 3.0 to 12.0% by weight of the composition, and the mass ratio of the hydrophilic surface-active substances to the lipophilic surfactant is in the range from 1:1.5 to 1:2,5. The composition may contain ethanol as co-solvent medicines and disclosed compositions containing 15-25% by weight of ethanol.

There is still a need for pharmaceutical compositions having improved stability which contribute to systemic absorption.

This invention discloses a liquid pharmaceutical composition where the active ingredient is dissolved in a liquid carrier comprising the combination of long chain glycerides and lipophilic surfactants. Compositions in accordance with this invention are stable and contribute to systemic absorption, they can be used for compositions intended for oral administration, containing medicaments or active ingredients, C particularly useful for oral compositions, containing undecanoate testosterone (also known as TU).

In accordance with this invention provides a liquid pharmaceutical composition, comprising a drug dissolved in a liquid carrier, and the carrier liquid includes:

a) the glycerides of long chain fatty acids having a chain containing from 14 to 22 carbon atoms, which is present in the amount of approximately from 15 to 70%, preferably from about 15 to 60% by weight of the specified liquid media;

b) lipophilic surfactant having an HLB less than 10, and is present in the amount of approximately from 30 to 60% by weight of the specified liquid medium.

The composition in accordance with this invention contains a carrier liquid, essentially not containing free fatty acids, and contains less than 10% by weight of ethanol.

The composition may further include a hydrophilic surfactant which may be present in amounts of about 0 to 35% by weight of a liquid medium.

In one of the embodiments of the present invention provides a liquid pharmaceutical composition for peror the media essentially includes:

a) the glycerides of long chain fatty acids having a chain containing from 14 to 22 carbon atoms; and

b) neuroglial.

Presently discovered that the stability problem associated with free fatty acids, can be avoided by applying glycerides, in which fatty acids atrificial glycerin with the formation of the neutral compound, which is less reactive. Thus, this invention minimizes or eliminates the use of free fatty acids in the compositions.

Suitable glycerides for use in this invention are mono-, di - and triglycerides. Preferred glycerides are triglycerides, as they have the highest amount of fatty acids. As a result of lipolysis in the gastrointestinal tract long-chain glycerides can release long-chain fatty acids. The presence of long-chain triglycerides is desirable for the promotion of lymphatic absorption, similar to the corresponding fatty acids. See, for example, Henk de Nijs, Acta Technol., 33(4) pp. 163-168 (1987) discussed the increase lymphatic absorption by applying triglycerides, and various mechanisms absorptivities surfactants and optional additional hydrophilic surfactant increases the solubility of the drug in the liquid triglyceride media while maintaining stability of the composition.

The invention in particular can be used in pharmaceutical compositions containing medicines, such as active ingredients, compounds, prodrugs, etc., when combining them with the free fatty acids have problems related to stability. The preferred compositions of this invention are compositions containing undecanoate testosterone (TU).

In the description and the claims, the terms "drug" and "active ingredient" are used interchangeably to refer to pharmaceutical compounds or molecular structures. When used in the context of the present invention these terms apply to pharmaceutical compounds that can be used together with the liquid carrier of the present invention to obtain the target pharmaceutical compositions.

The phrase "essentially free of free fatty acids" when used in the context of the descriptions of pharmaceutical compositions in accordance with this invention means that the liquid medium contains less than 1 wt.% fatty acids that do not form an ester with a polyol such as glycol.

This invention includes a liquid pharmaceutical composition, ocupacional fatty acids, having a chain containing from 14 to 22 carbon atoms, which is present in the amount of approximately from 15 to 70%, preferably from about 15 to 60% by weight of the specified liquid media;

b) lipophilic surfactant having an HLB less than 10, and is present in the amount of approximately from 30 to 60% by weight of the specified liquid medium.

The composition in accordance with this invention contains a carrier liquid, essentially not containing free fatty acids, and preferably contains less than 10% by weight of ethanol.

The composition may further include a hydrophilic surfactant which may be present in amounts of about 0 to 35% by weight of a liquid medium.

Suitable drugs or active ingredients that can be used in this invention are those, where in the presence of free fatty acids having problems with stability. Such drugs or prodrugs include, but are not limited to, compounds containing ester groups, which can lead to interesterification, compounds containing th communication as well as compounds which contain amino groups, which can lead to the formation of amide linkages. Examples of such drugs or active ingredients include undecanoate testosterone, hexanoate hydroxyprogesterone and other steroid esters, retinilpalmitat, fenofibrate, halogenated, retinol and tocopherol. The preferred compositions of this invention are compositions containing as active ingredient undecanoate testosterone.

Suitable for use in this invention, long-chain (C14-C22) triglycerides include, but are not limited to, peanut oil, soybean oil, castor oil, corn oil, safflower oil, olive oil, stone fruit apricot oil, sesame oil, cottonseed oil, sunflower oil, palm oil and rapeseed oil. Triglycerides are present in amounts comprising from about 15 to 70% by weight of a liquid medium, preferably in amounts of about 40 to 60% by weight of a liquid medium.

Suitable long-chain monoglycerides, which can be used include monooleate glycerin.

Suitable for use in dannie HLB less than 10 (HLB<10). Lipophilic surfactant having an HLB value less than 10, which can be used include, but are not limited to: mono - and diglycerides of fatty acids; esters of acetic, succinic, lactic, citric and tartaric acids and mono - and diglycerides of fatty acids; mono - and diesters of propylene glycol and fatty acids; polyglyceryl esters of fatty acids, ethoxylates of castor oil and hydrogenated castor oil; acid ethoxylates and ethoxylates esters; esters of fatty acids sorbitan; unsaturated poliglecaprone glycerides, ethoxylates of alcohols; as well as copolymers and block copolymers of polyoxyethylene and polyoxypropylene.

Examples of mono - and diglycerides of fatty acids that can be used as lipophilic surfactants include, for example, mono/dicaprylate glycerol mono/dicaprylate/capret glycerin, monocaprylin of glycerol, monostearate of glycerol, mono/dirichelet glycerin, kaprilat/capret glycerin, monooleate glycerin, dilaurate glycerol and glycerol monostearate.

Esters of acetic, succinic, lactic, citric and/or tartaric acids and mono - and/or diglycerides of fatty acids that can be used as lipo is aprilat/capret diglyceride, mono/diskriminirovaniya monoglycerides, citrate glycerylmonostearate, lactate monostearate/citrate glycerol, cocat/citrate/lactate glycerol.

Mono - and/or diesters of propylene glycol and fatty acids, which can be used include, for example, neuroglial (monolaurate propylene glycol) and dicaprylate/dicaprate propylene glycol.

Polyglyceryl esters of fatty acids suitable as lipophilic surfactants include polyglycerol.

Can also be used ethoxylates castor oil and hydrogenated castor oil having a low content of ethoxylate and HLB less than 10, for example, when 5 moles of ethylene oxide interacts with 1 mol of castor oil.

Ethoxylates acids, ethoxylates of esters formed by the interaction of ethylene oxide with fatty acids or esters of fatty acids and glycerol, which can be used include polyoxyethylene(4) - lauric acid, polyoxyethylene(2)stearic acid, polyoxyethylene(3)stearic acid, glycerin 12 SW dioleate.

Esters of fatty acids and of sorbitol, suitable for use as lipophilic surfactants, kimery unsaturated poliglecaprone of glycerides include polyoxyethylene stone fruit apricot kernel oil, polyoxyethylene corn oil, polyoxyethylene b oil.

The ethoxylates of alcohols which may be used include polyoxyethylene (3) alerby simple ether, polyoxyethylene (2) alerby simple ether.

As lipophilic surfactants can also be used by representatives of copolymers and block copolymers of polyoxyethylene and polyoxypropylene.

Lipophilic surfactant is used in amounts varying from about 30 to 60%, usually from about 40 to 60% by weight of a liquid medium.

Preferred lipophilic surface-active substances intended for use in liquid media, are mono - and/or diesters of propylene glycol and fatty acids. Most preferred as a lipophilic surfactant is neuroglial (monolaurate propylene glycol).

In the following embodiment, in addition to the long-chain the glycerides and lipophilic surface-active ingredient of the present invention can be used pharmaceutically acceptable hydrophilic surfactant, Kolesova, include:

a) phospholipids, in particular lecithins, preferably soybean lecithins;

b) fatty acid derivatives polyoxyethylenesorbitan, such as monolaurin of polyoxyethylene (20), monopalmitate of polyoxyethylene(20), monopalmitate of polyoxyethylene(20) monostearate polyoxyethylene(20) sorbitol and monooleate of polyoxyethylene (20);

(C) ethoxylates of castor oil or hydrogenated castor oil, for example polyoxyethylene(35) castor oil, polyoxyethylene(40) gidrirovannoe castor oil, polyoxyethylene(40) castor oil and polyoxyethylene (60) gidrirovannoe castor oil;

a) ethoxylates of fatty acids, for example polyoxyethylene stearate(8), monolaurin of polyoxyethylene(30) stearate and polyoxyethylene(20) of oleate polyoxyethylene(15);

e) ethoxylates alcohols, for example, alerby simple ether of polyoxyethylene(10), alerby simple ether of polyoxyethylene(30), fat (C12-C14simple ester of polyoxyethylene (20);

(f) copolymers and block copolymers of polyoxyethylene and polyoxypropylene;

g) alkylphenol surfactants, such as polyoxyethylene(9-10)Nonylphenol, polyoxyethylene(9)Nonylphenol;

h) saturated polyglucosides(8).

The composition can contain up to 40 wt.% hydrophilic surfactants by weight of a liquid medium.

In the compositions in accordance with this invention can be used with other traditional ingredients or additives. For example, antioxidants, such as d-alpha-tocopherol, BHA, BHT a cosolvent, such as ethanol, diethylene glycol, monotropy ether plasticizers such as propylene glycol, etc.

Compositions in accordance with this invention can be obtained by using traditional methods such as described by Lacy et al., in PCT application WO 95/24893, published on 21 September 1995 Typical way to obtain the media systems of the present invention begins with the weighing of the oil component in a suitable vessel made of stainless steel, then weigh lipophilic surfactant and add it to the container. The mixing of the two liquids is carried out using a homogenizing mixer or other device with high speed mixing. If the substance is solid at room temperature, applying heat sufficient to achieve a liquid state without chemical decomposition. When using hydrophilic surface-dobavlaut last under stirring. Then weigh your drug, add it to the combined liquid and stirring is continued until the receipt or homogeneous solution or suspension. Then the composition is subjected to deaeration, then encapsulate in a hard or soft capsule. In some cases, to facilitate the process of the filling composition can be kept at an elevated temperature, using a suitable private housing vessel.

The composition can be encapsulated in capsules, soft gel or a hard shell. Methods for encapsulation in soft gel are listed in theory and Practice of Industrial Pharmacy (Lachman & Leiberman, 2ndEdition, publ. Henry Kimpton Publishers, London). Methods of liquid filling capsules with a hard shell disclosed in Hardcapsules-Development and Technology, edited by K. Ridgeway (published in Pharmaceutical Press) (1987).

Hereinafter the invention will be illustrated using the following examples, which should not be understood as limiting the invention.

Examples from 1A to 14A

Obtaining compositions of liquid media

Get fourteen compositions of liquid carrier for drugs, including the following relevant ingredients, the contents of which are expressed in wt. including:

Example:
- 25

Neuroglial - 40

Monopalmitate of polyoxyethylene (20) - 35

Peanut butter - 40

Neuroglial - 60

Peanut butter - 40

Monooleate glycerol - 60

Castor oil - 60

Neuroglial - 40

Soybean oil - 50

Neuroglial - 50

Soybean oil - 20

Mono/dicaprylate glycerol - 50

Kaprilat glycerin and kaprilat/capret peg (8) - 30

Castor oil - 60

Mono/dicaprylate glycerol - 40

Castor oil - 40

Neuroglial - 55

Ethanol - 5

Castor oil - 30

Mono/dicaprylate glycerol - 40

Polyoxyethylene (35) castor oil - 30

Castor oil - 50

Neuroglial - 30

Kaprilat glycerin and kaprilat/capret peg (8) - 20

Peanut butter - 40

Monooleate glycerol - 30

Polyoxyethylene (35) castor oil - 25

Ethanol - 5

Peanut butter - 25

Neuroglial - 60

Kaprilat glycerin and kaprilat/capret peg (8) - 15

Peanut butter - 60

Mono/dicaprylate glycerol - 40

Examples from 1V to 14V

Obtaining pharmaceutical compositions, compositions containing a liquid medium

The compositions containing the active ingrediemur 1A - 14A, with 12 wt. including testosterone undecanoate (TU). The resulting composition contains undecanoate testosterone in a stable form, which is suitable for encapsulation in obtaining capsules soft gel.

Example 15

Definition of comparative stability testosterone undecanoate (TU)

Accelerated stability studies are conducted using pharmaceutical compositions containing undecanoate testosterone as the active ingredient in the samples, which use a carrier liquid in accordance with this invention, and the control of liquid media.

Five samples containing undecanoate testosterone produced in accordance with the formulations shown in examples 1B - 5B. Prepare a control sample containing undecanoate testosterone in combination with oleic acid. Then all six samples stored for three months.

After three months, each of the samples examined for the content of testosterone undecanoate. It was found that in the five samples containing composition obtained in accordance with this invention, contained at least 86%, or even at least 90% of active ingredient, whereas in the control sample with the nye show the samples obtained in accordance with this invention demonstrate improved stability in time of the original active ingredient (i.e. testosterone undecanoate) during storage compared with the control sample containing the active ingredient with oleic oil.

This invention can be used in the manufacture of pharmaceutical compositions for oral administration, where, as you know, there are problems with the stability of the drug or active ingredient associated with the use of free fatty acids. Examples of such drugs or active ingredients include sex hormones, such as undecanoate testosterone. Compositions of the present invention increase the solubility of such compounds and improve their stability during storage, and can be successfully used in capsule formulations with soft gel and hard shell.

Full disclosure of all patents, patent applications and publications are incorporated herein by reference as if each had been individually incorporated by reference. This invention has been described with reference to various specific and preferred embodiments and techniques. However, it should Ponomarenko departures from the spirit and scope of this invention.

1. Liquid pharmaceutical composition for oral administration comprising the medicinal substance, which is undecanoate testosterone dissolved in a liquid carrier, and the specified carrier liquid includes a) the glycerides of long chain fatty acids having from 14 to 22 carbon atoms, in the amount of approximately 15-70% by weight of a liquid medium; (b) lipophilic surfactant having an HLB less than 10, in the amount of about 30-60% by weight of the liquid carrier and the liquid carrier, essentially, does not contain free fatty acids.

2. Liquid pharmaceutical composition according to p. 1, where the glycerides is a long-chain triglyceride having from 14 to 22 carbon atoms.

3. Liquid pharmaceutical composition according to p. 2, where long-chain triglyceride is selected from the group consisting of peanut oil, soybean oil, castor oil, corn oil, safflower oil, olive oil, stone fruit apricot kernel oil and sesame oil, and combinations thereof.

4. Liquid pharmaceutical composition according to p. 1, where the glycerides of long chain fatty acid is a mono - or diglyceride.

5. Liquid farmd of monooleate glycerin.

6. Liquid pharmaceutical composition according to p. 1 wherein the lipophilic surfactant is selected from the group consisting of mono - and diglycerides of fatty acids; esters of acetic, succinic, lactic, citric and tartaric acids and mono - and diglycerides of fatty acids; mono - and diesters of propylene glycol and of fatty acids, ethoxylates of castor oil and hydrogenated castor oil; acid ethoxylates and ethoxylates esters; esters of fatty acids and sorbitol; unsaturated poliglecaprone of glycerides, ethoxylates of alcohols; and copolymers and block copolymers of polyoxyethylene and polyoxypropylene, as well as their combinations.

7. Liquid pharmaceutical composition according to paragraph 6, where the lipophilic surfactant is monoether of propylene glycol and fatty acids.

8. Liquid pharmaceutical composition according to p. 7, where the lipophilic surfactant is neuroglial.

9. Liquid pharmaceutical composition according to p. 1, additionally comprising a hydrophilic surfactant.

10. Liquid pharmaceutical composition according to p. 9, where the hydrophilic surfactant selected from the group consisting of Wannago castor oil, the ethoxylates of fatty acids, ethoxylates of alcohols, copolymers and block copolymers of polyoxyethylene and polyoxypropylene, alkylphenolic surfactants and poliglecaprone medium chain triglycerides, and combinations thereof.

11. Liquid pharmaceutical composition according to p. 1, further comprising ethanol.

12. Liquid pharmaceutical composition according to p. 11, which contains less than 15 wt.% of ethanol.

13. Liquid pharmaceutical composition for oral administration comprising undecanoate testosterone dissolved in a liquid carrier, and the specified liquid medium consists essentially of (a) glycerides of long chain fatty acids having from 14 to 22 carbon atoms, taken in an amount of approximately 15-70% by weight of a liquid medium, and (b) europiccola, taken in an amount of approximately 30-60% by weight of a liquid medium.

14. Liquid pharmaceutical composition according to p. 13, where the glycerides of long chain fatty acid is a triglyceride.

15. Capsule soft gel, containing liquid pharmaceutical composition under item 1.

16. Capsule soft gel, containing liquid pharmaceutical composition under item 13.

17. Capsi shell, containing liquid pharmaceutical composition according to p. 13.

 

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