ES2436344A1 - Pharmaceutical composition of diacetylmorphine and naloxone for oral administration - Google Patents

Pharmaceutical composition of diacetylmorphine and naloxone for oral administration Download PDF

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Publication number
ES2436344A1
ES2436344A1 ES201230814A ES201230814A ES2436344A1 ES 2436344 A1 ES2436344 A1 ES 2436344A1 ES 201230814 A ES201230814 A ES 201230814A ES 201230814 A ES201230814 A ES 201230814A ES 2436344 A1 ES2436344 A1 ES 2436344A1
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Prior art keywords
naloxone
mg
diacetylmorphine
characterized
hydrochloride
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ES201230814A
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ES2436344B1 (en
Inventor
Rosa Pardina Clar
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OneDose Pharma SL
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OneDose Pharma SL
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • A61K31/485Morphinan derivatives, e.g. morphine, codeine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2027Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Abstract

Pharmaceutical composition of diacetylmorphine and naloxone for oral administration; comprising diacetylmorphine or one of its pharmaceutically acceptable salts, naloxone or one of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient, with a weight ratio between diacetylmorphine: naloxone is between 24: 1 and 26: 1. The invention also comprises a tablet with this composition and the use of said composition or tablet for the preparation of a medicament for the treatment of addiction to opioid substances.

Description

Pharmaceutical composition of diacetylmorphine and naloxone for oral administration.

Object of the invention.

The present invention relates to a pharmaceutical composition of diacetylmorphine and naloxone for oral administration. Said composition is characterized in that the weight ratio between diacetylmorphine and naloxone is between 24: 1 and 26: 1, which makes it possible to achieve a good efficacy in the substitute treatment in drug addiction, with greater safety against its abuse by injection. It also refers to a tablet comprising the composition, and the use of the composition and the tablet for the preparation of a medicament for the treatment of addiction to opioid substances.

Field of application of the invention.

The invention is applicable in the preparation of medicaments for the treatment of addiction to opioid substances.

State of the art

Dependence on opioid substances, and in particular on heroin, is a recognized health problem that also has serious social complications.

A strategy usually used to address the problem of dependence on heroin or other opioids is the replacement treatment, which consists of administering to the dependent individuals an opioid agonist substitute, orally, in a relatively stable dose and under medical control and that usually It is complemented with social and psychological therapies. Said treatment has the objective of avoiding the abusive consumption of heroin and thus avoiding the medical risks derived from said use, such as adulteration, overdose, and risk of infection by the human immunodeficiency virus, and it is ultimately intended, normalization and insertion social of drug dependent patients.

The opioid agonist most traditionally used as a substitute treatment in drug addiction is methadone. However, since not all patients respond favorably to such treatment, it has been necessary to develop new opioids suitable for this indication, in order to have alternative therapies to methadone, as described, for example, in the article Castellano Gómez M., Towards the diversification of opioid agonist treatments, Addictive disorders, 2003, 5 (4), 291-4.

Thus, the use of other opioid agonists has been described for substitute treatment in drug dependence such as, for example, buprenorphine, morphine, levo alpha acetyl methadol, hydrocodeine and diacetylmorphine (heroin).

A possible problem derived from the substitute treatment with opioid agonists by oral route is the improper use that can be made of them, especially through incorrect intravenous administration, either by the patient himself, or through their illegal distribution. That is why safer oral formulations have been developed, based on the combination of said opioid agonists with opioid antagonist substances of low oral bioavailability, so that oral administration of the combination only triggers the desired pharmacological effect of the agonist, while, In case of a hypothetical incorrect intravenous administration, the opioid antagonist would act by blocking the action of the agonist, which would result in a deterrent effect for drug abuse.

Some combinations of agonists and opioid antagonists have been described in the prior art to achieve a safer oral maintenance drug treatment. Naloxone is the most commonly used opioid antagonist in this area. For example, in the article Shearer et al., The acceptability, safety, and tolerability of methadone / naloxone in a 50: 1 ratio, Exp. Clin. Psychopharmacol., 2009; 17 (3), 146-53, describes the use of the methadone / naloxone combination as a substitute treatment in drug addiction.

Likewise, the Suboxone® pharmaceutical specialty consists of the combination of buprenorphine and naloxone in the form of tablets for sublingual administration, and is indicated for replacement therapy in opioid dependence, so that naloxone has the function of preventing improper intravenous use .

International patent application WO-A-2007/082935 refers to the combination of morphine and a low oral availability opioid antagonist, preferably naloxone. Naloxone has a mainly deterrent function against an abusive non-oral use of the composition, while having a preventive effect of the development of morphine tolerance, as well as of some of its adverse effects, such as constipation and sexual dysfunction. The combination is in a pharmaceutical form characterized in that both components cannot be easily separated manually, to avoid undue separation of morphine.

European patent application EP-A-1810714 refers to the combination of heroin and naloxone for non-intravenous administration, in the substitute treatment of drug addiction. Naloxone exerts the aforementioned deterrent function and, additionally, reduces the constipation caused by heroin and also reduces the risk of developing heroin tolerance. The amount of naloxone is said to be between 0.1 mg and 8 mg of naloxone per 100 mg of heroin, although no specific composition of such combination is described herein.

Despite the various formulations proposed in the state of the art, there remains a need to have an alternative composition for substitute treatment in patients with dependence on opioid substances, which is effective and at the same time is safe, so as to achieve minimize the risk of improper use of the composition.

Description of the invention

The object of the present invention is a pharmaceutical composition for oral administration comprising diacetylmorphine or a pharmaceutically acceptable salt thereof, naloxone or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the weight ratio between diacetylmorphine: naloxone is between 24: 1 and 26: 1.

The authors of the present invention have developed a pharmaceutical composition for oral administration comprising the combination of diacetylmorphine and naloxone in a weight ratio such that it has an improved effect in relation to the compositions described in the state of the art, since it allows an action Effective replacement therapy of diacetylmorphine by oral administration and at the same time ensures a complete inhibition of the opioid effect of diacetylmorphine by naloxone in the hypothetical case of undue intravenous administration.

Diacetylmorphine

Diacetylmorphine is the International Common Denomination (INN) corresponding to the diacetate of (5th, 6th) -7,8dideshydro-4,5-epoxy-17-methylmorphinan-3,6-diol. It is an opioid derived from morphine, specifically the diester 3,6-morphine diacetate, also known by the names heroin, diamorphine, acetomorphine, or morphine diacetate.

Diacetylmorphine can be obtained from morphine, for example, as described in the article Small L., Chemistry of the Opium Alkaloids, Public Health Reports, Washington, 1932, Supplement No. 103.

Diacetylmorphine is a potent opioid analgesic that can be used medically for the treatment of severe pain. It is also used as a substitute therapy in drug addiction.

In the context of the present invention, the term "diacetylmorphine" refers broadly to diacetylmorphine as such, as well as to any of its solvated forms or polymorphic forms.

Pharmaceutically acceptable salts of diacetylmorphine refer to acid addition salts, which can be prepared according to conventional methods well known to those skilled in the art, using pharmaceutically acceptable organic or inorganic acids and substantially non-toxic. Such acids include hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, maleic acid, malonic acid, succinic acid, citric acid, tartaric acid, malic acid, salicylic acid, phthalic acid, etc. Preferably, hydrochloric acid is used.

 In a preferred embodiment of the invention, diacetylmorphine is in the form of its hydrochloride salt.

Naloxone

The term naloxone is the International Common Denomination (INN) by which the product 17-allyl-4,5 a-epoxy-3,14-dihydroximorfinan-6-one is commonly known. It is a specific opioid antagonist.

Naloxone can be prepared, for example, according to the procedure described in British patent application GBA-939287.

 In the context of the present invention, the term naloxone also includes its solvated and polymorphic forms.

Pharmaceutically acceptable salts of naloxone refer to acid addition salts, which can be prepared according to conventional methods well known to those skilled in the art, using pharmaceutically acceptable organic or inorganic acids and substantially non-toxic. Such acids include hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, maleic acid, malonic acid, succinic acid, citric acid, tartaric acid, acidic acid, salicylic acid, phthalic acid, etc. Preferably, hydrochloric acid is used.

 In a preferred embodiment of the invention, naloxone is in the form of its hydrochloride salt.

Compositions

The pharmaceutical composition of the invention is characterized in that diacetylmorphine and naloxone are in a weight ratio between 24: 1 and 26: 1, that is to say, for each unit of weight of naloxone, there are between 24 and 26 units of weight of diacetylmorphine

The pharmaceutical composition of the invention can be prepared using methods that are well known to those skilled in the art, such as those contained in pharmaceutical technology manuals, such as the Remington The Science and Practice of Pharmacy book, 20th edition, Lippincott, Williams & Wilkins , Philadelphia, 2000 [ISBN: 0-683-306472]. Preferably the composition of the invention is prepared by direct mixing of the active ingredients and excipients.

For the preparation of the pharmaceutical composition of the invention it is important that the two active ingredients are intimately mixed, together with the corresponding excipient (s), so that a homogeneous mixture is obtained that does not allow the separation of the two active ingredients, a prerequisite to ensure its safe use, and to avoid an undesired intravenous administration of diacetylmorphine separately.

Among the pharmaceutically acceptable excipients that can be included in the pharmaceutical composition are, for example, anti-caking agents such as colloidal silica, tribasic calcium phosphate, calcium silicate, magnesium silicate, magnesium trisilicate or talc; diluting agents such as anhydrous lactose, lactose monohydrate, calcium phosphate, hydrogen anhydrous calcium phosphate, calcium hydrogen phosphate dihydrate, calcium sulfate, calcium carbonate, calcium carboxymethylcellulose, microcrystalline or powdered cellulose, cellulose acetate, dextrates, dextrins, dextrose, fructose glyceryl palmitoestearate, kaolin, lactitol, magnesium carbonate, magnesium oxide, maltitol, maltodextrins, maltose, polymethacrylates, pregelatinized starch, sodium chloride, starch, sucrose or sucrose; lubricating agents such as magnesium stearate, calcium stearate, glyceryl palmostearate, poloxamers, magnesium oxide, sodium benzoate, colloidal silica, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc or glycerin behenate; suspending agents such as xanthan gum, guar gum, alginic acid, bentonite, carbomers, sodium or calcium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropyl alginate, microcrystalline or powdered cellulose, colloidal anhydrous silica, catholic magnesium dextrin, aluminasic silica, aluminasic silica, aluminasic silica, aluminas, silica maltitol, povidone, sorbitan esters or tragacanth; binding agents such as magnesium trisilicate, cellulose, starch, dextrin, dextrose, polydextrose, maltose, matodextrin, ethyl cellulose, methylcellulose, polymethacrylates, talc, povidone, stearic acid or sucrose; disintegrating agents such as low-grade hydroxypropylcellulose, tribasic calcium phosphate, sodium or calcium carboxymethylcellulose, croscarmellose sodium, crospovidone or methylcellulose; dispersing agents such as poloxamers or sorbitan esters; sweetening agents such as aspartame, mannitol, sorbitol, sodium saccharin, sodium cyclamate, sucrose, dextrose, fructose, glucose, inulin, isomalt, lactitol, maltose, maltol, mannitol, sucralose, trehalose, xylitol or thaumatine; flavoring and flavoring agents, and / or mixtures thereof.

The physical-chemical characteristics of the excipients, as well as the name of the commercial products under which they are marketed, can be found in the R.C. Rowe et al., Handbook of Pharmaceutical Excipients, 4th edition, Pharmaceutical Press, London, 2003 [ISBN: 0-85369-472-9].

The pharmaceutical composition of the invention may be in any form suitable for oral administration. Preferably it is in powder or granulate form for oral suspension, tablets or capsules. More preferably the pharmaceutical composition is in the form of tablets. Preferably the tablets are prepared by direct compression of the mixture comprising the active ingredients and the excipients.

The pharmaceutical composition of the invention is dosed according to a unit dosage form, which contains a therapeutically effective dose of the active ingredients. Each unit dosage form corresponds, for example, to a tablet, a capsule or a single-dose powder or granules for suspension.

Preferably, the pharmaceutical composition of the invention is dosed according to a unit dosage form containing: between 25 mg and 500 mg of diacetylmorphine, expressed as equivalent weight of diacetylmorphine hydrochloride, and between 0.97 and 20.8 mg of naloxone, expressed as equivalent weight of naloxone hydrochloride, more preferably between 100 mg and 300 mg of diacetylmorphine and between 3.9 and 12.5 mg of naloxone, and even more preferably 200 mg of diacetylmorphine and 8 mg of naloxone.

In an even more preferred embodiment, the diacetylmorphine is in the form of its hydrochloride salt and the naloxone is in the form of its hydrochloride salt.

That is, in an even more preferred embodiment the pharmaceutical composition of the invention is dosed according to a unit dosage form containing: between 25 mg and 500 mg of diacetylmorphine hydrochloride, and between 0.97 and 20.8 mg of hydrochloride. naloxone, more preferably between 100 mg and 300 mg of diacetylmorphine hydrochloride and between 3.9 and 12.5 mg of naloxone hydrochloride, and even more preferably 200 mg of diacetylmorphine hydrochloride and 8 mg of naloxone hydrochloride.

In one embodiment of the invention, the unit dosage form easily allows its subdivision into lower fractional doses, to facilitate a better adjustment of the appropriate therapeutic dose during treatment. Thus, when the unit dosage form is a tablet, it can be grooved so that it can be conveniently divided into half, a quarter, or three quarters of the dose, for example. Preferably the tablets are grooved.

In a preferred embodiment, the tablets of the invention comprise as excipients: calcium hydrogen phosphate, povidone, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate and talc.

In another preferred embodiment, the tablets of the invention comprise as excipients: lactose monohydrate, povidone, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate and talc.

In a preferred embodiment the content of calcium and lacto hydrogen phosphate is between 5% and 25% by weight with respect to the total weight of the composition, povidone between 3% and 7% by weight with respect to weight. total composition, microcrystalline cellulose between 10% and 40% by weight with respect to the total weight of the composition, croscarmellose sodium between 3% and 7% by weight with respect to the total weight of the composition, and silicon dioxide, magnesium stearate and talc between 1% and 5% by weight with respect to the total weight of the composition. The sum of the percentages of the different excipients and the active ingredients is 100%.

The weight of the tablet may be between 300 mg and 1000 mg, preferably between 400 mg and 600 mg, and even more preferably 500 mg.

The authors of the invention have developed a pharmaceutical composition comprising diacetylmorphine and naloxone in such a proportion that it gives an improved safety profile, since the relationship between both substances is ideal for allowing a complete intravenous inhibition, by naloxone, from the opioid effect of diacetylmorphine, as can be seen from the publication Moro Sánchez et al. Opioids I. Pharmacology. Acute intoxication, in: Drug dependence. Pharmacology. Pathology. Psychology. Legislation. Chapter 6. Eds: Lorenzo P, Ladero J.M., Leza J.C., Lizasoain I., 2009., Pan American Medical Editorial, p. 117

129.

That is why the use of the composition or tablet of the invention for the preparation of a medicament for the treatment of addiction to opioid substances is also part of the invention.

 Or put another way, the composition and tablet of the invention is also part of the invention for use in the treatment of addiction to opioid substances.

Examples

Example 1: Diacetylmorphine and naloxone tablets

The tablets were prepared using the components detailed in the following table:

Components
Amount (mg) Function

Diacetylmorphine hydrochloride
200.00 Active substance

Naloxone hydrochloride
8.00 Active substance

Calcium hydrogen phosphate
77.00 Diluent

Povidone (PVP K25)
25.00 Binder

Microcrystalline cellulose
150.00 Diluent

Croscarmellose sodium
25.00 Disintegrating

Colloidal Silicon Dioxide (Aerosil®)
5.00 Lubricant

Magnesium stearate
5.00 Lubricant

talcum powder
5.00 Lubricant

Total
500.00

In a mixer, diacetylmorphine hydrochloride, naloxone hydrochloride, calcium hydrogen phosphate, povidone and microcrystalline cellulose, croscarmellose sodium were incorporated and mixed until a homogeneous mixture was obtained. Colloidal silica, magnesium stearate and talc were then incorporated, and the whole was mixed again. With the mixture obtained, tablets were prepared, each weighing 500 mg.

Each tablet contained 200 mg of diacetylmorphine hydrochloride and 8 mg of naloxone hydrochloride. Taking into account the molecular weights of diacetylmorphine hydrochloride (405.87), naloxone hydrochloride (363.84) diacetylmorphine (369.41) and naloxone (327.37), each tablet comprises 182 mg of diacetylmorphine and 7.2 mg from

10 naloxone, so that the weight ratio diacetylmorphine: naloxone is 25.28: 1.

Example 2: Diacetylmorphine and naloxone tablets

The tablets were prepared following substantially the procedure described in Example 1 using the components detailed in the following table:

Components
Amount (mg) Function

Diacetylmorphine hydrochloride
200.00 Active substance

Naloxone hydrochloride
8.00 Active substance

Lactose monohydrate
77.00 Diluent

Povidone (PVP K25)
25.00 Binder

Microcrystalline cellulose
150.00 Diluent

Croscarmellose sodium
25.00 Disintegrating

Colloidal Silicon Dioxide (Aerosil®)
5.00 Lubricant

Magnesium stearate
5.00 Lubricant

talcum powder
5.00 Lubricant

Total
500.00

Each tablet contained 200 mg of diacetylmorphine hydrochloride and 8 mg of naloxone hydrochloride, which corresponds to a weight ratio of diacetylmorphine hydrochloride: naloxone hydrochloride of 25: 1, and a weight ratio of diacetylmorphine: naloxone of 25.28: one.

Claims (16)

  1.  CLAIMS
    1.- Pharmaceutical composition of diacetylmorphine and naloxone for oral administration; comprising diacetylmorphine
    or one of its pharmaceutically acceptable salts, naloxone or one of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable excipient, characterized in that the weight ratio between diacetylmorphine: naloxone is between 24: 1 and 26: 1.
  2. 2. Composition according to claim 1, characterized in that the diacetylmorphine is in the form of its hydrochloride salt.
  3. 3. Composition according to any of claims 1 or 2, characterized in that the naloxone is in the form of its hydrochloride salt.
  4. 4. Composition according to any one of claims 1 to 3, characterized in that it is dosed according to a unit dosage form containing between 25 mg and 500 mg of diacetylmorphine hydrochloride.
  5. 5. Composition according to claim 4, characterized in that the unit dosage form contains between 100 mg and 300 mg of diacetylmorphine hydrochloride.
  6. 6. Composition according to claim 5, characterized in that the unit dosage form contains 200 mg of diacetylmorphine hydrochloride.
  7. 7. Composition according to claim 6, characterized in that the unit dosage form contains 200 mg of diacetylmorphine hydrochloride, and 8 mg of naloxone hydrochloride.
  8. 8. Composition according to any of claims 1 to 7, characterized in that it is in the form of a powder or granulate for oral suspension, tablets or capsules.
  9. 9. Composition according to claim 8, characterized in that it is in the form of tablets.
  10. 10. Tablet comprising the composition of any of claims 1 to 7.
  11. 11. Tablet according to claim 10, characterized in that it comprises as excipients: calcium hydrogen phosphate, povidone, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate and talc.
  12. 12. Tablet according to claim 10, characterized in that it comprises as excipients: lactose monohydrate, povidone, microcrystalline cellulose, croscarmellose sodium, silicon dioxide, magnesium stearate and talc.
  13. 13.- Compressed according to any of claims 10 to 12, characterized in that it is grooved.
  14. 14. Tablet according to any of claims 10 to 13, characterized in that it is prepared by direct compression.
  15. 15. Use of the composition according to any of claims 1 to 9 or of the tablet according to any of claims 10 to 14 for the preparation of a medicament for the treatment of addiction to opioid substances.
    SPANISH OFFICE OF THE PATENTS AND BRAND
    Application no .: 201230814
    SPAIN
    Date of submission of the application: 29.05.2012
    Priority Date:
    REPORT ON THE STATE OF THE TECHNIQUE
    51 Int. Cl.: A61K31 / 485 (2006.01) A61P25 / 36 (2006.01)
    RELEVANT DOCUMENTS
    Category
    56 Documents cited Claims Affected
    X
    EP 1810714 A1 (HERMANN, HOLGER LARS) 25.07.2007, page 4, column 5, paragraph 26; claims. 1-15
    X
    EP 1897544 A1 (HERMANN, HOLGER LARS) 12.03.2008, column 8, paragraphs 33,34,35; claims. 1-15
    TO
    WO 03013479 A1 (EURO-CELTIQUE, S.A.) 02.20.2003, pages 10, lines 15-33. 1-15
    TO
    US 20110027455 A1 (BOEHM, G.) 03.05.2011, page 5, paragraph 42; page 6, paragraphs 52.53. 1-15
    TO
    US 20120101118 A1 (FLEISCHER et al.) 26.04.2012, claims. 1-15
    Category of the documents cited X: of particular relevance Y: of particular relevance combined with other / s of the same category A: reflects the state of the art O: refers to unwritten disclosure P: published between the priority date and the date of priority submission of the application E: previous document, but published after the date of submission of the application
    This report has been prepared • for all claims • for claims no:
    Date of realization of the report 06.19.2013
    Examiner H. Aylagas Cancio Page 1/4
    REPORT OF THE STATE OF THE TECHNIQUE
    Application number: 201230814
    Minimum documentation sought (classification system followed by classification symbols) A61K, A61P Electronic databases consulted during the search (name of the database and, if possible, terms of
    search used) INVENES, EPODOC, WPI, NPL, EMBASE, MEDLINE, BIOSIS, XPESP, XPESP2
    State of the Art Report Page 2/4
     WRITTEN OPINION
    Application number: 201230814
    Date of Completion of Written Opinion: 06.19.2013
    Statement
    Novelty (Art. 6.1 LP 11/1986)
    Claims Claims 1-15 IF NOT
    Inventive activity (Art. 8.1 LP11 / 1986)
    Claims Claims 1-15 IF NOT
    The application is considered to comply with the industrial application requirement. This requirement was evaluated during the formal and technical examination phase of the application (Article 31.2 Law 11/1986).
     Opinion Base.-
    This opinion has been made on the basis of the patent application as published.
    State of the Art Report Page 3/4
     WRITTEN OPINION
    Application number: 201230814
     1. Documents considered.-
    The documents belonging to the state of the art taken into consideration for the realization of this opinion are listed below.
    Document
    Publication or Identification Number publication date
    D01
    EP 1810714 A1 (HERMANN, HOLGER LARS) 07.25.2007
    D02
    EP 1897544 A1 (HERMANN, HOLGER LARS) 12.03.2008
    D03
    WO 03013479 A1 (EURO-CELTIQUE, S.A.) 02.20.2003
    D04
    US 20110027455 A1 (BOEHM, G.) 03.05.2011
    D05
    US 20120101118 A1 (FLEISCHER et al.) 04.24.2012
  16.  2. Statement motivated according to articles 29.6 and 29.7 of the Regulation of execution of Law 11/1986, of March 20, on Patents on novelty and inventive activity; quotes and explanations in support of this statement
    The present application refers to a pharmaceutical composition of diacetylmorphine (heroin) and naloxone for oral administration, characterized in that the weight ratio between diacetylmorphine: naloxone is between 24: 1 and 26: 1. Both compounds are in the form of their hydrochloride salt. Specifically, the composition formed by 200 mg of diacetylmorphine hydrochloride and 8 mg of naloxone hydrochloride is claimed. It also refers to the use for the treatment of addiction to opioid substances.
    Document D1 refers to a combination of heroin and naloxone for non-intravenous administration in the substitute treatment of drug addiction. Both compounds are in the form of hydrochloride salt (reiv. 8 and 9). Administration can be oral, nasal, pulmonary, rectal or topical (reiv. 5). The amount of naloxone may be between 0.1 mg and 8 mg per 100 mg of heroin and a dose of 8 mg of naloxone per 100 mg of heroin is specifically claimed (claim 10). That is to say with a weight ratio of 1: 12.5.
    Document D2 refers to oral combinations in the form of powder, beads, globules or pellets, of opioid agonists and antagonists and specifically the morphine: naloxone mixture in a 100: 5 ratio (see page 5, column 8, paragraph 33). Examples 2 and 3 cite heroin dependence. This document also claims other mixtures in which heroin is cited between a list of opioid agonists and naloxone among another list of opioid antagonists (see claim 5).
    Documents D3 and D4 both refer to compositions and methods to prevent abuse of opioid substances. Both documents mention that the intravenous administration of 1 mg of naloxone blocks the effect of 25 mg of heroin (see page 10, lines 25-33 of document D2 and page 6, paragraph 53 of document D3).
    Document D5 refers to the choice of mixtures of agonists and antagonists between two listings among which are heroin and naloxone (see claims 12-16).
    Therefore, while it is possible to recognize novelty for the composition set forth in claim 1, it is not possible to recognize inventive activity since the state of the art shows combinations for oral administration of opioid agonists such as heroin, morphine, codeine, methadone, etc. together with opioid antagonists such as naloxone, naltrexone, nalorphine, etc., these combinations have weight ratios of 12.5: 1 (document D1) and of
    20: 1 (document D2) in both cases the second component is naloxone. In the absence in the description of a proven and improved effect for the claimed selection (24: 1 to 26: 1), as regards the efficacy in the treatment of addiction to opioid substances, said selection is considered arbitrary and lacking inventive activity.
    Consequently, in view of documents D1 and D2, the matter corresponding to claims 1-15 lacks inventive activity according to article 8.1 of the L.P.
    State of the Art Report Page 4/4
ES201230814A 2012-05-29 2012-05-29 Pharmaceutical composition of diacetylmorphine and naloxone for oral administration Active ES2436344B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
ES201230814A ES2436344B1 (en) 2012-05-29 2012-05-29 Pharmaceutical composition of diacetylmorphine and naloxone for oral administration

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ES201230814A ES2436344B1 (en) 2012-05-29 2012-05-29 Pharmaceutical composition of diacetylmorphine and naloxone for oral administration
PCT/ES2013/070272 WO2013178846A1 (en) 2012-05-29 2013-04-30 Pharmaceutical composition comprising diacetylmorphine and naloxone for oral administration

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WO2003013479A1 (en) * 2001-08-06 2003-02-20 Euro-Celtique S.A. Compositions and methods to prevent abuse of opioids
EP1810714A1 (en) * 2006-01-19 2007-07-25 Holger Lars Hermann Use of a combination of heroin and naloxon for drug substitution
EP1897544A1 (en) * 2006-09-05 2008-03-12 Holger Lars Hermann Opioid agonist and antagonist combinations
US20110027455A1 (en) * 2002-09-20 2011-02-03 Garth Boehm Sequestering subunit and related compositions and methods
US20120101118A1 (en) * 2006-01-27 2012-04-26 Euro-Celtique S.A. Tamper resistant dosage forms

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003013479A1 (en) * 2001-08-06 2003-02-20 Euro-Celtique S.A. Compositions and methods to prevent abuse of opioids
US20110027455A1 (en) * 2002-09-20 2011-02-03 Garth Boehm Sequestering subunit and related compositions and methods
EP1810714A1 (en) * 2006-01-19 2007-07-25 Holger Lars Hermann Use of a combination of heroin and naloxon for drug substitution
US20120101118A1 (en) * 2006-01-27 2012-04-26 Euro-Celtique S.A. Tamper resistant dosage forms
EP1897544A1 (en) * 2006-09-05 2008-03-12 Holger Lars Hermann Opioid agonist and antagonist combinations

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