Abuse-proof solid pharmaceutical composition

Abstract

The present invention relates to an abuse-proof solid pharmaceutical composition comprising an active ingredient with potential for abuse, silica in an amount of from 10 mg to 1000 mg, guar flour in an amount of from 100 mg to 300 mg, and a water soluble diluent in an amount of from 500 mg to 5000 mg.

Claims

1. An abuse-proof solid pharmaceutical composition comprising an active ingredient with potential for abuse, silica in an amount of from 100 mg to 300 mg, guar flour in an amount of from 100 mg to 300 mg, and a water soluble diluent in an amount of from 1000 mg to 4000 mg; wherein the active ingredient with potential for abuse is an opioid; wherein said silica and said guar flour are present in relative amounts such that the solid pharmaceutical composition is soluble in 100 ml of water, but the solid pharmaceutical composition forms a non-injectable gel or non-injectable viscous solution if placed in 10 ml of water, and wherein said opioid is at least one member selected from the group consisting of alfentanil, allilprodine, alphaprodine, benzylmorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diamorphone, diampromide, dihydrocodeine, dihydromorphine, dimenoxadolo, dimepheptanol, dimethylthiambutene, dipipanone, eptazocine, etorphine, dihydroetorphine, ethylmethyltiambutene, ethylmorphine, heroin, fentanyl, hydrocodone, hydromorphone, isomethadone ketobemidone, levorphanol, lofentanil, meperidine (pethidine), meptazinol, metazocine, methadone, metopon, morphine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, oxycodone, oxymorphone, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine, and mixtures thereof.

2. The solid pharmaceutical composition according to claim 1, wherein said silica is anhydrous silica.

3. The solid pharmaceutical composition according to claim 1, wherein said silica is hydrated silica.

4. The solid pharmaceutical composition according to claim 1 comprising guar flour in an amount of from 150 mg to 250 mg.

5. The solid pharmaceutical composition according to claim 1 comprising guar flour in an amount of about 200 mg.

6. The solid pharmaceutical composition according to claim 1, wherein said guar flour has an average diameter lower than 100 μm.

7. The solid pharmaceutical composition according to claim 1, wherein said guar flour has an average diameter of from 10 μm to 80 μm.

8. The solid pharmaceutical composition according to claim 1, wherein said water soluble diluent is selected from the group consisting of a maltodextrin, powdered sucrose, crystalline sucrose, lactose, dextrose, mannitol, sorbitol, xylitol, and mixtures thereof.

9. The solid pharmaceutical composition according to claim 1, wherein said water soluble diluent has an average diameter lower than 500 μm.

10. The solid pharmaceutical composition according to claim 1, wherein said water soluble diluent has an average diameter of from 20 μm to 350 μm.

11. The solid pharmaceutical composition according to claim 1 comprising a secondary active ingredient, without potential for abuse, that is an analgesic.

12. The solid pharmaceutical composition according to claim 1, wherein said composition, when dissolved in about 10 mL of water, shows an osmolarity equal to or higher than 600 mOsM.

13. The solid pharmaceutical composition according to claim 1, wherein said active ingredient with potential for abuse is oxycodone.

14. The solid pharmaceutical composition according to claim 1, wherein said silica and said guar flour are present in a mass ratio of 0.5:1 or less.

15. The solid pharmaceutical composition according to claim 1, wherein said silica and said guar flour are present in a mass ratio of 0.25:1 to 0.5:1.

16. The solid pharmaceutical composition according to claim 1, wherein said guar flour has an average diameter of from 30 μm to 80 μm.

17. The solid pharmaceutical composition according to claim 1, wherein said water soluble diluent is present in an amount of 1500 mg to 3500 mg.

18. The solid pharmaceutical composition according to claim 10, wherein said water soluble diluent has an average diameter of from 40 μm to 300 μm.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The abuse-proof solid pharmaceutical composition of the present invention comprises at least one active ingredient with potential for abuse.

(2) The active ingredient with potential for abuse used in the present invention may be any active ingredient with potential for abuse, preferably selected from opioids, tranquillisers (anti-anxiety and anti-psychotics), stimulants and narcotics.

(3) The opioids usable in present invention are preferably selected from alfentanil, allilprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diamorphone, diampromide, dihydrocodeine, dihydromorphine, dimenoxadolo, dimepheptanol, dimethylthiambutene, dipipanone, eptazocine, etorphine, dihydroetorphine, ethylmethyltiambutene, ethylmorphine, heroin, fentanyl, hydrocodone, hydromorphone, isomethadone, ketobemidone, levorphanol, lofentanil, meperidine (pethidine), meptazinol, metazocine, methadone, metopon, morphine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, oxycodone, oxymorphone, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil, tramadol, tilidine and mixtures thereof.

(4) Preferably, the opioids useful in present invention are oxycodone, oxymorphone, and mixtures thereof.

(5) Active ingredients with potential for abuse include amphetamines, such as for example amphetamine, amphepramone, bupropion, cathine, cathinone, clobenzorex, ephedrine, phenylethylamine, phentermine, foledrine, methamphetamine, methylenedioxymethamphetamine (MDMA), norfenfluramine, norpholedrine, ortetamine, pirovalerone, and pseudoephedrine, and barbiturates, such as for example allobarbital, amobarbital, aprobarbital, alfenal, barbital, brallobarbital, butobarbital, hexobarbital pentobarbital, phenobarbital, secobarbital, thiopental, and talbutal.

(6) Other active principles with potential for abuse are benzodiazepines, such as alprazolam, bromazepam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, flunitrazepam, lorazepam, nitrazepam, oxazepam, temazepam and triazolam.

(7) Further active principles with potential for abuse are mebicar, fabomotizole, selank, bromantane, emoxypine, azapiron (buspirone), hydroxyzine, pregabalin, and propofol.

(8) The abuse-proof solid pharmaceutical composition of the present invention may also contain a secondary active ingredient, without potential for abuse, such as for example an analgesic.

(9) Examples of analgesics usable in the present invention are, for example, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs) and cyclo-oxygenase-2 (COX-2) inhibitors.

(10) Suitable NSAIDs usable in present invention are, for example, aspirin, benzydamine, ibuprofen, diclofenac, naproxen, flurbiprofen, fenoprofen, ketoprofen, ketorolac, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen, indomethacin, benzadac, sulindac, ibufenac, tolmetin, zomepirac, tiopinac, zidomethacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, and isoxicam.

(11) Suitable COX-2 inhibitors usable in the present invention are, for example, celecoxib, parecoxib, etoricoxib, firocoxib, flosulide, meloxicam, nabumetone, and nimesulide.

(12) Preferably, the secondary active ingredient in the composition of the present invention is selected from the group consisting of aspirin, acetaminophen, ibuprofen, or ketoprofen.

(13) The active ingredients contained in the pharmaceutical composition of the present invention, both those with potential for abuse and the secondary ones, may be present in their free form or as a salt with a pharmaceutically acceptable acid or base.

(14) The active ingredients including an acid function can be transformed in their salt with a pharmaceutically acceptable organic or inorganic base, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine, tripropylamine, ethylenediamine, monoethanolamine, diethanolamine, triethanolamine, guanidine, morpholine, piperidine, pyrrolidine, piperazine, 1-butylpiperidine, 1-ethyl-2-methylpiperidine, N-methylpiperazine, 1,4-dimethylpiperazine, N-benzylphenethylamine, N-methylglucosamine, tris(hydroxymethyl) aminomethane, ammonia, sodium hydroxide, calcium hydroxide, potassium hydroxide, aluminium hydroxide, iron hydroxide, magnesium hydroxide, zinc hydroxide, arginine and lysine.

(15) The active ingredients including a basic function can be transformed in their salt with a pharmaceutically acceptable organic or inorganic acid such as acetic acid, ascorbic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid, paratoluenesulfonic acid, citric acid, lactic acid, tannic acid, benzoic acid, aspartic acid, glutamic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and nitric acid.

(16) The abuse-proof solid pharmaceutical composition of the present invention comprises silica in an amount of from 10 mg to 1000 mg, guar flour in an amount of from 100 mg to 300 mg, and a water soluble diluent in an amount of from 500 mg to 5000 mg.

(17) Preferably, the abuse-proof solid pharmaceutical composition of the present invention comprises silica in an amount of from 50 mg to 500 mg, more preferably from 100 mg to 300 mg.

(18) Preferably, the silica used in the composition of the present invention is anhydrous silica or hydrated silica.

(19) Advantageously, the abuse-proof solid pharmaceutical composition of the present invention comprises anhydrous silica in an amount of from 50 mg to 100 mg, or hydrated silica in an amount of from 100 mg to 200 mg.

(20) The guar flour or gum is the product of grinding the endosperm of guar seeds Cyamopsis tetragonoloba, an herbaceous plant of legume crops typical of the region of India and Pakistan. The main component is a galactomannan, a trisaccharide composed of galactose and mannose units, polymerized to form α-D-mannopyranosil chains bound with a glycosidic bond β-D-(1-4) and having molecular weight of between 200,000 and 300,000 Dalton, to form a linear chain 1-4 with short lateral branches 1-6 of galactose, with a galactose/mannose ratio of about 2:1. Guar gum is also called guaran or often abbreviated as GG.

(21) Preferably, the abuse-proof solid pharmaceutical composition of the present invention comprises guar flour in an amount of from 150 mg to 250 mg, advantageously in an amount of about 200 mg.

(22) Preferably, the guar flour useful in present invention has a fine granulometry, with an average diameter of less than 100 μm, preferably less than 80 μm. On the basis of experience gained from the present invention, the Applicant in fact believes that a guar flour with granulometry greater than 100 μm is not suitable for the purposes of the present invention.

(23) Advantageously, the guar flour useful in the present invention has an average diameter of from 10 μm to 80 μm, and particularly from 30 μm to 80 μm.

(24) Preferably, the abuse-proof solid pharmaceutical composition of the present invention comprises a water-soluble diluent in an amount of from 1000 mg to 4000 mg, more preferably from 1500 mg to 3500 mg.

(25) Advantageously, the abuse-proof solid pharmaceutical composition of the present invention comprises a water-soluble diluent in an amount of from 2000 mg to 3000 mg.

(26) Water-soluble diluents preferably used in the pharmaceutical composition of the present invention are, for example, maltodextrins, sucrose powder, crystalline sucrose, lactose, dextrose, mannitol, sorbitol, xylitol, etc.

(27) Advantageously, the preferred water-soluble diluent is selected from the group consisting of maltodextrin with DE of between 10 and 20, preferably between 15 and 20, sucrose powder, and crystalline sucrose.

(28) Preferably, the water-soluble diluent useful in present invention has a fine granulometry, with an average diameter of less than 500 μm, preferably less than 400 μm. On the basis of experience gained from the present invention, the Applicant in fact believes that a water-soluble diluent with granulometry greater than 500 μm is not suitable for the purposes of the present invention.

(29) Advantageously, the water-soluble diluent useful in the present invention has an average diameter of from 20 μm to 350 μm, and particularly from 40 μm to 300 μm.

(30) The pharmaceutical composition of the present invention may include other ingredients typically used in the preparation of formulations to be taken orally such as, for example, pH regulators, buffering agents, sweeteners, flavourings, and the like.

(31) Examples of suitable pH regulators are for example sodium bicarbonate, calcium carbonate, magnesium carbonate, sodium phosphate, sodium citrate, and the like.

(32) Useful examples of buffering agents are represented by basic sodium phosphate, dibasic sodium phosphate, citrate buffer (sodium citrate/citric acid), and the like.

(33) Examples of suitable sweetening agents include aspartame, saccharin, acesulfame, and so on.

(34) Examples of suitable flavoring agents include grapefruit flavor, raspberry flavor, lemon flavor, orange flavor, caramel flavor, vanilla flavor, cream flavor, and the like.

(35) The pharmaceutical composition of the present invention may be formulated as a tablet, granulate, or water-soluble powder to be taken orally after dissolution in the appropriate volume of water, preferably about 100 ml, namely the volume contained in a standard glass.

(36) The pharmaceutical composition of the present invention may also be formulated in effervescent compositions. In this case, effervescent agents are added to the composition. Effervescent agents typically comprise an acid-base pair able to develop a gas when dissolved in water. Useful examples of effervescent agents are represented by acid-base pairs comprising an organic acid such as, for example, citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid, and mixtures thereof, and a carbonate or bicarbonate of alkali or alkaline earth metal such as, for example, calcium carbonate, sodium bicarbonate, sodium sesquicarbonate, and mixtures thereof.

(37) The pharmaceutical composition of the present invention, when dissolved in about 10 mL of water shows osmolarity equal to or greater than 600 mOsm, preferably equal to or greater than 800 mOsm, and more preferably ranging from 800 to 1,500 mOsm.

(38) The following examples are intended to further illustrate the present invention without limiting it in any way.

EXAMPLES

(39) In the following examples, injectability tests and solubility tests were conducted.

(40) Injectability tests were conducted using a 10 ml syringe with G21 needle (green) with nominal outside diameter of 0.8 mm or G18 needle (pink) with nominal outside diameter of 1.2 mm. The tests were always conducted at 22° C. filling the syringe with 10 ml of the solution under examination and placing the syringe vertically on a dedicated holder. The test is conducted by measuring the time taken to complete the spill of 10 ml of solution from the time a 1 kg weight is placed on the plunger, or noting the failure to pass.

(41) Solubility tests were conducted by dissolving or trying to dissolve increasing amounts of the composition in 100 ml of deionized water at 22° C. The resulting solution or dispersion was observed visually and photographed under a digital microscope (27×). The visual inspection of the appearance of the resulting dispersion or solution was scored from 1 to 4, respectively good, sufficient, insufficient, bad. The digital microscopic examination examined whether agglomerations were present or not.

Example 1

Guar Flour

(42) Increasing amounts of guar flour were used to test solubility and injectability.

(43) The amounts of guar flour employed to carry out the solubility test are shown in the following Table 1 together with the obtained results.

(44) TABLE-US-00001 TABLE 1 Digital microscopy evaluation- Quantity (mg) Visual evaluation Agglomerates 50 1 No 200 2 No 250 2 Yes 300 4 Yes

(45) The solubility test therefore indicated a maximum amount of 200 mg of guar flour in order to obtain an acceptable solution in 100 ml.

(46) To carry out the injectability test, four different batches of guar flour were used from different suppliers with different granulometry, as shown in the following Table 2. The previous solubility test had been performed with batch 1.

(47) TABLE-US-00002 TABLE 2 Average Fraction < 75 μm Fraction > 500 μm Batch granulometry (μm) (%) (%) 1 68.09 53.91 0.00 2 54.78 63.72 0.00 3 116.3 16.10 0.00 4 53.5 65.75 0.00

(48) The amounts of guar flour used for each batch are shown in the following Table 3 together with the obtained results. A first test conducted with water alone was conducted as a reference (R).

(49) TABLE-US-00003 TABLE 3 G21 needle G18 needle Batch Quantity(mg) Passage Time Passage R 0 Yes 14 Yes 1 50 Yes 18 Yes 75 Yes 20 Yes 100 Yes 25 Yes 125 Yes 41 Yes 150 Yes 60 Yes 175 Yes 107 Yes 200 No — Yes 2 50 Yes 17 Yes 100 Yes 25 Yes 150 Yes 63 Yes 3 50 Yes 13 Yes 100 Yes 23 Yes 150 Yes 27 Yes 4 50 Yes 17 Yes 100 Yes 22 Yes 150 Yes 65 Yes

(50) The injectability test conducted up to 200 mg showed that with guar flour alone it was not possible to make a composition that was soluble in 100 ml water and at the same time not injectable if dissolved in 10 ml of water.

(51) The obtained results suggested that the granulometry affects the thickening capability. Batch 3 showing the highest average granulometry was the batch with lower thickening capability.

Example 2

Anhydrous Silica

(52) Increasing amounts of anhydrous silica were used to test solubility and injectability.

(53) To carry out the solubility test, the amounts of anhydrous silica shown in the following Table 4 together with the obtained results were used.

(54) TABLE-US-00004 TABLE 4 Quantity (mg) Visual evaluation Agglomerates 1000 1 No 2000 2 No 4000 3 Yes 6000 4 Yes

(55) The solubility test therefore indicated a maximum amount of 2000 mg of anhydrous silica in order to obtain an acceptable solution in 100 ml. These amounts showed the good solubility of anhydrous silica in water, and a poor thickening effect was predicted for amounts of less than 1000 mg.

(56) The amounts of anhydrous silica employed to carry out the injectability test are shown in the following Table 5 together with the obtained results.

(57) TABLE-US-00005 TABLE 5 Quantity G21 needle G18 needle (mg) Passage Time Passage 100 Yes 14 Yes 200 Yes 17 Yes 300 Yes 45 Yes 500 Yes 48 Yes 600 Yes 60 Yes 750 Yes 300 Yes

(58) The results of the injectability test confirmed the unsuitability of anhydrous silica for the intended objects. The amounts of anhydrous silica necessary to obtain a non-injectable solution would have created a solution, although visually acceptable, with poor palatability.

Example 3

Hydrated Silica

(59) Injectability and solubility tests performed with hydrated silica did not produce significantly different and better results than those obtained with anhydrous silica. In contrast, hydrated silica proved even more soluble with a lower thickening effect also with quantities up to 1000 mg that showed the passage to the injectability test with G21 needle within 64 seconds.

Example 4

Xanthan Gum

(60) Solubility tests performed with xanthan gum produced, already with low quantities, visually insufficient dispersions with the presence of several agglomerates. This product was therefore discarded without further testing.

Example 5

Binary Combinations

(61) The injectability test was repeated using 200 mg of guar flour mixed with the amounts of hydrated silica or anhydrous silica given in following tables 6a and 6b together with the obtained results. The guar flour used corresponded to batch 1 of example 1.

(62) TABLE-US-00006 TABLE 6A Anhydrous silica G21 needle G18 needle (mg) Passage Time Passage Time 25 No Yes 13 50 No — No — 75 No — No — 100 No — No —

(63) TABLE-US-00007 TABLE 6b Hydrated silica G21 needle G18 needle (mg) Passage Time Passage Time 50 No — Yes 12 75 No — Yes 35 100 No — No —

(64) The obtained results surprisingly showed that relatively small amounts of silica, well below those required if used alone, have a synergistic and disruptive effect in combination with guar flour.

(65) The Applicant has in fact surprisingly noted that with a G18 needle using anhydrous silica in an amount of 25 mg there was a passage in a short time, while increasing the amount to 50 mg, instead of observing, as one would have expected, a moderate increase in the time of passage, a sharp increase in the viscosity of the solution was observed which resulted in no passage.

(66) Similarly, the Applicant surprisingly observed that the same sharp increase in the viscosity of the solution also occurred with hydrated silica passing from the amount of 75 mg to the amount of 100 mg.

(67) The solubility test conducted with the mixture of 200 mg guar flour and 100 mg anhydrous or hydrated silica produced optimal results in both cases, with a visual assessment of 1 (good) and the total absence of agglomerates visible at the digital microscope (27×).

Example 6

Water-Soluble Diluent

(68) In order to make a pharmaceutical composition, several water-soluble diluents were tested in combination with 100 mg of anhydrous silica and 200 mg of guar flour. The type and amount of water-soluble diluent is shown in the following Table 7 together with the results obtained in the solubility and injectability tests.

(69) TABLE-US-00008 TABLE 7 Injectability with Solution Diluent Quantity (mg) G18 needle appearance Sorbitol 3000 No 1 Sucrose 3000 No 1 Lactose 3000 No 1 Maltodextrin 3000 No 1

(70) The data summarized in table 7 showed that commonly used diluents did not affect the appearance of the solution in the solubility test and retained the non-injectability also with G18 needle.

Example 7

Pharmaceutical Composition

(71) On the basis of the obtained results, a formulation of a water-soluble granulate containing ibuprofen and oxycodone was prepared. The qualitative and quantitative composition of the formulation is shown in the following Table 8.

(72) TABLE-US-00009 TABLE 8 Components Quantity (mg) Sodium ibuprofen 512 Oxycodone 20 Sodium bicarbonate 50 powder Natural lemon flavoring 70 Anhydrous silica 100 Acesulfame K 70 Maltodextrin 2988 Guar flour 200 Granulate 2100 Total 6110

(73) The granulate used in the preparation of the formulation was previously prepared by wet granulation of 100 mg of ascorbic acid, 1,000 mg of powdered sucrose and 1,000 mg of crystalline sucrose.

(74) The formulation of Table 8 was subjected to the same injectability and solubility tests described above. The results are summarized in the following Table 9.

(75) TABLE-US-00010 TABLE 9 Injectability with Injectability with Solution G21 needle G18 needle appearance No No 1

(76) The osmolarity of the solution obtained by dissolving the formulation of Table 8 in 10 ml of deionized water, measured with Gonotec Osmomat 030 osmometers, was equal to about 855 mOsm.