Oral drug delivery system comprising high viscosity liquid carrier materials

ES 2 553 136 T3

DESCRIPTION

Oral drug delivery system comprising high viscosity liquid carrier materials

Field of the invention

The invention relates to dosage forms comprising drug formulations. More specifically, the present invention relates to formulations including high viscosity liquid carrier materials (HVLCM) and their use to deliver drugs.

Background

Techniques and compositions for the pharmacological administration of pharmaceuticals, including oral administration, are well known. For example, antihistamines, decongestants, and antacids are usually given as solid tablets. Pain relievers have been taken orally in tablet form for many years, for example, salicylic acid, morphine, Demerol ™ (meperidine), codeine, and Percocet ™ (oxycodone). Controlled release and sustained release pharmaceutical compositions have also been available for many years; for example, antipsychotic, melatonin formulations, Contac 400 Time Capsule ™ (phenylpropanolamine hydrochloride and chlorpheniramine maleate) provide release of an active agent over several hours. Pain relievers are particularly interesting for controlled release formulations, and common controlled release formulations for pain relievers include OxyContin® (oxycodone), MS Contin ™ (morphine), CS Contin ™ (codeine).

Formulating drugs for administration, particularly oral administration, poses certain challenges. One challenge is to produce a controlled release dosage form that provides a relatively stable dose of drug over the approximately eight hours it takes for the dosage form to pass through the gastrointestinal tract. Sustained release is typically achieved by providing the tablet with a coating that delays release or by formulating the tablet so that it disintegrates relatively slowly, releasing the drug as it does so. However, a tablet that has already been swallowed is subjected to significant mechanical and chemical stresses as it passes through the esophagus, stomach, duodenum, jejunum, ileum, large intestine and colon, thus providing a challenge. significant in maintaining controlled release of the drug formulation. Acids, enzymes, and peristalsis can cause the tablet to break down, exposing the interior of the tablet and increasing the surface area of ​​the tablet material. This will tend to increase the rate of drug delivery or, instead, adversely affect the controlled release properties of the dosage form.

Another challenge is to produce a dosage form, including an oral dosage form, that reduces the potential for drug overuse. In particular, opioids, CNS depressants, and stimulants are often abused. According to a 1999 study conducted by the National Institute on Drug Abuse (NIDA), approximately 4 million people, approximately 2 percent of the population 12 years of age and older, were using (at the time of the study ) non-prescription drugs. Of these, 2.6 million misused painkillers, 1.3 million misused sedatives and tranquilizers, and 0.9 million misused stimulants.

Although many prescription drugs can be abused, the most common classes of drugs used excessively are: (1) opioids - often prescribed to treat pain; (2) CNS depressants - used to treat anxiety and sleep disorders; and (3) stimulants - prescribed to treat narcolepsy and attention deficit / hyperactivity disorder.

Opioids are a class of powerful narcotics that include, for example, morphine, codeine, oxycodone, and fentanyl, and related drugs. Morphine is often used to relieve severe pain. Codeine is used for more moderate pain. Other examples of opioids that may be prescribed for pain relief include oxycodone (eg, OxyContin® - an oral controlled-release form of the drug); propoxyphene (for example, Darvon ™; hydrocodone (for example, Vicodin ™; hydromorpfone (for example, Dilaudid ™); and meperidine (for example, Demerol ™). In addition to relieving pain, opioids can also produce a feeling of euphoria and, when taken in large doses, can cause respiratory depression that can be fatal.

CNS depressants slow down normal brain function by increasing GABA activity, thus producing a drowsy or calming effect. At higher doses, some CNS depressants can become general anesthetics, and at very high doses, they can cause respiratory failure or death. CNS depressants are often overused, and abuse of CNS depressants often occurs in conjunction with the abuse of another substance or drug, such as alcohol or cocaine. There are many deaths each year due to such drug abuse. CNS depressants can be divided into two groups, based on their chemistry and pharmacology: (1) barbiturates such as mephobarbital (eg, Mebaral ™) and pentobarbital sodium (eg, Nembutal ™), which are used to treat anxiety, tension and disorders of the

ES 2 553 136 T3 sleep; and (2) benzodiazepines, such as diazepam (eg, Valium ™), chlordiazepoxide HCl (eg, Librium ™), and alprazolam (eg, Xanax ™), which can be prescribed to treat anxiety, stress reactions acute and panic attacks. Benzodiazepines that have a more sedative effect, such as triazolam (eg Halcion ™) and estazolam (eg ProSom ™) can be prescribed for the short-term treatment of sleep disorders.

Stimulants are a class of drugs that enhance brain activity and cause increased alertness, attention, and energy accompanied by increases in blood pressure, heart rate, and respiration. Stimulants are frequently prescribed to treat narcolepsy, attention deficit hyperactivity disorder (ADHD), and depression. Stimulants can also be used for the short-term treatment of obesity and for patients with asthma. Stimulants such as dextroamphetamine (Dexedrine ™) and methylphenidate (Ritalin ™) have chemical structures that are similar to key brain neurotransmitters called monoamines, which include norepinephrine and dopamine. Stimulants increase the levels of these chemicals in the brain and body. In turn, this increases blood pressure and heart rate, narrows blood vessels, increases blood glucose, and opens the airways of the respiratory system. In addition, the increase in dopamine is associated with a feeling of euphoria that can accompany the use of these drugs. Taking high doses of a stimulant can lead to irregular heartbeats, dangerously high body temperatures, and / or the possibility of cardiovascular failure and fatal attacks. Taking high doses of some stimulants repeatedly over a short period of time can lead to hostility or feelings of paranoia in some individuals. A common and particularly dangerous cocktail of drugs is produced when stimulants are mixed with antidepressant agents or over-the-counter cold medicines that contain decongestants. Antidepressants can potentiate the effects of a stimulant, and stimulants in combination with decongestants can cause blood pressure to become dangerously high or lead to irregular heart rhythms, which in extreme cases can be fatal.

Solid dosage forms are particularly susceptible to abuse. For example, tablets for oral drug administration can be crushed into a powder. Addicted people and those who consume these drugs excessively crush the tablet to inhale the drug through the nose. Addicts also crush the tablet to extract the drug into alcohol or water to produce a concentrated injectable drug solution. The administration of various drugs consumed excessively in this way produces a sudden high dose of the drug in the bloodstream causing a feeling of euphoria to the user. These well known techniques of drug overuse have been used for many years with all types of drugs.

A particularly important example of a highly addictive drug commonly abused by crushing (for nasal inhalation) and / or extraction into alcohol or water (for intravenous injection) is oxycodone. Oxycodone is a powerful pain reliever that is available in tablet form (Oxycontin®, Purdue Pharmaceuticals) and is manufactured in tablet strengths of 10 mg, 20 mg, 40 mg, 80 mg, and 160 mg. Oxycontin® tablets are formulated as time-release tablets (approximately 12 hours release), but, as is evident, crushing and crushing the tablet destroys any controlled release properties. Overconsumption of Oxycontin® has been claimed to have resulted in at least 120 deaths nationwide so far (http://www.stopoxycontinaddiction.com/oxycontin-addiction.htm). 5 mg of Oxycontin® have both the active ingredient (oxycodone) and a Percocet ™. So chewing / snorting a crushed 40mg Oxycontin® is like taking 16 Percocet ™ at once or an 80mg Oxycontin® is like taking 16 Percocet ™ all at once. Overdose results in reduced pupil size, slow breathing, dizziness, weakness, seizures, loss of consciousness, coma, and sometimes death.

The above problems present a clear and long-perceived challenge by drug manufacturers to produce drug dosage forms that also allow desirable drug release kinetics and reduce the possibility of overconsumption.

Sullivan et al., Proceed. Int'l. Symp. Control. Rel. Bioact. Mater. 25 (1998) Controlled Release Society Inc., pages 918 and 919, describe sustained release orally administered delivery systems incorporated into soft gelatin capsules. Six compositions containing theophylline are disclosed. One of the compositions also comprises sucrose acetate isobutyrate (SAIB), ethyl lactate and cellulose acetate isobutyrate. Another of the compositions also comprises SAIB, ethyl lactate and cellulose acetate propionate. The other four compositions only comprise SAIB and ethyl lactate in addition to theophylline.

Summary of the invention

The invention relates to an oral dosage form for use in a method of treating the human or animal body by therapy, wherein the oral dosage form comprises a formulation comprising:

- 20% to 90% by weight of sucrose acetate isobutyrate (SAIB),

ES 2 553 136 T3

- from 0.01 to 75% by weight of cellulose acetate butyrate (CAB),

- from 1 to 75% by weight of a rheology modifier selected from isopropyl myristate, caprylic / capric triglyceride, ethyl oleate, dimethyl phthalate and benzyl benzoate,

- from 0.01 to 75% by weight of a solvent and

- a drug that is an opioid, a central nervous system (CNS) depressant or a stimulant.

The formulations of the invention exhibit desirable drug release kinetics and / or binge-preventing characteristics.

The present invention also provides an oral dosage form for use as defined above, wherein the drug is an opioid and the method of treatment is a method of treating pain.

A particular advantage of the dosage form of the invention is that, in a particular embodiment, it provides an oral dosage form comprising a formulation present in amounts effective to reduce the rate of drug extraction, for example, with water, ethanol or other solvents, while simultaneously providing desired drug release kinetics. This reduced extraction speed helps prevent excessive consumption and reduces the risk of improper use.

Brief description of the figures

FIG. 1-4 are graphs showing representative results from a binge drinking impairment study. The units in the graphs are the relative percentage of cumulative release versus time (minutes).

FIG. 5 is a chemical scheme showing the structure of SAIB, which is a hydrophobic fully esterified sucrose derivative, at a nominal ratio of six isobutyrates to two acetates.

FIG. 6 is a graph showing representative drug dissolution results in a simulated gastrointestinal environment (% cumulative release versus time).

FIG. 7 is a representative photograph of a 100% SAIB formulation after exposure to -80 ° C (-112 ° F) for eight hours and pounded with a hammer. It should be noted that the structure of the controlled release matrix is ​​preserved.

FIG. 8 is a representative photograph of a formulation comprising SAIB + solvent, after exposure to a temperature of -80 ° C for eight hours and pounding with a hammer.

FIG. 9 is a representative photograph of a formulation of the invention (PTI-821, which is SAIB: EL: IPN: CAB at a ratio of 67: 26: 3: 4) contained in a soft gelatin capsule and containing 9 mg of drug), after exposure to -80 ° C for eight hours and pounding with a hammer.

Specific embodiments of the invention

Abbreviations used throughout the disclosure are as follows:

HVLCM: High Viscosity Liquid Carrier Material

SAIB: Sucrose acetate isobutyrate

EL: Ethyl Lactate

IM (or IPM): Isopropyl Myristate

CAB: Cellulose Acetate Butyrate

OC (or OXY): Free base or oxycodone salt.

Drug delivery device refers to a device for holding or containing and releasing a drug wherein, upon administration of the drug delivery device to a subject, in particular a human subject, the drug is released from the device. of drug delivery in a subject. The maintenance or containment device can be any type of containment device, including injectable devices (pumps, etc.) and ingestible devices, including a tablet, pill, capsule, or formulation. Many drug delivery devices are described in "Encyclopedia of Controlled Drug Delivery" (1999), Edith Mathiowitz (Ed.), John Wiley & Sons, Inc.

Dosage form refers to a drug and a drug delivery device.

Formulation refers to one or more ingredients or compounds. For example, a drug formulation is any drug combined with any of pharmaceutically acceptable excipients, additives, solvents, carriers, and other materials.

ES 2 553 136 T3

High Viscosity Liquid Vehicle Materials (HVLCM) refers to non-polymeric, non-water soluble liquids with a viscosity of at least 5,000 mPa.s (5,000 cP) at 37 ° C that do not crystallize in an orderly manner under environmental or physiological conditions. HVLCMs can be carbohydrate-based and can include one or more cyclic carbohydrates chemically combined with one or more carboxylic acids, such as sucrose acetate isobutyrate (SAIB). The present invention employs SAIB.

Rheology modifier refers to a substance that possesses both a hydrophobic and a hydrophilic moiety. In general, the rheology modifiers used with the invention have a log octanol-water partition coefficient of between about -7 and +15, preferably between -5 and +10, more preferably between -1 and +7. . The term "rheology" refers to the deformation and / or flow property of a liquid, and rheology modifiers are used to modify the viscosity and flowability of a liquid formulation. The rheology modifier used in the present invention is selected from caprylic / capric triglyceride (Migliol 810), isopropyl myristate (IM or IPM), ethyl oleate, dimethyl phthalate and benzyl benzoate.

Network former refers to a compound that forms a network structure when introduced into a liquid medium (such as an HVLCM). Network formers can be added to the liquid formulation (such as to an HVLCM) such that, upon exposure to an aqueous environment, they form a three-dimensional network within the formulation. Network formers include cellulose acetate butyrate, which is a component of the oral dosage form used in the present invention.

Solvents refers to any substance that dissolves another substance (solute). Solvents can be used in a SAIB formulation to dissolve other components such as the drug, the network former, the rheology modifier, and, if present, the stabilizer. Solvents can include alcohols, organic acids and their derivatives, organic acid esters and compounds that possess an alcohol and organic acid moiety, for example, ethyl lactate (EL) or triacetin, dimethylsulfoxide (DMSO), propylene carbonate, M-methylpyrrolidone (NMP), ethyl alcohol, benzyl alcohol, glycofurol.

Stabilizer refers to any substance used to inhibit or reduce degradation (eg chemical) or other substances with which the stabilizer is mixed. Illustrative stabilizers are generally antioxidants that prevent oxidative damage and degradation, eg, sodium citrate, ascoryl palmitate, vitamin A, and propyl gallate, and / or reducing agents.

In situ refers to laboratory conditions that simulate conditions in the GI tract of a mammal (see Table 1).

Placebo refers to formulations without active drug (eg, a placebo solution from Table 1).

Detailed description

It should be noted that the examples described herein are merely illustrative and do not in any way limit the scope of the invention.

Dosage forms and drug delivery devices suitable for the delivery of a drug are disclosed. Some of these devices are suitable for the oral administration of a drug. The dosage form or device includes a formulation that includes SAIB, a specified network former, a specified rheology modifier, and a solvent. In particular, the formulation can be loaded with a drug and will release the drug over a period of time where it is in an aqueous environment and, in particular, an environment similar to that of the GI tract of a mammal. While not wishing to be bound by theory, it is believed that the network former allows the formation of a micro-network within the formulation upon exposure to an aqueous environment. This micro-lattice formation appears to be due, at least in part, to a phase inversion (eg, a change in glass transition temperature, Tg) of the lattice former. The result is believed to be a skin or surface layer of precipitated network former at the interface between the dosage form and the aqueous environment of the GI tract, as well as the formation of a three-dimensional micro-network of precipitated network former within the form of dosage.

Preferred dosage forms comprising the drug delivery devices of the invention do not substantially emulsify as they pass through the GI tract, but instead substantially maintain their integrity (deformability and / or surface characteristics) as they pass through the GI tract and release drug. While not wishing to be bound by theory, it is believed that the formulation forms a network on the surfaces and / or in the main phase. The surfaces are renewed so that the concentration gradient is maintained at the surfaces for desirable drug release kinetics. The dosage form when it is exiting the GI tract can maintain a substantial proportion of its weight; for example, desirable dosage forms may have a weight that is not less than about 50% of the weight of the dosage form after oral administration. This weight percentage can vary with the different formulations used in dosage forms and can be at least 60%, 70%, 80% or even 90% of the original weight.

ES 2 553 136 T3

The disclosed dosage form allows drug release even over a prolonged period, such as for several hours. The total period of drug release in an amount sufficient to be an effective dose may be greater than 20 hours or greater than 17 hours, or greater than 15 hours or greater than 12 hours or greater than 10 hours or greater than 8 hours or more than 6 hours or more than 4 hours or more than 2 hours or more than 1 hour. The amount of drug sufficient to provide an effective dose is determined from the therapeutic range of the drug, which is determined from, for example, clinical trials, and such information can be readily obtained by one of ordinary skill in the art.

The disclosed drug delivery device includes various components in addition to carrier material (SAIB). Additional compounds may be present in amounts ranging from about 75% by weight to amounts as low as 0.01% by weight of the total formulation. These additional components include the following types of compounds:

• Solvents, for example, Ethyl Lactate (EL) or Triacetin, DMSO, Propylene Carbonate, NMP, Ethyl Alcohol, Benzyl Alcohol, Glycofurol, α-Tocopherol, Migliol 810, Isopropyl Alcohol, Diethyl Phthalate, PEG 400, Citrate triethyl, benzyl benzoate.

• Network formers: cellulose acetate butyrate (eg CAB 171-15, CAB 381-2 and CAB 381-20, supplied by Eastman Chemicals, the characteristics of which are described in Table 2).

• Rheology modifiers: for example, caprylic / capric triglyceride (Migliol 810), isopropyl myristate (IM or IPM), ethyl oleate, dimethyl phthalate and benzyl benzoate.

• Optionally, stabilizers, for example antioxidants such as sodium citrate, ascorbyl palmitate and propyl gallate and / or reducing agents. Other examples include ascorbic acid, vitamin E, sodium bisulfite, butylhydroxyltoluene, BHA, acetylcysteine, monothioglycerol, phenyl-a-natylamine, lecithin, EDTA.

These and additional compounds (described in more detail below) can be modified to control the rate of release of a drug and / or the maximum dose (eg, solubility) of a drug used with the drug delivery device of the invention. ("Handbook of Pharmaceutical Excipients", 3^toed., A. Kibbe, Am. Pharm. Assn, pub.).

In certain embodiments, the disclosed orally administered drug delivery device can be formulated to produce certain controlled levels of drug in plasma over a particular period. Obviously, this is of great importance in maintaining a plasma drug level within an appropriate therapeutic range. An appropriate therapeutic range will vary depending on the drug, but can range from femtogram / ml levels to above microgram / ml levels for a desired period of time. For example, a single dose of a drug dosage form disclosed herein may result in the maintenance of plasma drug levels at greater than 5 ng / ml for a period of greater than 8 hours. In other embodiments, the plasma drug level achieved using a single dose may be greater than 5 ng / ml for a period greater than 10 hours, greater than 12 hours, greater than 14 hours, greater than 16 hours; more than 18 hours or more than 20 hours. In yet other embodiments, the plasma drug level achieved using a single dose can be greater than 5 ng / ml, greater than 10 ng / ml, greater than 15 ng / ml, greater than 20 ng / ml, greater than 30 ng. / ml, greater than 40 ng / ml, greater than 50 ng / ml for a period of 4, 8, 10, 12, 14, 16, 18 or 20 hours.

The maximum drug concentration in plasma can be reached in a time after administration of between 0.1 h at approximately 24 h or approximately 0.25 h at 10 h or approximately 0.25 h at 8 h or approximately 0.5 h at 6 h , or about 0.5 h to 4 h, or about 0.5 h to 2 h or about 0.5 h to 1 h. The time to maximum plasma concentration can be adjusted by adjusting various components of the drug delivery device as shown herein. Modification of the components modifies the viscosity or other rheological characteristics of the formulation, and concomitantly modifies the rate of drug release (described in detail below). The rate of reduction in plasma drug concentration with time can also be adjusted by varying the components of the drug delivery device. Any desired release profile can be achieved by modifying the components as described herein.

The plasma levels obtained can be adjusted by adjusting the formulation and other components of the drug delivery device, and desirable plasma levels will depend on the therapeutic range or its index for any particular drug. One of skill in the art can easily determine the desired therapeutic index, and in view of the present disclosure, the adjustment of the various components to achieve the desired release characteristics for a particular drug would be a matter of routine experimentation.

In certain embodiments, the release profile of the drug during the release period is preferably approximately stable over time, sufficient to provide a therapeutic dose during the release period and preferably exhibits a reduced rapid release effect compared to a

ES 2 553 136 T3 conventional tablet formulation. As can be seen in Fig. 6 (described in more detail below), the drug delivery device of the invention can release the drug (in this case, oxycodone) at an approximately stable rate for a period of at least 24 hours. The release rate is particularly stable from about 1 hour to more than 24 hours. This differs from a commercial tablet formulation (OxyContin®) which provides substantial drug release during the first 5 h period. In the case shown in Fig. 6, the dosage form in which the drug delivery device of the invention is used provides long-term in vitro release with less than 40% of the drug released in 24 hours, whereas the commercial dosage form provides almost 100% release in 24 hours. The time to 90% drug release can be modified by varying the formulation and other components of the device, and can be as little as 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, or 20 hours. , or up to approximately 24 hours.

The release rate of the drug from the dosage form can be varied depending on the drug used and the required dose. Release rates can be different in different parts of the GI tract, and release rates can be averaged during transit time through the GI tract (approximately 8-24 h). Typical average release rates can vary substantially. For many drugs, they can range from about 0.01 to 500 mg / h, 0.5 to 250 15 mg / h, 0.75 to 100 mg / h, 1.0 to 100 mg / h, 2 0 to 100 mg / h, 5 to 100 mg / h, 10 to 100 mg / h, 10 to 80 mg / h, 20 to 50 mg / h or about 20 to 40 mg / h.

Dosage guidelines for the drug can be determined by the physician in accordance with conventional practices. Once a day or twice a day (BID) doses can be used to maintain a sufficient clinical effect, for example, to maintain pain relief.

An important advantage of the dosage forms disclosed herein is that they have characteristics that prevent excessive consumption and / or a reduced risk of misuse. The dosage form and the formulation contained therein are not susceptible to crushing, powdering, or extraction using ethanol or water. In particular, SAIB is a viscous liquid and therefore formulations containing SAIB avoid the possibility of crushing for the purpose of inhalation. Furthermore, the formulation of the invention has the characteristic of being resistant to extraction of the drug using ethanol or water, compared to a tablet formulation of a drug.

In certain preferred embodiments, the drug delivery device is comprised of a drug formulation encapsulated within a container or capsule, preferably biodegradable, such as a capsule or a gelatin capsule (gelcap), in which the capsule is formed. by a substance that degrades or dissociates when exposed to conditions present in the gastrointestinal tract of a mammal. Capsules and gelcaps are well known in drug delivery technology, and one of skill could select such a capsule as appropriate for the delivery of a certain drug. Once the capsule has dissolved or dissociated from the formulation, in general, the formulation of the invention remains intact, especially for hydrophobic formulations, and passes through the GI tract without emulsification or fragmentation.

In certain more specific embodiments, the invention encompasses an oral dosage form comprising the formulation contained within a biodegradable capsule, wherein the capsule is composed of a substance that degrades when exposed to conditions present in the gastrointestinal tract of a mammal. In certain embodiments, the capsule comprises gelatin or synthetic polymers such as hydroxyethylcellulose and hydroxypropylmethylcellulose. Gelcaps can be of a hard or soft variety. Gelatin capsules are suitable for the administration of liquid formulations such as vitamin E and cod liver oil. Gelatin capsules are shelf stable, but once in the acidic environment of the stomach (low pH, less than about 4-5), the gelcap dissolves over a period of 10-15 minutes. In certain embodiments, the drug delivery device further comprises at least one component selected from the group consisting of: ethyl lactate, triacetin, propylene carbonate, glycofurol, triethyl oleate, isopropyl myristate, cellulose acetate butyrate, and derivatives of the same.

The orally administered drug delivery device of the invention comprises sucrose acetate isobutyrate (SAIB) as the HVLCM carrier material. SAIB is a highly viscous non-polymeric liquid at a temperature ranging from -80 ° C to more than 100 ° C, it is a fully esterified sucrose derivative, at a nominal ratio of six isobutyrates to two acetates (Figure 6) . It is manufactured by the Eastman Chemical Company as a mixed ester, and the resulting mixture does not crystallize, but exists as a highly viscous liquid. It is a low molecular weight, non-crystalline, hydrophobic molecule that is insoluble in water and has a viscosity that varies with temperature. For example, pure SAIB exhibits a viscosity of approximately 2 million mPa.s (cP) at room temperature and approximately 600 mPa.s (cP) at 80 ° C. SAIB has a unique solution viscosity ratio insofar as SAIB solutions in a number of organic solvents is significantly lower than these viscosity values ​​for pure SAIB and therefore SAIB and organic solvent solutions become capable of being processed using conventional equipment such as mixers, liquid pumps and gelcap production machines. SAIB also has applications in drug formulation and administration, for example, as described in U.S. Patent Nos.

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5,747,058, 5,968,542, 6,413,536 and 6,498,153. In the present invention, SAIB is used as HVLCM, and can be present in significantly varying amounts. For example, amounts of at least about 50, 60, 70, 80, 90, 95, 97, 98, 99, 99.5, and 99.9% by weight can be used. In the examples, various formulations containing SAIB are described.

In addition, certain embodiments of the disclosed drug delivery device allow oral administration of compounds such as proteins, which would not normally be considered orally administrable effectively, because administration in conventional oral compositions would likely cause breakdown of the active ingredient by acids or stomach enzymes.

One embodiment of the invention relates to opioid dosage forms suitable for oral administration, including those that provide desirable drug release kinetics and / or limit the likelihood of opioid misuse of the dosage forms by patients or others. In such an embodiment, the opioids can be dissolved or dispersed in the components of the formulation of the invention. Suitable opioid compounds that can be administered according to the invention include, for example, those that are used, in general, as analgesics, narcotics and / or anesthetics, and include alfentanil, allylprodin, alphaprodin, anileridine, apomorphine, apocodeine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocin, cyclophen, cyprenorphine, desomorphine, dextromoramide, dezocine, diampromide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxyafethyl butyrate, dipipanone, eptazocin, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitacene, fentanyl, heroin, hydrocodone, hydroxymethylmorphinan, hydromorphone, hydroxypetidine, methamphanedone, levomethane, levomethanopholiphenolphonol, isphenomethadone, hydroxymethylmorphinan , methylmorphine, metopon, morphine, myrophin, nalbuphine, narcein, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, ohmefentanil, opium, oxycodone, oxymorphone, papaveretum, pentazocine, fenadoxone, phenomorphan, phenazocin, phenoperidine, pholcodine, piminodine, pyritramide, proeptazine, promedol, profadol, properidine, propyram, propoxyphene, sumadoliphentanyl, nalfentanyl nalmefene, methylnaltrexone, naloxone iodomethylate, nalorphine, naloxonazine, nalide, nalmexone, nalbuphine, nalorphine dinicotinate, naltrindole (NTI), naltrindole isothiocyanate (NTII), naltriben (NTB), nor-binfaltorphimine (nor-BNI), β-funaltrexamine (b-FNA), BNTX, cyprodime, ICI-174,864, LY117413, MR2266, etorphine, DAMGO, CTOP, diprenorphine, naloxone benzoylhydrazone, bromethocin U50,488, U69,593, spiradoline, DPDPE, [D-Ala2, Glu4] deltorphin, DSLET, Met-enkephalin, Leu-enkephalin, β-endorphin, dynorphin A, dynorphin B, α-neoendorphin, or an opioid that has the same pentacyclic nucleus as nalmaphene, naltrexone, buprenorphine, levorphanol, meptazinol, pentazocine, dezocine, or their pharmacologically active salts or esters.

Oral dosage forms of these opioids can be prepared simply by mixing SAIB, a rheology modifier, network former, active agent, solvent, and any additives and filling the resulting mixture in a gelatin capsule. Alternative formulations may include emulsifying the mixture in water and introducing this emulsion into the gelatin capsule, or using one or more of the techniques described herein to produce the dosage form.

Preferred embodiments of the present invention provide an inexpensive, easy-to-use, and effective oral oral dosage form that allows sustained drug release, with favorable drug release kinetics, while traversing the gastrointestinal tract, and is subject to to a lesser extent to overuse compared to current capsule and tablet dosage forms. The invention encompasses a controlled release oral drug delivery device. A drug delivery device of the present invention encompasses a drug-SAIB formulation which may be included in a gelatin capsule suitable for oral administration and which also includes the following additional components in the formulation to effect drug delivery kinetics appropriate: solvents, eg, ethyl lactate (EL) or triacetin, DMSO, propylene carbonate, NMP, ethyl alcohol, benzyl alcohol, glycofurol; network formers: cellulose acetate butyrate (CAB 171-75, CAB 381-2 and CAB 381-20 administered by Eastman Chemicals); rheology modifiers: caprylic / capric triglyceride (Migliol 810) and other plasticizers selected from isopropyl myristate (IM or IPM), dimethyl phthalate, ethyl oleate and benzyl benzoate; optionally stabilizers, for example antioxidants such as sodium citrate, ascoryl palmitate and propyl gallate. A specific example of a formulation for use in the drug delivery device of the invention contains oxycodone free base and / or hydrochloride salt, SAIB, ethyl lactate, isopropyl myristate, and CAB. An illustrative embodiment, used by the inventors to produce the data disclosed herein, is formulated as follows: oxycodone free base, 10 mg per gelcap, 65% SAIB, 27% ethyl lactate, isopropyl myristate at 3% and CAB 381-20 at 5% (all percentages are percentages by weight). Said formulation is available in a soft gelcap.

The dosage form of the invention can comprise one or more drugs. The amount of drug / s and the percentages of components in the formulation can vary. Typical average amounts can vary substantially. For many drugs, they can range from about 0.1 mg to 1,000 mg or from about 1 mg to 500 mg or from about 2 mg to 250 mg or from about 2 mg to 150 mg or from about 5 mg to 100 mg or about 5 mg to 50 mg. The exact amount of drug desired can be determined by standard methods well known in the pharmacological field, and will depend on the type of drug, and the pharmacokinetics and pharmacodynamics of said drug.

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The percentage by weight of SAIB can vary depending on the characteristics of the desired dosage form, and can include, for example, from about 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.5% to about 100%. Illustrative formulations disclosed herein contain 99%, 71%, 70%, 65%, 63%, 61.6%, 59%, 50%, 40%, 30%, 20%, or even less amounts of SAIB . The SAIB content can be varied to modify the viscosity or other rheological properties of the formulation and to modify the rate at which the drug is delivered. Using the information presented herein, those skilled in the art could modify the SAIB content of the formulation to suit various drugs of different hydrophobicity or hydrophilicity, and determine the optimal rate of drug release from the formulation.

The dosage form of the invention comprises one or more solvents. The weight percent of the solvent (s) (such as EL) may vary depending on the characteristics of the desired dosage form, and may be, for example, from about 0% to about 60% or from about 20% to about 50% or from about 25% to about 48%. Illustrative formulations disclosed herein include those with 48%, 45%, 36.3%, 31.4%, 29.5%, 29%, 27%, and 23% EL. Again, using the information presented herein, the skilled person could adjust the percentage of solvent and determine the optimal amount needed to deliver a certain drug. More than one solvent can be used in a SAIB formulation.

The dosage form of the invention comprises one or more specified rheology modifiers. The weight percent rheology modifier (s) may vary depending on the characteristics of the desired dosage form, and may range, for example, from about 0.1% to about 10% or from about 0.5% to about 5% or about 1% to about 4%. Illustrative formulations disclosed herein include those with 3.5%, 3% and 1% and 0% IM. Using the information presented in this document, the person skilled in the art could adjust the percentage of viscosity of the formulation or other rheology modifier, and determine the optimal amount necessary for the administration of a certain drug. More than one rheology modifier can be used in a SAIB formulation.

The weight percent of network former / s can vary depending on the characteristics of the desired dosage form, and can be, for example, from about 20% or from about 0.1% to about 10% or from about 0, 5% to about 9% or from about 1% to about 8.6%. Illustrative formulations disclosed herein include those with 8.6%, 7.8%, 5%, 4.5%, 3%, 2.1%, 2%, 1%, 0.5%, and 0 % CAB. Different types of CABs (eg, CAB 381-20, CAB 381-2, and CAB 171-15) can be used to influence the desired drug release characteristics. Again, using the information presented herein, one of skill in the art could adjust the percentage of the network former and determine the optimal amount needed to deliver a particular drug. More than one network former can be used in a SAIB formulation.

Formulations of the invention may use cellulose acetate butyrate of varying acetyl and butyryl content such as CAB 381-20, CAB 381-2 and CAB 171-15. CAB allows in situ formation of a microarray within the SAIB-drug formulation. Even without wishing to be bound by theory, it appears that the microgrid formation mechanism appears to be due, in part, to phase inversion (eg, change in Tg) of network builders. That is, when SAIB formulations containing the specified CAB type of network former (eg, CAB 381-20) are exposed to or immersed in aqueous environments such as the gastrointestinal (GI) tract of mammals, the formers Network previously dissolved in SAIB formulations will precipitate as a result of migration of water and other biologically available liquid components, which will result in a polymeric precipitation process and the production of polymeric networks within the drug delivery device. The formation of micro-networks will begin at the surface of the formulation mass and the polymeric network will gradually propagate towards the center of the formulation mass, resulting in a progressive increase in the viscosity of the SAIB formulation in situ.

Together with network formers, solvents such as ethyl lactate and rheology modifiers such as isopropyl myristate, when formulated in SAIB, appear to confer a number of unexpected characteristics on SAIB formulations. Characteristics include rheological characteristics (eg, viscosity), drug release kinetics, and characteristics that prevent excessive consumption.

Drug release rates in early and / or late time periods were found to increase with increasing content of the network-forming polymers in the presence of varying concentrations of ethyl lactate and isopropyl myristate. However, the effects of ethyl lactate (EL) varied and, for example, during early periods of time (0-6 hours), increasing EL concentration increased the drug release rate, while in periods of delayed time (6 to 24 hours), the drug release rate decreased with increasing EL concentration. Also, in particular, the extractability of the SAIB and drug formulations using ethanol solutions was systematically reduced by adding the specified CAB polymers regardless of the ethyl lactate and ethyl lactate concentrations.

ES 2 553 136 T3 isopropyl myristate.

Furthermore, it was found that the addition of the specified CAB polymer to the SAIB formulations steadily increased the viscosity of the SAIB formulations before and after immersion in aqueous media at 37 ° C. However, it was found that the addition of other components, ie, ethyl lactate and isopropyl myristate, lowered the viscosity before immersion in water, but increased the viscosity after immersion in water. Such observations were not to be expected based on prior knowledge of solvents and plasticizers in SAIB and drug formulations.

The present invention allows the adjustment of a series of performance characteristics of SAIB formulations by adjusting the proportions of each ingredient in the formulation such as solvents, rheology modifiers and network formers, including optimization thereof. The present invention also discloses new and surprising interrelationships between formulation ingredients, which produce unobvious and unique formulation rheology, drug release kinetics, rate and degree of drug absorption in vivo, and / or desirable characteristics to prevent consumption. Excessive including reduced drug extractability, eg, by aqueous or alcoholic solutions.

The invention provides a dosage form that reduces or eliminates drug overconsumption in which the route of overconsumption may include, for example, snorting, inhalable, intravenous, sublingual, buccal, subcutaneous, percutaneous, vaginal, rectal, or intraocular media. . The present dosage form has several important characteristics to prevent excessive consumption: it cannot be crushed (for excessive nasal inhalation) and it provides a formulation, for example, that makes alcohol extraction or extraction of the drug very difficult, generating a low drug production.

The dosage forms of the invention show unexpectedly favorable drug release kinetics. For example, the SAIB / oxycodone formulation provides better pharmacokinetic parameters such as shorter Tmax, higher and / or equivalent Cmax and AUC (area under the curve) and better bioavailability of the drug compared to a currently marketed formulation (e.g. example, OxyContin®).

Another unexpectedly favorable property of the formulation of the invention is that the bolus of the formulation appears to remain substantially intact as it passes through the GI tract. For example, the SAIB-based formulation is released from the gelatin capsule when the capsule dissolves, but the bolus of the formulation itself does not emulsify as it passes through the stomach, intestine, or colon even though it is believed that is kneaded or deformed by GI motility (peristaltic movement). Without wishing to be bound by theory, it is believed that surface renewal occurs by relatively constant renewal of surface drug concentration by diffusion of the drug from within the bolus, and by deformation and refolding of the surface or by some combination of these mechanisms.

In a particular embodiment, the invention provides an oral dosage form comprising a formulation contained in a biodegradable capsule, in which the formulation comprises the SAIB drug, a rheology modifier, the network former and a solvent, and in the that the capsule is made up of a substance that degrades when exposed to conditions present in the gastrointestinal tract of a mammal. In preferred embodiments, the capsule can be made from gelatin or synthetic polymers. In particular embodiments, the drug can be an opioid such as oxycodone. It can be seen that the drug release kinetics of dosage forms having various incorporated formulations are both unexpected and favorable for the administration of drugs such as oxycodone.

Preparation of formulations

A method of preparing an illustrative formulation of the invention is presented, using SAIB as the HVLCM. Other SAIB formulations can be prepared by varying this method. The ratios refer to weight percent ratios for SAIB / Ethyl Lactate / Isopropyl Myristate / CAB 381-20, respectively.

A formulation comprising SAIB / EL / IPM / CAB (65: 27: 3: 5) is prepared as follows: an appropriate amount of ethyl lactate was placed in a beaker and, while stirring slowly, added CAB and IPM (stir bar on stir plate); allowed to fully become a solution (stir bar on stir plate) - the resulting mixture was left at 37 ° C for 3 days; Hot SAIB (80 ° C) was added (shaken by hand, then placed on the stir plate) - the 65: 27: 3: 5 mixture was left for a period of about 48 h at 37 ° C; The mixture was heated to 70 ° C for ~ 2 hours and homogenized with a 20mm probe at approximately 4000 rpm for 20-30 seconds; Oxycodone base (at 9 mg / g) was added and the mixture was heated to 70 ° C for 1 h, then left overnight. The mixture was reheated to 70 ° C to fill soft gelcaps using a hypodermic needle and the corresponding syringe.

Formulations, viscosity and dissolution (Table 1)

ES 2 553 136 T3

Table 1 presents the viscosity and dissolution data for various formulations. Viscosity values ​​were determined at 26 ° C and 37 ° C (± 0.1 to 0.3 ° C) using the Brookfield LV DV III and HDBV digital rheometer models and the CPE 52 cone (n = 1 ea) . The oxycodone content ranged from 9 to 12 mg per gelcap in SAIB formulations (lot No. X03502 only contains SAIB and oxycodone).

In addition to the compositions of the SAIB formulations, Table 1 also shows the viscosity at 37 ° C for the formulations, both before and after immersion in water at 37 ° C for 6 hours (the column marked as placebo - H2O is refers to the viscosity of the solution before immersion in water, and the column marked as placebo + H2O refers to the viscosity of the solution after immersion in water). The 37 ° C conditions and immersion in water were intended to simulate in vivo conditions.

Table 1 also shows the cumulative amount of oxycodone released (mg) during two separate periods. One period is 0 to 6 hours and the other is 6 to 24 hours.

The information in Table 1 was analyzed and the following semi-empirical equations were obtained (see equations 1-3). Equations 1-3 were obtained from the information in Table 1 for Oxycodone and SAIB gelcap formulations X03511 to X03518 (8 different formulations).

Equation 1 demonstrates that the dissolution rate of the drug from time intervals of 0-6 hours increases with increasing concentrations of EL, IPM and CAB polymers (statistical confidence is high, r = 0.9).

Equation 2 shows that the 6-24 hour drug dissolution rate increases with increasing IPM and CAB, but decreases with increasing EL.

Equation 3 shows that the drug dissolution rate from 0 to 24 hours increases with increasing EL, IPM and CAB.

The results expressed in equations 1-3 are unexpected. Increasing CAB would be expected to slow the dissolution rate. Instead of increasing CAB, it appears that the dissolution rate increases in the presence of EL and IPM. Furthermore, the role of EL changes depending on the time intervals of interest.

Equations 4-5 were calculated using viscosity values ​​of the formulation before immersion in water at 37 ° C for 6 hours. As can be seen from equations 4-5, the correlation coefficient is excellent (r2 = 0.93 to 0.96). Both equations predict that viscosity will increase with increasing CAB, while viscosity will decrease with increasing EL and IPM. This was to be expected based on the theories of solution rheology.

Equations 6-7 were obtained from the viscosity values ​​of the formulation after immersion in water at 37 ° C for 5 hours. As can be seen from these equations, as expected, increasing CAB increases viscosity after immersion in water. However, equations 6 and 7 predict that increasing EL increases the dip viscosity. This was not to be expected. One would expect that the effect of increasing EL in the dip viscosity would be to reduce the viscosity.

Table 1 presents data for the Oxycodone and SAIB X03502 formulation (for reference only). X03502 did not contain any formulation ingredients (pure SAIB), but delivered a significant amount of oxycodone during the dissolution test (0.42 mg for 0-6 hours and 0.65 mg for 6-24 hours). As can be seen from the in situ viscosity data (51,200 mPa.s [cP]), which is significantly reduced in situ, oxycodone was released at a low rate but with a good rate control mechanism.

Table 1 also shows a number of other interesting formulations. For example, X03503 (for reference only) (SAIB / IPM 99/1), showing significant rheology modifying effect of 1% IPM, showed higher drug delivery rate compared to SAIB formulation pure.

In addition, Table 1 presents SAIB formulations containing CAB 171-15. As can be seen in formulations X03505 to X03508 (for reference only), the viscosities before and after immersion in water are quite significantly different from the formulations containing CAB 381-20BP. As a result, the oxycodone and SAIB formulations containing CAB 171-15 exhibited significantly different oxycodone release kinetics from those containing an equivalent weight percent of CAB 381-20.

The semi-empirical equations derived from the dissolution experimental data are presented below. The equations can be used to calculate the dissolution and extraction of oxycodone free base, and the viscosity of placebo SAIB solutions before and after immersion in water at 37 ° C for 5 hours.

1. Pharmaco solution with% by variable weight of the components

Cumulative drug dissolution was measured as a function of weight percent EL, IPM, and CAB 381-20BP. Eight formulations of oxycodone and SAIB are shown with corresponding in vitro dissolution data. The

ES 2 553 136 T3 formulations were used in GLP and non-GLP pharmacokinetic studies in dogs. Batches X03511 to X03518 (n = 8).

For the following equations Y = cumulative amounts of drug dissolved (mg) or extracted (wt%) and x1, x2 and x3 are the weight percentages of EL, IPM and CAB 381-20BP, respectively.

to. Time interval from 0 to 6 h.

= 3 /) 2-0.15VH-0.57x2-IV7Vx3: I^to - 0.9 (Equation

I)

b. Time interval of 6-24 h.

= 1.59 + 0.0547x1 - 0.3557x2 - 0.417 * 3: i³ = 0.95 (Equation

2)

c. Time interval of 0-24 h.

-1.05-0.0027H-0.21 (7x2 + 7H): r¹ = 0.93 (Equation

3)

two. Viscosity of placebo solutions of SAIB at 37 ° C, before and after immersion in water.

(a) For such SAIB placebo solutions containing CAB 381-20BP (n = 13) before immersion in water at 37 ° C:

Z = 3359.02- 19226 xl - 227.88 x2 + 1240.29 x3 :: f * - 0.93 (Equation 4}

Alternative correlation

Ln Z = * 8.47 - 0.1x1 - 0.137x2 4 * 0.585x3:: r¹ «= 0.96 (Equation 5) (b) For placebo SAIB solutions containing CAB 381-20BP (n = 13) after immersion in water at 37 ° C for 5 hours:

Ln Z1 = 3.8 + 0.056x1 - 0.00911x2 + 1.02x3! í I^to = 0.96 (Equation 6)

The alternative correlation is:

Zl = -42327.04 + 292.95x1 + 405.64 x2 + 12173.84x3:: r * = 0.8 (Equation 7)

Where Z and Z1 are the viscosity (mPa.s) of said SAIB placebo solutions before and after immersion in water at 37 ° C for 5 hours.

The above equations and equation 8, given below, obtained with respect to an illustrative drug (oxycodone) allow to formulate dosage forms in which the prevention of excessive consumption and the drug release kinetics can be varied and optimized to any degree. , as well as other features. Similar equations can be developed with respect to other illustrative drugs.

ES 2 553 136 T3

Table 1: Rheological characteristics and in vitro drug release properties of SAIB and oxycodone formulations

<td rowspan="2">Lot No.</td><td rowspan="2">Composition (% by weight)</td><td>Viscosity 37 ° C</td><td>(mPa.s) to</td><td colspan="2">Dissolution properties (mg of drug released during 0-6 and 6-24 h)</td>

<td>Placebo - H2O</td><td>Placebo + H2O</td><td>Σ 0-6 h (mg)</td><td>Σ 6-24 h (mg)</td>

<td>t X03502</td><td>SAIB (100)</td><td> 137,000</td><td> 51,200</td><td> 0,42</td><td> 0,65</td>

<td>t X03503</td><td>SAIB / IPM (99/1)</td><td> 79,773</td><td> 33,338</td><td> 0,63</td><td> 0,78</td>

<td>t</td><td>SAIB / EL / CAB 171-20</td><td></td><td></td><td></td><td></td>

<td>X03504</td><td> (50/48/2)</td><td></td><td></td><td></td><td></td>

<td>t</td><td>SAIB / EL / CAB 171-15</td><td rowspan="2"> 2,046</td><td rowspan="2">1.14 x 10⁶</td><td rowspan="2"> 2,82</td><td rowspan="2"> 3,53</td>

<td>X03505</td><td> (50/45/5)</td>

<td>t</td><td>SAIB / EL / CAB 171-15</td><td> 1,618-</td><td rowspan="2"> 5,270-9,380</td><td rowspan="2"> 1,09/1,45</td><td rowspan="2"> 2,33/2,27</td>

<td>X03506</td><td> (70/27/3)</td><td> 2,670</td>

<td>t X03507</td><td>SAIB / EL / CAB 170-15 (61.6 / 36.3 / 2.1)</td><td> 325</td><td> -</td><td></td><td></td>

<td>t</td><td>SAIB / EL / CAB 171-15</td><td rowspan="2"> 48</td><td rowspan="2"> 262</td><td rowspan="2"> 1,21</td><td rowspan="2"> 2,76</td>

<td>X03508</td><td> (70/29,5/0,5)</td>

<td>X03511</td><td>SAIB / EL / IPM / CAB 381-20BP (59 / 31.4 / 1 / 8.6)</td><td> 6,296</td><td>120e3</td><td> 1,7</td><td> 3,1</td>

<td>X03512</td><td>SAIB / EL / IPM / CAB 381-20BP (59.8 / 31.4 / 1 / 7.8)</td><td> 35,720</td><td> 346,000</td><td> 1,42</td><td> 2,4</td>

<td>X03513</td><td>SAIB / EL / IPM / CAB 381-20BP (71/23/1/5)</td><td> 3,274</td><td> 4,092</td><td> 1,02</td><td> 1,14</td>

<td>X03514</td><td>SAIB / EL / IPM / CAB 381-20BP (65/27 / 3.5 / 4.5)</td><td> 2,892</td><td> 14,349</td><td> 1,61</td><td> 2,83</td>

<td rowspan="2">X03515</td><td>SAIB / EL / IPM / CAB</td><td> 4,040-</td><td> 31,221-</td><td rowspan="2"> 1,7</td><td rowspan="2"> 2,74</td>

<td>381-20BP (65/27/3/5)</td><td> 7,010</td><td> 30,427</td>

<td>X03516</td><td>SAIB / EL / IPM / CAB 381-208P (63/29/3/5)</td><td> 2,920</td><td> 38,000</td><td> 2,11</td><td> 3,1</td>

<td>X03517</td><td>SAIB / EL / IPM / CAB 381-20BP (63/29 / 3.5 / 4.5)</td><td> 875</td><td> 5,300</td><td> 1,97</td><td> 2,84</td>

<td rowspan="2">X03518</td><td>SAIB / EL / IPM / CAB</td><td> 4,040-</td><td> 31,221-</td><td rowspan="2"> 2</td><td rowspan="2"> 3,1</td>

<td>381-20BP (65/27/3/5)</td><td> 7,010</td><td> 30,427</td>

<td>t</td><td>SAIB / EL / CAB 171-15</td><td> 1,618-</td><td rowspan="2"> 5,270-9,380</td><td rowspan="2"> 1,64</td><td rowspan="2"> 2,5</td>

<td>X03520</td><td> (70/27/3)</td><td> 2,670</td>

<td colspan="6">t = for reference only</td>

Table 2: Illustrative CABs

<td>CAB Types (Managed by Eastman Chemicals)</td><td>Butyryl content (%)</td><td>Acetyl content (%)</td><td>Hydroxyl content (%)</td><td>Melting point (° C)</td><td>Glass transition temperature (° C)</td><td>Molecular weight (average No.)</td>

<td> 171-15</td><td> 17</td><td> 29,5</td><td> 1,5</td><td> 127-40</td><td>NA</td><td>NA</td>

<td> 381-2</td><td> 36-38</td><td> 13,5-14,5</td><td> 1,3-1,7</td><td> 171-185</td><td> 130-133</td><td> 40.000</td>

<td> 381-20</td><td> 36</td><td> 15,5</td><td> 0,8</td><td> 185-196</td><td> 128</td><td> 66.000-83.000</td>

Measurement of drug dissolution rates in low pH solution (FIG. 6)

A soft gelcap containing one of several SAIB and oxycodone formulations was placed in a conventional glass beaker with a shaker mechanism (as defined by Apparatus II of the United States Pharmacopeia; VK 7000 USP II Solution Analyzer ). 900 ml of 0.1N HCl solution at 37 ° C was introduced into the beaker and the solution was stirred at 50 rpm for 2 hours. During that period, the gelcap dissolved, and the SAIB and drug formulation was exposed to the low pH solution, beginning the dissolution of the oxycodone. A series of 1 ml samples was taken and the oxycodone concentration was determined by HPLC (Perkin Elmer 200 LC Series Pump, or equivalent; UV detector, Perkin Elmer 235C diode array detector, or equivalent). After the initial dissolution step, the contents of the beaker were modified to adjust the pH from 1 to 6.8 by adding sodium phosphate buffer. The temperature was maintained at 37 ° C and the dissolution of the drug continued for a further 22 hours. Additional 1 ml samples were taken at various time points and the oxycodone concentration was determined by HPLC. The cumulative percentage of oxycodone dissolved in the medium was calculated for each time interval and a graph was plotted (FIG. 6).

Figure 6 shows the data obtained in a drug dissolution experiment. The graph shows the data

ES 2 553 136 T3 of a SAIB and drug formulation in a soft gelcap (square shaped data points) compared to a commercial oxycodone tablet (OxyContin®) (diamond shaped data points) that were used as a reference. The y-axis represents the cumulative percentage of oxycodone released and the x-axis represents time (h).

The SAIB and oxycodone formulation in Figure 6 contained the following ingredients by weight percentages: 10 mg oxycodone free base per gelcap, 65% SAIB, 27% ethyl lactate, 3% isopropyl myristate, and CAB 381- 20 to 5%. The commercial oxycodone product contained 80 mg of oxycodone. A number of other SAIB and oxycodone gelcap formulations were tested for drug dissolution, and the results are given in Table 1.

As is evident from Figure 6, the commercial oxycodone tablet showed a large initial burst of oxycodone release, with almost 50% being administered within the first hour and 80% over a six hour period. Drug release after rapid discharge was slow compared to initial rapid discharge. On the other hand, the SAIB and oxycodone formulation did not show a rapid discharge effect and showed a more controlled and prolonged release of the drug throughout the trial period.

Drug extraction in ethanol

An important feature of the invention is that the formulations can be prepared such that the extraction of drug from the formulations using traditional ethanol extraction (traditionally used by drug abusers) is much less effective than in the case of the formulations in tablets and capsules of the previous chemistry.

FIGS 1-4 are graphs showing the results of a study on the impediment of binge drinking. The objective was to determine the amount of oxycodone that would be extracted from a dosage form comprising a formulation of SAIB and oxycodone in a soft gelcap using a simple alcohol extraction, as used by those who overconsume the drugs. The units in the graphs are percent cumulative release versus time (min).

The method used to produce data for the binge drinking impairment study was as follows. Each soft gelcap was filled with 0.75 ml of formulation and filled into 18 ml of 0.1N HCl in a 60 ml amber flask, and stirred at 240 rpm on an orbital shaker for 30 minutes. After 30 minutes, 12 ml of 200 ° ethanol (200 alcohol content) was added to each flask. The solutions were shaken by hand and a 1 ml sample was taken from each flask at T = 0. The solutions were placed back on the orbital shaker to continue stirring at 240 rpm. 1 ml samples were taken after 10, 20, 30, 40, 60 and 180 minutes of additional shaking from each flask. Results were plotted on a linear scale of cumulative release (%) versus time (min).

FIG. 1 shows the percentage of the cumulative amounts of extracted drug in percentage of initial drug loading in the SAIB formulations versus time (min) for 9 formulations. Each formulation contains 12 mg / ml of oxycodone. Formulation ID numbers and formulations component ratios are shown in the key. The proportions (percent by weight) of each ingredient correspond to, SAIB: EL: IM: CAB.

From the data presented in Figure 1, it can be seen that all ingredients and their proportions affect the drug extractability. Using regression analysis, the following empirical equation refers to the cumulative percent of drug extracted as a function of percent by weight of each ingredient.

Ln Cum% = 4.04 + 0.0132 x 1 + 0.0518 x 2 - 0.1994 x 3: r² = 0.75 (equation 8), where Cum% indicates the cumulative percentage of drugs extracted during the entire time interval, and x1, x2 and x3 are the weight percentages of EL, IPM and CAB 381-20. As can be seen, the weight percent of drug that was extracted by the alcohol solution described above decreased with increasing CAB 381-20 (see formulations 25662-02, 256-62-04, 256-62-06 and 256-62-08). However, it was not evident that the addition of the well-known rheology modifier, IPM, added to the formulations containing 4% by weight of CAB 381-20, did not affect the alcohol extraction of the drug, as demonstrated by the formulation 256-62-16. This runs counter to common sense in the art of pharmaceutical formulations. That is, IPM, which is a SAIB rheology modifier, would have been expected to dilute the SAIB formulations and facilitate drug extraction, but it did not. It was also found that when the CAB content was 3% by weight as in formulation 25662-12, the addition of 3% by weight of IPM significantly increased the drug extractability by solution in alcohol versus formulations that did not they contained IPMs such as formulation 256-62-04. Therefore, it was concluded that the low drug extractability of SAIB formulations with an alcohol can be produced not only due to the optimal CAB weight percentage, but also due to the optimal ratio between CAB and IPM.

FIG. 2 shows the cumulative percentage of alcohol-extracted oxycodone free base versus time (min) for 4 formulations. Soft gelcaps were filled with each formulation. Each gelcap contained 12 mg / ml of oxycodone free base.

ES 2 553 136 T3

In this experiment, the effects of different proportions of IPM to CAB were evaluated for the drug extractability of sAiB formulations in alcohol. The proportion ranged from 0.25 to 0.78. For the given range of proportions, it was unexpectedly found that increasing the contents of ethyl lactate, isopropyl myristate and CAB in a coordinated manner reduced the extractability of the drug in alcoholic solution. From this experiment, it was found that iPm and CAB were quantitatively interchangeable with each other, so that increasing one component and reducing the other by the same weight percent produced a formulation with invariable rheological properties. This discovery is particularly surprising in light of the fact that IPM is a rheology modifier that makes SAIB formulations dilute (less viscous), while CAB is supposed to make them more consistent and less deformable. Therefore, it was not expected that increasing IPM would have the same effect as increasing CAB.

FIG. 3 shows the cumulative percentage of drug extracted in alcoholic solution from various SAIB formulations versus time (min) for 4 formulations. Each formulation contains 12 mg / ml of oxycodone. These formulations had IPM to CAB ratios ranging from 0.6 to 0.78 and a calibrated content of ethyl lactate ranging from 27-29% by weight. The figure shows that at the end of the 180 min extraction experiment, the percentage extracted was approximately the same for all 4 formulations. However, at the end of the first 60 minutes, the percentage of extracted drug was found to be higher with formulations containing higher amounts of ethyl lactate. It was also found that an extremely low increase in ethyl lactate content led to a large increase in drug extraction.

FIG. 4 shows the cumulative percentage of extracted drug in alcohol versus time (min) for 3 formulations. Each formulation contains 9 mg / ml of oxycodone. This experiment showed that ethyl lactate has a greater influence on the extraction capacity of the drug in alcohol than CAB, by a factor of more than double. This was another unexpected discovery, since it would have been reasonable to believe that the CAB is a highly efficient matrix / network builder.

Drug extraction in water

Another experiment was carried out to determine the degree to which the formulation of the invention had characteristics of preventing excessive consumption, in particular, to determine the extraction capacity of oxycodone in water. Generally, the person who consumes the drug excessively can crush and crush an oxycodone tablet and dissolve it in water to extract the drug into an aqueous solution for injection. In the present experiment, the experimental dosage form was a SAIB and oxycodone gelcap with a formulation of SAIB: EL: IPM: CAB at a ratio of 67: 26: 3: 4, contained in a soft gelatin capsule and containing 9 mg of the drug (oxycodone free base). The control dosage form used was 9 mg Oxycontin® tablet. Each dosage form was crushed with a mortar, and ground and ground in 5 ml of water. The resulting solution / suspension was then filtered through a 0.45 micron filter into a flask and diluted to 50 ml with water. Then, the oxycodone concentration was quantified by HPLC. The results were as follows: for the control (OxyContin® tablets), 100% oxycodone was extracted from the crushed tablet in water. For the experimental SAIB formulation, only about 21% oxycodone was extracted in water. This shows that the present formulation has significant drug overconsumption prevention characteristics compared to the Oxycontin® tablet, because the drug cannot be efficiently extracted into water.

Physical treatment

Another possible method of drug overconsumption is to reduce the temperature and mechanically crush a drug formulation to produce a powder that can then be inhaled or dissolved in a solution for injection. An experiment was carried out to determine the characteristics of the present formulation, in particular, with respect to the reduction of the temperature and the mashing. In this procedure, the formulation was placed in a laboratory freezer at -80 ° C for 8 hours, after which it was struck sharply with a hammer. One formulation comprised 100% SAIB, one formulation comprised SAIB plus a solvent (26% EL), and one formulation was the SAIB: EL: IPM: CAB formulation at a ratio of 67: 26: 3: 4 and free base oxycodone (see above). For the first formulation (100% SAIB), the results were as follows: in a period of approximately 45 seconds after crushing, the fragments were thawed and returned to the state of a high viscosity liquid. The structure of the controlled release matrix of the formulation was preserved. For the second formulation (SAIB + solvent): within approximately 30 seconds after crushing, the formulation mass appeared highly viscous and sticky, and did not break into distinct fragments. Again, the controlled release matrix structure was preserved. For the PTI-821 formulation: within a period of approximately 30 seconds after crushing, the formulation was found to be very viscous and sticky, and did not fracture into pieces. Once again, the controlled release matrix structure was preserved. Therefore, attempting to overconsume by lowering the temperature and crushing would not produce a drug form that could be easily overconsumed. See Figures 7-9.

ES 2 553 136 T3

Additional comments

It was found that optimal SAIB formulations, exhibiting desirable pharmacokinetic profiles, should possess the following viscosity characteristics: SAIB solution viscosity at 37 ° C should be in the range of 1,000-30,000 mPa.s (1,000-30,000 cP). Furthermore, SAIB formulations after immersion in water at ° C or aqueous buffer (pH 1-10) for 4-5 hours should optimally have a viscosity at 37 ° C ranging from 3,000-50,000 mPa.s (3,000-50,000 cP).

Although a number of the examples provided above refer to compositions according to the invention containing oxycodone in amounts of about 10 mg per gelcap of SAIB formulations, greater or lesser amounts of drug can be incorporated (eg 5 mg, 20 mg, 40 mg, 80 mg, 160 mg and the like) to SAIB gelcap according to the invention.