Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
  • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
  • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
  • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present invention relates to the field of pharmaceutical safety dosage fonns.
• OXYCONTIN ® ER tablets are prone to abuse and misuse when their dosage units are broken, chewed, crushed, dissolved, or otherwise disrupted, rather than being taken whole as intended.
• Other narcotic and analgesic drugs are liable to similar misuse.
• Other types of drugs, including those which are not amenable to abuse, may, nonetheless, be inappropriately used. Such inappropriate use can lead to adverse reactions in persons so using the drugs and can give rise to adverse reactions and even death.
• metformin sustained-release e.g., GLUCOPHAGE ® XR, metformin hydrochloride extended-release tablets supplied by Bristol- Myers Squibb
• metformin sustained-release is chewed, or the tablets otherwise disrupted prior to ingestion, rather than the tablets being swallowed whole, dangerous lowering of a person's blood glucose level may result. Nery large numbers of pharmaceuticals may be inappropriately ingested in this way and a method for reducing or eliminating the undesired effects has long been desired.
• sustained-release fonn has provided the advantages of more convenient dosing schedules, increased patient compliance, more even blood levels, improved therapeutic activity, or others.
• the dosage of active pharmaceutical ingredient in these sustained-release fo ⁇ nulations is greater than the dosage of the co ⁇ esponding immediate-release formulation. This presents the danger of "dumping" in which the sustained-release mechanism fails, either intentionally or unintentionally, so that potentially dangerous dosages of the active phannaceutical ingredient (agonist) are delivered to the patient causing dangerously high blood levels of the agonist.
• the Physicians ' Desk Reference (PDR), 56th Edition, states for GLUCOTROL ® XL Extended Release Tablets (supplied by Pfizer), under "Information for Patients", that "Patients should be informed that GLUCOTROL XL Extended Release Tablets should be swallowed whole.
• U.S. Patent No. 5,375,957 in the name of Kaiko et al. recognizes that oral and parenteral abuse of oral opioid formulations can occur by self-administration of more than the prescribed oral dosage.
• Kaiko et al. discusses an appropriate ratio between analgesic agonist and antagonist in such dosage forms to ensure analgesic efficacy is maintained.
• Kaiko et al. contemplates that the antagonist be absorbed into the blood in normal use along with the agonist.
• Kaiko et al. distinguishes itself over prior art that teaches inclusion of antagonists in oral opioid analgesic dosage fonns, which are themselves not orally active, but which counteract the analgesic effects of the opioid upon parenteral administration.
• Kaiko et al. describes the commercially available combination of pentazocine and naloxone, wherein the amount of naloxone does not interfere with the pentazocine upon oral administration.
• the antagonist would still be absorbed into the blood in normal use along with the agonist, but would not provide any pharmacological activity.
• Pharmaceutical dosage fonns that permit absorption into the blood of an antagonist are inefficient because of the resulting potential to hinder the activity of the agonist during normal use. This limits the amount of antagonist that can be used. This also limits the potential amount of antagonist activity that can be incorporated into the dosage fonn to less than the amount of activity that will substantially inhibit the agonist activity.
• the antagonist naloxone
• the antagonist can be present in amounts that are not orally active, this may not be possible or desirable with antagonists for other drugs. Also, even if the antagonist is not orally active, it may still be absorbed by the blood and impact the patient during nonnal use of the dosage fonn. Additionally, as in Gordon et al., if the antagonist is inactive with oral use then it cannot provide protection against dumping of the agonist if the sustained-release tablet is mechanically disrupted. Furthennore, lack of oral activity may not deter oral abuse.
• Such pharmaceutical safety dosage forms include a pharmaceutical as well as an antagonist for the pharmaceutical.
• the antagonist In normal use, that is when the dosage forms are administered or taken by the person in need of drug treatment, the antagonist has no significant bioavailability.
• the antagonist has significant bioavailability only when the pharmaceutical safety dosage form is disrupted.
• Disruption of the dosage fonn means in this context the mechanical, chemical or other alteration of the dosage form in such a fashion as to release or make biologically available the antagonist. Disruption does not mean the dissolution of the dosage form or its delivery of the pharmaceutical in accordance with the intended mechanism of use of the dosage form.
• the phannaceutical safety dosage forms of the present invention can be administered orally, parenterally, rectally, vaginally, transdennally, via aerosol, via nasal spray, or otherwise such as via implantation.
• a normal mechanism of delivery of the pharmaceutical is intended consistent with good medical and phannaceutical practices. Delivery of the pharmaceutical in any of these intended ways for the dosage forms of the invention does not deliver a substantial amount of the antagonist into the bloodstream. Rather, the antagonist is maintained in such a way as not to be substantially bioavailable via such intended method of administration. In short, it is intended that the antagonist "pass through" the patient and be substantially eliminated thereby. Thus, the antagonist is intended not to become bioavailable to the patient and not to require systemic inactivation or excretion therefrom. The overall loading of active compounds is, thus, minimized and limited to only the intended pharmaceutical when the dosage fonn is used as intended.
• the present invention generally contemplates placing one or more antagonist pharmaceutical products within the dosage formulation of the agonist phannaceutical product so that, under normal conditions, the antagonist is substantially not bioavailable.
• disruption of the formulation through any of a variety of means, will release the antagonist thereby diminishing the effects of the agonist.
• OXYCONTIN ® supplied by Perdue Pharma
• Extended Release tablets abuse narcotic abusers are crushing the tablets to disrupt the sustained-release mechanism thereby gaining a large immediate dose of narcotic.
• Tins invention contemplates, in one example, placing a narcotic antagonist in coated beads in OXYCONTIN ® (supplied by Perdue Pharma) Extended Release tablets for which the coating maintains the beads intact throughout the digestive system, under normal use, thereby blocking any significant bioavailability of the antagonist.
• OXYCONTIN ® supplied by Perdue Pharma
• Extended Release tablets for which the coating maintains the beads intact throughout the digestive system, under normal use, thereby blocking any significant bioavailability of the antagonist.
• the abuser crushes the tablets, the abuser will also crush the beads thereby exposing the antagonist within the beads to dissolution in the gastrointestinal tract thereby facilitating bioavailability of the antagonist.
• blood glucose lowering drugs such as metformin (e.g., GLUCOPHAGE ® XR supplied by Bristol-Myers Squibb) or glipizide (e.g., GLUCOTROL XL ® Extended Release Tablets supplied by Pfizer) containing beads of a hyperglycemic agent such as epinepherine or others; anti-hypertensive drugs such as propranolol (e.g., LNDERAL ® LA Long-Acting capsules supplied by Wyeth-Ayerst), metoprolol (e.g., TOPROL-XL ® supplied by AstraZeneca), nifedipine (e.g., PROCARDIA XL ® Extended Release tablets supplied by Pfizer, ADALAT ® CC supplied by Bayer), diltiazem (e.g., CARDIZEM ® CD supplied by Biovail), or ni
• metformin e.g., GLUCOP
• Figure 1 shows a dosage fonn of the invention containing pluralities of microdosage forms.
• Figure 1A depicts two different types of bead types of microdosage forms.
• Figure IB shows a multi-layered bead for use in one embodiment of the invention.
• Figure 2 depicts an osmotic drug dosage fonn in accordance with the invention.
• Figure 3 shows a dosage form of the invention containing microdosage forms and particulated forms.
• Figure 4 shows a dosage fonn of the invention containing two different types of microdosage forms.
• antagonist is delivered from the dosage form, (i.e., becomes bioavailable), only when the dosage form is physically or otherwise disrupted through use in a manner not intended by the drug manufacturer.
• the oxycodone is delivered over a period of time to a patient ingesting a dosage form so as to provide extended narcotic effect to such patient.
• An antagonist for the narcotic, naloxone is present in the dosage form, but is not released from the dosage form; it does not become bioavailable, in nonnal use.
• the antagonist, naloxone is also released.
• the naloxone is preferably present in an amount sufficient to interfere with the narcotic effect of the oxycodone, thus frustrating the attempted abuse of the drug.
• the present dosage fonns are amenable to the delivery of a wide variety of narcotic and non-narcotic drugs in a manner having improved safety.
• a drug which is capable of abuse or of significant adverse effect if inappropriately ingested during or following disruption of the dosage form must be one which has an antagonist.
• an antagonist is preferably a compound or composition which is capable of interfering or negating all or some of the effects of the therapeutic drug. This may be achieved either biochemically, physically, physiologically, or otherwise.
• narcotic antagonist naloxone
• an effective antagonist in the context of this invention, may act otherwise, e.g. through stimulation of an excretion or breakdown mechanism for the drug.
• the mechanism of action of antagonists which may be employed herein is not intended to be limiting in any way. Any compound, group of compounds or composition which can interfere effectively with the action of a drug may be considered to be an antagonist for the drug, providing the overall objectives of this invention are met.
• dosage forms which can release antagonist under such conditions if this is the particular activity that is intended to be counteracted by inclusion of the antagonist in the dosage fonn.
• the antagonist can be formulated to protect against one or more such disruption activities.
• microdosage forms Many pharmaceuticals are provided in capsule dosage forms containing within them microdosage forms.
• One embodiment of the present invention provides a pharmaceutical and an antagonist for the pharmaceutical in a dosage form where each is contained within microdosage forms, e.g., coated beads, mini tablets, and tablets.
• the beads containing the drug are coated or formulated so as to release the drag on an intended time profile.
• the beads containing the antagonist are either formulated or coated so as to prevent significant bioavailability of the antagonist when the dosage fonn is consumed as intended.
• Specific coatings which can attain the foregoing objectives are numerous and well-known to phannaceutical chemists and formulators.
• Figure 1 depicts a conventional capsule dosage form comprising a shell, 10 and containing pluralities of microdosage fonns, e.g. beads, 12. There are preferably at least two different kinds of beads, beads (or other microdosage forms) containing the drag and beads (or other microdosage forms) containing antagonist.
• the drag-containing beads are formulated so as to release drug when administered to a patient in accordance with conventional practice.
• the antagonist-containing beads are formulated so as not to deliver antagonist to a patient in normal use.
• beads 16 can represent a formulated drag 24 within a saccharide, polymer, or other matrix designed to deliver the drag, e.g. in the small intestine of a patient.
• Another type of bead 14 comprises antagonist for the drag 20 coated by coating 22 the whole being fo ⁇ nulated to resist antagonist delivery until all beads are eliminated from the patient, e.g. in the stool.
• the drag-containing beads may be coated and the antagonist not coated as may be desired by the routineer in the art.
• three or more different types of beads may be employed, for example, when extended-release of drug is desired or there are different active ingredients.
• the preparation of diverse types of beads and the use of a wide variety of coatings and formulation components is an advanced art and is well known to persons skilled in drag formulation. All such may find utility herein.
• FIG. IB A further exemplification of the invention is shown in Figure IB.
• the figure depicts a multi-layer microdosage fonn or bead 30.
• Drag 32 is coated by coating 34 designed to deliver the drag to a patient at a desired time and in a desired location, e.g. the stomach.
• the whole, in this embodiment, preferably su ⁇ ounds a formulation of antagonist 36 for the drag which is so formulated as not to release antagonist when ingested under normal conditions.
• the antagonist is designed to pass through the body of the patient unabsorbed.
• FIG. 4 presents a conventional capsule dosage form comprising a shell 70, and containing two different types of microdosage forms, e.g., tablets 74 and beads 78. It is understood that neither the drug nor its antagonist are limited to certain microdosage forms.
• a drug 72 may be contained in tablets 74 which are fonnulated for time-release, and its antagonist 76 may be contained in beads 78 fonnulated or coated to not deliver the antagonist during normal use of the dosage fonn.
• the drug may be contained in beads fonnulated for time-release and its antagonist may be contained in tablets coated to prevent significant bioavailability when the dosage form is used as intended.
• a further embodiment of the present invention comprises a drag in the fonn of a powder, in an amorphous form or with one or more polymorphs, in tabletable form together with antagonist in a microdosage form such that it is substantially insoluble in gastric or other fluid.
• a powdered drug, along with excipients, such as fillers, binders, disintegration agents, lubricants, colorants, or other conventional adjuvants is combined with one or more beads, mini tablets, powder, or other forms containing antagonist.
• the antagonist forms are formulated or coated in such a way as to render them substantially insoluble in the gastrointestinal tract or other locus of administration.
• An antagonist that is substantially insoluble in the human body for example, is prevented from being released before the antagomst is excreted from the body.
• powders can be formulated so as to prevent dissolution in bodily fluids and/or prevent significant bioavailability. Solubility of polymorphs or solvates, for example, are dependent on the crystallized structure of the molecules, and thus, have different solubilities. Hence, certain polymorphs or solvates may be insoluble in the body, but readily soluble in specific solvents. The preparation of polymorphs or solvates are discussed by numerous patents on numerous molecules, e.g.
• a tabletted dosage form in accordance with one embodiment of the invention is provided.
• the tabletted dosage form 60 is formed from powdered drug 62 together with conventional adjuvants, such as excipients and the like. Beads, mini tablets, or the like 64 comprising antagonist for the drag 66 axe included within the tablet. Other variations of such tabletted dosage forms may also be employed. It is understood that neither the drug nor its antagonist are limited to certain particulated forms or microdosage forms. Thus, a drag may be present in time-release powder fonn and its antagonist may be present as a polymorph which is insoluble in the body, but readily soluble in specific solvents.
• a conventional capsule dosage form may contain a drag in time-release powdered form and an antagonist to the drag in tabletted form, shellacked to prevent bioavailability upon nonnal use of the dosage form.
• FIG. 2 A further dosage fonn in accordance with this invention is depicted in Figure 2.
• This is a type of osmotic pump drag delivery dosage form 40.
• a shell 41 contains a compartment containing drug 42 as well as a compartment containing an osmotic agent 50.
• the two compartments are preferably separated by a piston 48.
• both the drug- containing compartment and the osmotic agent-containing compartment have an orifice sealed by plugs 46 and 52, respectively.
• the plugs 46 and 52 dissolve, exposing both the drag-containing compartment and the osmotic agent-containing compartment to body fluid.
• the present invention may be applied to such osmotic drag dosage fonns.
• a formulation of antagonist 54 su ⁇ ounds the dosage fonn.
• the antagonist formulation is generally kept away from those orifices as shown. Since osmotic drug delivery vehicles may take a diversity of physical shapes, the shape and location of antagonist will reflect such geometry.
• the antagonist formulation is one which does not release antagonist to the body of a person co ⁇ ectly ingesting the dosage form, it may also be coated if prefe ⁇ ed to achieve a similar result. In any event, physical or other disruption of the dosage fonn will release the antagonist as well as the drag.
• Another example could be coated beads of the antagonist that reside in one or more compartments of the osmotic drug delivery vehicle.
• Another aspect of the present invention is a method of administering pharmaceuticals by providing pharmaceutical safety dosage fonns that include a phannaceutical and an antagonist for the phannaceutical where the microdosage fonns provide insignificant bioavailability when the dosage fonn is administered as intended.
• Insignificant bioavailability in the context of this invention is intended to mean that the antagonist does not interfere with the drug in a meaningful way and that the person to whom the dosage form is administered is not burdened with a significant loading of antagonist.
• Drug dosage forms of this invention are preferably administered through the alimentary canal orally or anally. Delivery otherwise to the body from outside of the digestive tract, parenteral administration, may also benefit from this invention and employs, e.g. subcutaneous, intravenous, intravaginal, intramuscular, transdermal, nasal, aerosol, or other routes of administration.
• narcotics and narcotic antagonists include, but are not limited to, codeine, oxycodone, propoxyphene, pentazocine, and derivatives thereof.
• narcotic antagonists include, but are not limited to, naloxone, nalmefene, and derivatives thereof.
• Another combination of agonist and antagonist is sympathomimetics, e.g. amphetamines, and adrenergic beta blockers. Sympathomimetic agonists along with antihistamines can also be combined with adrenergic beta blockers.
• Reference to derivatives of chemicals discussed herein include, but are not limited to, chemical derivatives and salts and bases thereof.
• Drags which are not prone to abuse may also be administered using the safety dosage forms hereof.
• drags intended for sustained-release in the body can give rise to unpleasant and undesired reactions if over-administered.
• the disraption of dosage fonns containing, e.g. diabetes drags, blood pressure lowering drugs and many other types of pharmaceuticals can give rise to diabetic shock or shock-inducing low blood pressure.
• diabetes drags include, but are not limited to, hypoglycemic agents, and examples of antagonists to hypoglycemic agents include, but are not limited to, hyperglycemic agents.
• blood pressure-lowering drags include, but are not limited to, adrenergic beta blockers, calcium channel blockers, and ACE inhibitors.
• antagonists to blood pressure-lowering drags include, but are not limited to, sympathomimetics. Including antagonists for these drugs as taught hereby can guard against accidental overdose, if, for example, sustained-release tablets are chewed.
• dosage forms can include any pharmaceutical combined with an emetic agent, e.g., ipecac, which is released upon disraption of the dosage fonns.
• an emetic agent e.g., ipecac
• Cetiriziiie HCl/pseudoephedrine HC1 Adrenergic beta blocker fexofenadine HCl/pseudoephedrine HC1

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