CA2614899A1 - Metering and packaging of controlled release medication - Google Patents

Abstract

Controlled quantities of powdered medication are formed in controlled release packages using electrostating metering. Also provided are combination medication therapy delivery packages comprising two or more active pharmaceuticals segregated from one another in a single delivery package.

Description

METERING AND PACKAGING OF CONTROLLED
RELEASE MEDICATION

Field of the Invention The present invention relates to the metering and packaging of precise quantities of pharmaceuticals and drugs for medical uses. The invention has particular utility in the metering and packaging of combinations of two or more pharmaceuticals and drugs for the same or c-morbid therapy, and will be described in connection with such utility, although other utilities are contemplated.
Related Art The conveni.ence of administering a single dose of a medication which releases multiple active ingredients in a controlled fashion and in a chose-n location over an extended period of time, as opposed to the admixiistration of a number of single doses at regular intervals, has long been recognized in the pharmaceutical arts. The advantage to the patient and clinician in having consistent and uniform blood levels of medication over an extended period of time are likewise recognized. The advantages of a variety of controlled-release dosage forms are well known. Among the most important advantages are: (1) increased contact tinie for the drug to allow for local activity in the stomach, small intestine, colon, or other locus of activity; (2) increased and more efficient absorption for drugs which have specific absorption sites; (3) the ability to reduce the number of dosages per period of time; (4) employment of less total drug; (5) m;,,im;7ation or elimination of local and f or systemic side effects; (6) minimization of drug accumulation associated with chronic dosing; (7) improved efficiency and safety of treatment; (8) reduced fluctuation of drug level; and (9) better patient compliance with overall disease management.
In accordance with the present invention there is provided a pharmaceutical delivery package comprising fixed unit dose quantities of fixed quantities of two or more different active pharmaceutical ingredients (a) combined in a single delivery package,-and (b) segregated from one another within the package.

Additionally, many experts believe controlled release drug delivery has many important non-therapeutic ramifications as well, including a financial saving to the patient in terms of fewer lost work days, reduced hospitalization and fewer visits to the physician.
It is known that certain design parameters are critical to proper drug delivery. Typically, they are: (1) delivering the drug to the target tissue;
(2) supplying the drug for a predetermined period of tirne; and (3) fabricating a delivery system that provides drug in the desired spatial and temporal pattern. Controlled release drug delivery systems are interided to utilize these parameters to achieve the aforementioned advantages as compared to conventional pharmaceutical dosing.
Previously direct placement of medication onto a substrate generally was linv.ted to medical placement of large doses or required technology where the active pharmaceutical was mixed with the substrate or matrix to provide differential delivery, or coated with a material with desired release characteristics.
As used herein "controlled-release" is used to describe a system, i.e.
method and materials for making an active ingredient available to the patient in accordance with a preselected condition, i.e. time, site, etc.. Controlled-release includes the use of instantaneou.s release, delayed release and sustained release. "Instantaneous release" refers to immediate release to the patient. "Delayed release" means the active ingredient is not made available until some time delay after administration. Typically; dosages are administered by oral ingestion, although other forms of administration are contemplated in accordance with the present invention. "Sustained release"
refers to release of active ingredient whereby the level of active ingredient available to the patient is maintained at some level over a period of time.
The method of effecting each type of release can be varied. For example, the active-ingredient can be placed on a semi-permeable membrane having predetermined diffusion, dissoltition, erosion or breakdown characteristics.
Alternatively, the active ingredient can be masked by a coating, a laminate, etc. Regardless of the method of providing the desired release pattern, the present invention contemplates delivery of a controlled-release system which'utilizes one or more of the "release" methods and materials.
Moreover, the present invention advantageously can be employed in the development of multiple different release system(s).
The patent and scientific literature is replete with various sustained release (SR) methods and materials. For common methods of obtaining SR
systems, see "Sustained and Controlled Release Drug Delivery Systems,"
Robinson, Joseph R., Ed., PP 138-171,1978, Marcel Dekker, Inc. New York, NY. For example it is known to filI polymeric cappules with a solid, liquid, suspension or gel containing a therapeutic agent which is slowly released by diffusion through the capsule walls. Heterogeneous matrices, for example, compressed tablets, control the release of their therapeutic agents either by diffusion, erosion of the matrix or a combination of both. Other SR systems focus on the fabrication of laminates of polymeric material and therapeutic agent which are then formed into a sandwich, relying on different diffusion or erosion rates to control xelease of the therapeutic agent. Liquid liquid encapsulation in a viscous syrup-like solution of polymer also has been known to be useful in controlling release of the therapeutic agent.
Additionally, it is generally known that heterogeneous dispersions or solutions of therapeutic agents in water-swellable hydrogen matrices are useful in controlling the release of the agent by slow surface-to-center swelling of the matrix and subsequent diffusion of the agent from the water-swollen part of the matrix.
During dissolution of a controlled-release matrix tablet, the dosage form generally remains as a non-disintegrating, slowly eroding entity from which the therapeutic agent leaches out, through a diffusion controlled process. Conventional SR formulations are generally designed to release their active ingredients over an extended period of time, usually 8-24 hours.
Conventional SR formulations use waxes or hydrophilic gums as the primary drug carriers to prolong the release of the active ingredients.
Starch USP (potato or corn) is commonly used as a component in conventional tablet or hard shell capsule formulations.
The existing sustained release technologies generally involve relatively complicated formulations and manufacturing processes which often are difEicult and expensive to precisely control. For example, one well known SR
delivery system, OROS, marketed by the Alza Corporation, involves laser drilling through a tablet to create passages for the release of the drug from the tablet core. In controlled release technologies, it is desirable to be able to incorporate the active ingredient in its controlled-release pattern in a single dosage unit without deteriorating the active ingredient. Moreover, the dosage unit should be able to deliver the system without interfering with -its release .pattern.
Various methods have been devised to enable controIled-release systems to be delivered to a patient without destruction of the delivery system during manufacturing, handling and distribution. For example, controlled-release systems have been provided in the form of beads or particles which are packaged in a gelatin capsule for oral dosage. This method of delivery of the controlled-release system prevents damage to the coating on the beads.
Furthermore, when controlled-release active ingredients are incorporated in compression tablets, it may be difficult for many people to swallow such tablets. -Moreover, dissolution of high compression tablets often initially is slow and erratic and may result in localized hot =spots of alimentary tract irritation where disintegration and release of the active ingredient finally occurs. And, present systems do not allow for the accurate deposition of doses of powdered medication onto different substrates either in single packets, layered packet, or multipackets on the same plane of the base substrate. The present invention overcomes the disadvantages of the prior art by offering, a simple and inexpensive means of incorporating active ingredient (the drug) with a multitude of controlled-release systems.
In our earlier U.S. Patent 5,699,649, granted December 23, 1997, we describe a method and apparatus for packaging microgram quantities of fine powders such as pharmaceuticals using electrostatic phototechnology techniques. More particularly, as described in our aforesaid U.S. Patent 5,699,649, the ability of powders to acquire an electrical charge advantageously is utilized for precisely measuring exact microgram quantities of the powder, whereupon these exact microgram quantities are then placed in individual containers, and the containexs sealed.
Electrostatic chaige has been employed to attract a given quantity of powder to a surface. An example of this is the laser printer or the electrostatic copy device where a drum is charged and toner particles are attracted and held in position by the charge. The charge on the drum is neutralized by the attracted toner powder, thus limiting the amount of toner in accordance with the charge image on the drum. The charged powder on the printer drum is then transferred to a sheet of paper or other carrier to give a final image.
In our U.S. Patent 5,699,649, electrostatic charge technology is employed for transferring a predetermined amount of a finely powdered pharmaceutical or drug to a'carrier or an intermediate such as a drum, carrying a charge of predetermined intensity and area, rotating the charged druin surface, carrying the predetermined amount of powdered pharmaceutical or drug on its surface, to a transfer station where the charge is overcome and the dry powder is transferred to a package which is then sealed. In lieu of a drum, a belt, or other movable surface is charged to a given potential in a localized area. Alternatively, a predetermined amount of powdered pharmaceutical or drug may be deposited directly in a package using electrostatic charge technology.
When a given amount of a powdered pharmaceutical or drug is to be packaged ; the charge and area of charge can be determined experimentally for each dose of pharmaceutical or drug and each particle size distribution. This can be done by controlling either the charged area for a given charge density or the total electrostatic charge on any individual charged area. These conditions can be adjusted to provide essentially the exact desired amount of the particular pharmaceutical or drug to be transferred at the transfer station.
In our U. S. Patent No. 5,960,609, we describe another electrostatic charge technology which may be adopted to be used for measuring and packaging unit doses of a pharmaceutical or drug in a readily ingestible form, i. e. as a tablet or capsule. The technology thus described also permits reproducible precise measurement and packaging of a pharmaceutical or drug, and which may be scaled from laboratory to pilot plant to full scale production without the need for recertification.
Summary of the Invention In accordance with one aspect of the invention, a pharmaceutical delivery package comprising two or more active pharmaceuticals (a) combined in a single delivery package, and (b) segregated from one another, wherein the single delivery package comprises an unitary structure for repeatable administration of fixed quantities of the two or more active ingredients to the user, wherein the pharmaceuticals are encapsulated within inert coatings, and wherein the two or more active ingredients comprise Ketoconazole and testosterone; Valacylovir and one or both of Cimetidine and Probenecid; Enalapril and a beta adrenergic-blocking agent, methyldopa, nitrate, a calcium blocking agent, hydrazine, Prazosin or Digoxin;
Omeprazole and B 12; of Omeprazole and Clarithoromycin; Tamoxifen and a diuretic; Isotretinoin and an oral contraceptive; Metformin HCI and Solfonylurea; a diuretic and an Angiotensin converting enzyme inhibitor (ACE inhibitor); a diuretic and an Angiotensin II Receptor Antagonist; a Beta Adrenergic Blocking Agent; a diuretic and a Calcium channel block; a diuretic and a Periferal Adrenergic Blocking Agent; a diuretic and an Adrenergic central stimulant; a diuretic and Endothelin A; an ACE inhibitor and a beta blocker; a biguanide and a sulfonylurea; a biguanide and a thiazolidinedione; Metaformin and an alpha glucosidase inhibitor; a short acting oral insulin with a sustained release oral insulin; an HMG-CoA reductase inhibitor with a bile acid sequestrant; an HMG-CoA reductase inhibitor with a niacin compound; an HMG-CoA reductase inhibitor with a hypolipidemia agent;
an HMG-CoA reductase inhibitor, a niacin compound and a hypolipidemia agent; digitalis plus an ACE inhibitor; digitalis plus an ACE inhibitor and a diuretic; digitalis plus an ACE inhibitor, a diuretic and a beta blocker; a rapid onset anti-histamine plus a sustained release anti-histamine; an antihistamine plus a Leukotriene modifier; a rapid acting 5-HT1 receptor agonist plus a long acting 5-HT1 receptor agonist; an anti-nausea plus a steroid; a quick onset H
blocker plus a proton pump inhibitor; a selective serotonin reuptake inhibitor (SSRI) fluoxetine and an Aminoketon; a protease inhibitor plus a nuclear reverse transcriptase inhibitor plus 2 d NRTI-Ziduvudine or Azidothymidine;
cyclosporine plus a steroid; cyclosporine plus a steroid, plus a PPI/H2;
Isoniazid, Pyrazidamide and Rifampin; a Calcium channel block plus a vasodilator; a Gamma Aminobutyric analog or a Gamma Aminobutyric stimulator plus a Benzodiazepine; an opioid and a non-opioid analgesic; an opioid and an antiemetic; an opioid and a bowel softener or evacuant; a cyclooxygenase-2 inhibitor plus Omeprazole; an anti-inflammatory plus Omeprazole; prednisone plus testosterone; prednisone plus estrogen; a selective serotonin reuptake inhibitor plus a benzodiazepinel; and an aminoketone plus Lorazepam.
In accordance with another aspect of the present invention, controlled quantities of powdered medication are formed in controlled release packages using electrostatic metering technology. The present invention also provides, in another aspect, combination medication delivery systems in which the active ingredients are segregated from one another.
Brief Description of the Drawings Further features and objects of the present invention will become clear from the following detailed description taken in conjunction with the accompanying drawings, wherein like numerals depict like parts, and wherein:
Fig. 1 is a schematic flow diagram showing the various steps involved in practicing the present invention;

Fig. 2 is an enlarged cross-sectional view of one embodiment of a controlled release tablet made in accordance 'with the present invention;
Fig. 3 is a view, sinmilar to Fig.1; and showing alternative steps involved in practicing the present invention;
Fig. 4 is a view, similar to Fig. 2, and showing an altemative form of a controlled release tablet made in accordance with the present invention;
Fig. 5 is a view similar to Fig. 2, and showing yet another alternative embodiment of the present invention;
Fig. 6 is a view, sunilar to Fig. 2, and showing yet another embodiment of the invention; and Figs.7-9 are views similar to Fig. 2, and showing yet other embodiments of the present invention.
Detailed Description of the Preferred Embodiments Referring now to Fig. 1, there is a schematic flow diagram of the various pieces of equipment needed- to perform in the total process from powder supply to packaged pharmaceutical or drug, i.e. in controlled release tablet form, containing a specified amount of ph.armaceutical or drug powder ..in the tablet or package. At 16 is indicated the pharmaceutical or drug powder supply which is fed into a device 18 for creating an aerosol of the powder. Next the powder particles are ionized at 20. As wiIl be indicated later, a number of these steps and pieces of equipment can be conibined_ At 24 is indicated a carrier surface capable of maintaining a space charge on its surface. This can be a plastic belt, for example, or a selenium drt.ln-i of the type used in Xerox TM photocopiers. This carrier surface 24 is passed through a charging station 25 where a predetermined electrostatic charge 25A (an electrostatic "image") is created on a predetermined area of the transfer surface. This charged surface 25A then passes through a step 26 wherein powder is deposited on the carrier surface in a sufficient amount 26A to neutralize the charge carried by the carrier surface. Thereafter, the carrier surface, carrying the predetermined amount 26A of powder on its surface, is S

passed to a powder discharging device 30 which discharges the powder 26A
from the surface 24 onto a membrane 29. Alternatively, the powder may be placed directly onto the membrane 29. The membrane 29 containing its charge of powder 26A, then passes through a sealing step 32 wherein a second membrane 34 which may be porous, permeable or semi-permeable covers and seals the discharged powder 26A on the membrane 29. There is thus produced an aliquot of powdered medicine 26A sandwiched between semi-permeable or permeable membranes 29 and 34.
This sandwiched material is then passed to a cutting station 38 wherein the sandwich is cut into individual tablets or wafers 36.
As mentioned previously in discussing Fig. 1, the carrier surface with the electrostatic charge carries a known amount of charge on its surface and the polarity of this charge is opposite to that of the powder particles suspended in the chamber. The charged particles migrate to the charged surface because of the attraction by the opposite nature of the charges. This migration of the particles continues until the charge on the carrier surface is neutralized.
The actual amount of powder mass transferred to the carrier surface is a function of the mass-to-charge ratio of the charged particles. Although it is difficult to achieve a linear relationship between the mass and the actual charge, it is possible to establish a fixed relationship between the surface area of the powder particles and the charge the powder pa.rticle is carrying at charge saturation. However, the surface area of a mixed group of powder particles of different sizes and shapes can be extremely difficult to calculate mathematically, particularly when the shapes are irregular, (e.g. non-spherical, microcrystalline, etc.) As mentioned earlier, the simplest method of determining the amount and area of charge to attract a given weight of particles is to estimate the correct area and charge and then apply the estimated charge to the estimated area on the carrier surface 24 and expose this selectively charged area to a mass of powder which has been ionized in the ionizing step. The amount of powder deposited can then be readily measured at the discharge step. Thereafter, either the size of the charged area or the amount of charge applied to the area at the charging station 25 can be adjusted upwardly or downwardly to provide the correct amount of charge, both in area and charge intensity, for picking up a desired weight of oppositely charged powder. Likewise, using the technology of our co-pending application Serial No. 09/097,104, larger quantities of medication may be deposited.
A feature and advantage of the present invention is to produce carefully controlled doses of controlled release medication. Electrostatic metering and packaging as above described permits exact dosing. And, by employing selected porous, permeable or semi-permeable membranes for encapsulatirig the powdered medicine aliquots, drug release rate and also site of drug release can be determined by adjusting membrane material and/ or membrane thickness.
The membranes should be formed of ingestible materials having a selected permeability porosity to fluids at a selected site or sites within the alimentary canal, so as to permit controlleci release of the medication. By way of example, one or both membranes 29, 34 may comprise.acid-dissolvable materials when it is desired to release the medication into the stomach or the membranes 29, 34 may be alkaline-dissolvable materials at differing pH's to release into chosen locations within the intestine. Porosity, membrane thickness, etc., may be selected to provide desired rate of dissolution at the site of interest.
The invention is susceptible to modification. For example, referring to Figs. 3 and 4 by adding a second powdered medicine supply and discharge station (shown generally at 40), a two-component controIled release tablet 48 may be formed (see Fig. 4) incorporating two different powdered medicines 50,52, encapsulated between membranes 29 and 34 for simultaneous controlled release.
Alternatively, as shown in Fig. 5, two different drugs 60, 62 may be layered on one another, separated by a membrane 64 so the two medications may be delivered sequentially either in the same location, or in different locations within the alimentary canal. Another feature and advantage of the multi-drug tablet of Fig. 4 and Fig. 5, as wiIl be discussed in detail herein below, is that two normally incompatible drugs may be to be safely packaged in a single tablet.
The. invention is susceptible to modification. For example, individual doses may be formed by electrostatic deposition in accordance with U.S.
Patent No. 5,714,007.
Other possibilities are possible. For example, referring to Fig. 6, the tablet 70 may incorporate an adhesive layer 72 such as a mucosal adhesive, which in turn is covered by an acid or.alkaline dissolvable protective membrane 74, which dissolves at a selected site allowing the adhesive to adhere, for example, to the intestinal wall, thereby increasing residence time of the medication in a chosen location. Alternatively, an acid or alkaline activatable adhesive may be applied to the outer surface of the tablet. In yet another possibility, the membrane may be a material which expands on contact with the acid or alkaline in the alimentary canal and becomes more porous whereby to slowly release medication in a chosen location within the alimentary canal.
As mentioned above, a particular feature and advantage of the present invention is that it permits packaging, within a single tablet of two or more different drugs normally considered to be incompatible. Certain drugs are known to cause undesirable side effects which need to be countered by a second drug. Fdr example, Omeprazolel which finds substantial utility as an oral antiulcer agent, also is known to block the release of B12 from its protein binding site in food. This can lead to perniczous anemia. The present invention permits packaging of time-release Omeprazole with Vitamin B12 in an appropriate dosage of, e.g. 25 gm -1 mg. After taking the medication, one membrane will dissolve allowing absorption of the B12, while the remaining membrane package carrying the Omeprazole will pass into the small intestine where the drug is released and absorbed.
The invention is susceptible to modification. For example, while the membranes have been described as being preformed, permeable, semipermeable or porous material, one or both membranes could be formed in place from a gel or liquid.
The ability to accurately place the dose of medication onto a plurality of substrates and seal the dose with other membranes in accordance with the present invention, allows for the fabrication of many different dosage forms;
by altering the substrates and encapsulating material a single unit dose form Can be fabricated with a plurality of different drugs in different coverings, membranes and barriers. This will provide a single dosage form with -multiple active ingredients each being delivered to the appropriate site for absorption. Altexnatively; two or more active medicaments may be combined in a single delivery container, i.e. pill, capsule or caplet without actually mixing the two or more ingredients. For example, referring to Fig. 7, the active ingredients are segregated from one another in a compartmentalized capsule 100. Alternatively, two or more tablets 102,104 each containing only one active ingredient, could be placed in a larger absorbable capsule or encased in a larger tablet 106. Or, as shown in Fig. 9, two or more active ingredients could each be formulated as encapsulated particles 10SA,108B, and the encapsulated mixed particles placed iri a capsule 110 where the only contact is between the particle inert coatings, etc.
There are many drugs which could benefit from combinations to improve patient benefit. However, with many active ingredients, there is a question of chemical interaction. Thus, several drugs are normally prescribed as separate tablets or capsules which presents a problem in terms of patient compliance, e.g. TB triple therapy, AIDS multi-drug therapy, anti-infectives, etc. Also, delivery of two or more active medicaments could reduce side effects, and/or improve therapeutic response which may in turn permit a decrease in the required dosage.
The combination of drugs of the present invention can be grouped into polypharmacy for a therapeutic area, and into polypharmacy for treatment of co-morbid diseases. The invention will now be described with reference to the following non-limiting examples.
(1) Omeprazolel and analogs and isomers - As noted above Omeprazole is an inhibitor of gastric secretion and also inhibits the absorption of certain drugs/compounds that require stomach acid such as Vitamin B12, the deficit of which results in pernicious anemia. A combination of B12 with Omeprazole would elirninate the potential problem.
(2) Valacyclovir2 and analogs and is used to treat Herpes Zoster. It is well known that two drugs Cimetidines and Probenecid4 both increase the AUC (area under curve) and Cmax. A combination drug can be constructed with a combination of either one or more of these components to provide more efficacy.
(3) Enalapril5 and analogs and isomers is an ACE inhibitor used for the treatment of hypertension. This drug has been used with the following and analogs and isomers beta adrenegic-blocking agents, methyldopa, nitrate, calcium blocking agents, Hydralazine6, Prazosin7 and Digoxin$ without clinically significant side effects. One or more of these agents may be combined with Enalapril to improve the compliance of patient with hypertension and hypertension and other cardiac diseases.
(4) Ketoconazole9 and analogs and isomers is used to treat fungal infections. One of the side effects is the reduction of Testosterone. This side effect could be mitigated by the combination of Testosterone or one of its isomers or analogs to overcome the side effect.
(5) Omeprazolel and analogs and isomers is also used in combination with ClarithoromycinlO for ulcer treatment. These two drugs may be combined as a single dose for patient compliance.
(6) Tamoxifenll and analogs and isomers used in treatment of breast cancer has a +/- 30% incident of water retention with weight gain >
5%. This can be a disturbing consequence for patients with an even more disturbing disease. The addition of a diuretic or combination diuretic provides a single dosage form for reduction in side effect and compliance.
(7) Isotretinoin12 and analogs and isomers used for the treatment of postular acne has a severe danger if taken by a woman who is pregnant. The incorporation of oral contraceptive medication eliminates the potential for pregnancy while medicated.

(8) Metformin HCI13 and analogs and isomers are hypoglycemic agents which have been used in combination with Sulfonylurea14 and analogs and isomers to treat Type 2 Diabetes. These two agents act in different ways on reducing glucose levels. A combination is helpful for those patients requiring more aggressive oral therapy for their diabetes.

(9) This example provides various drug combinations for treating hypertension.
Combinations for treating hypertension include:
Combination ## 113iuretic + Angiotensin converting enzyme inhibitor (ACE inhibitor) An example includes the following classes of diuretics:
1. Carbonic anhydrase ffiliibitors - e.g.
Dichlorophenamide15.
2. Loop diuretics, e.g. Purosemide16.
3. Potassium sparing diuretics, e.g. AldactoneW.

4. Thiazides and related drugs, e.g. Hydrochlorthiazide18 and Chlorthalidone'9.
5. A diuretic which is already formulated as a combination diuretic, e.g. Aldactazide, a combination of Spironolactone20 (potassium sparing diuretic + hydrochlorothiazide). This combination makes use of the different methods of action of two different diuretics separated by a barrier from an ACE inhibitor such as Enalapril maleate21, Fosinopril sodium22, or Lisinopril23.
Combination diuretics such as Zestoretic AstraZeneca a combination of Lisinopri12710 or 20 mg and Hydrochlorthiazide1712.5 or 25 mg, exist in tablet form comprising mixed active ingredients in the pill or tablet form. The present invention segregates the Lisinopril and Hydrochlorthiazide.
In accordance with the present invention, we can form e.g. 10 mg and 20 mg Lisinopri122 pills, and 12.5 and 25 mg Hydrochlorthiazidel7 pills and then put them together with a barrier between two active ingredients. Pills can be in the form of tablets, pills, capsules or other solid oral dosage forms.
Combination # 2 Diuretic + Angiotensin It Receptor Antagonist Diuretics as described in combination drug # 1 plus an angiotensin II
receptor antagonist such as Losartan potassium24 and/or Valsartan25.
These combinations also permit administration of two or more drugs which, if in direct contact, have an unacceptable reaction.
Combination # 3 Diuretic + Beta Adrenergic Blocking Agent Diuretic as described in combination #1, plus a beta adrenergic blocking agent such as Bioprolol fumarate26 or Metoprolol succinate27.
Combination # 4 Diuretic + Calcium chanel block Diuretic as described in combination #1, plus a Calcium chanel block such as Amlodipine28 or Nifedipine29.
Combination # 5 Diuretic + Periferal Adrenergic Blocking A ent Diuretic as described in #11, plus a periferal adrenergic blocking agent such as: Prazosin hydrochloride7.
Combination # 6 Diuretic + Adrenergic central stimulant Diuretic as described in #1, plus an adrenergic central stimulant such as: Methyldopa30 or Clonidine31.
Combination # 7 Diuretic + Endothelin A
This is a new class of drugs.
The drug barrier system of the present invention allows further drug.
combinations such as a Calcium chanel block combined with: beta blockers, ACE inhibitors, long acting nitrates, Digoxin8, oral hypoglycemic drugs as well as multiple combinations, and combinations with a diuretic and combination drugs # 2, 3, 4 or more of the above-mentioned compounds.
Combination #8 ACE Inhibitors + Beta Blockers The drug barrier system of the present invention also allows drug combinations such as ACE Inhibitors combined with Beta blockers, methyldopa nitrates, calcium channel blockers, Hydralazine6, Prazosin7, Digoxin8 as well as multiple combinations, and combinations with a diuretic and combination drugs # 2, 3, 4 or more of the above-mentioned compounds.

(10) This example provides various'drug combinations for treating diabetes.
Combination # 9 Biguanide such as Metaformin13 with a sulfonylurea such as Glipizide32.

Combination # 10 Biguanide such as Metaformin13 with a thiazolidinedione such as Rosiglitazone maleate33.

Combination # 11 Metaforrninl3 with an alpha glucosidase inhibitor such as Cerivastatin34.

Combination # 12 Short acting oral insulin with sustained release oral insulin.

(11) This example provides various drug combinations for treating hyperlipidernia.
Combination # 13 HMG-CoA reductase inhibitor such as Simvastatin35, Atorvastatin36, or Pravastatin37 with a bile acid sequestrant such as Colestipol hydrochloride38.
Combination # 14 A HMGCoA reductase inhibitor with a niacin compound.
Combination # 15 A HMG-CoA reductase inhibitor or combination #14 with a hypo]ipidemia agent such as Gemfibrozi139.

(12) This example provides various drug combinations for treating congestive heart failure.
Combination # 16 Digitalis plus an ACE inhibitor with or without a diuretic, and optionally including a beta blocker.
Combination # 17 Digitalis plus any of the combination drugs #1-#7.

(13) This example provides various drug combinations for treating asthma/allergy.
Combination # 18 Rapid onset anti-histamine plus sustained release anti-histamine.
Combination # 19 Antihistamine plus Leukotriene modifier, such as Loratadine40 plus Montelukast41.

(14) This example provides a drug combination for treating migraine.
Combination # 20 Rapid acting 5-HT1 receptor agonist such as Naratriptin HC142 plus a long acting 5-HT1 receptor agonist such as Sumatriptan43.

(15) This example provides a drug combination for treating post-operative/ post-chemotherapy nausea.
Combination # 21 Anti-nausea such as Doperidol44 plus steroid such as Dexamethasone45.

(16) This example provides various drug combinations for treating gastric/ duodenial ulcer.
Combination # 22 Quick onset H blocker such as Famotidine46 plus a proton pump inhibitor such as Omeprazolel.
Combination # 3 Selective serotonin reuptake inhibitor (SSRI) fluoxetine (Prozac47) and Aminoketon - Buptopion48.

(17) This example provides a drug combination for treating HIV.
Combination # 24 Protease inhibitor - Indinavir (Crixivan49) plus nuclear reverse transcriptase inhibitor - Efavirenz (Sustiva50) plus third drug, i.e. 2nd NRTI-Ziduvudine51 or Azidothymidine52.

(18) This example provides various drug combinations for treating anti-rejection cocktail after organ transplant.
Combination # 25 Cyclosporine-'~3 plus steroid - Prednisone54.
Combination # 26 Combination drug # 25 plus PPI/H2 for ulcer pxevention -Omeprazole1.

(19) This example pirovides a drug combination for treating infections with combination therapy such as tuberculosis.
Combination #27 Triple combination Isoniazid55 and Pyrazidamide56 and Rifampin57.

(20) This example provides a polypharmacy for treatment of co-morbid diseases.
Combination # 28 80% + of diabetics are also hypertensive. Therefore a combination of any of combination drugs # 7-12 which are the combinations for control of the diabetes with any of combination drugs #1-7 or the single component medicaments used in the anti-hypertensive combinations.
Combination # 29 Hyperlipidemia is frequently concurrent with cardiac disease therefore any of combination drugs # 13-17 plus any of combination drugs # 1-7.

(21) This example provides a polypharmacy for treatment of Angina.
Combination #30 A Calcium channel block such as Nifedipine29 plus a vasodilator such as nitroglycerin.

(22) This example provides a polypharmacy for treatment of seizure disorders.
Combination #31 A Gamma Aminobutyric analog such as Gabapentin58 or a Gamma Aminobutyric stimulator such as Divalproex Sodium59 plus a Benzodiazepine such as Alprazolam6o.

(23) This example provides various drug combinations for treating pain and the side effects of opioids:
Combination #32 An opioid and a non-opioid analgesic such as codeine and acetominophine.
Combination #33 An opioid and an antiemetic.
Combination #34 An opioid and a bowel softener or evacuant.

(24) This example provides polypharmacy for e]imimating or minimizing gastric irritation caused by a primary drug.

Combination #35 A cyclooxygenase-2 inhibitor such as Celecoxib61 plus Omeprazolel.
Combination #36 An anti-inflainmatory such as Naproxen62 plus Omeprazolel.

(25) This example provides polypharmacy for countering the effect of long term use of Prednisone54.

Combination #37 Prednisone54 plus testosterone to prevent muscle mass loss.
Combination #38 Prednisone-' 4 plus estrogen or progesterone to prevent bone mass loss.
It is also possible to package two or more doses of the same active ingredient in slow and fast release forms.

(26) This example provides polypharmacy for treating anxiety or panic disorder.
Combination #39 A selective serotonin reuptake inhibitor such as Paroxetine63 plus a Benzodiazepine such as Lorazepam64.
Combination #40 An aminoketone such as Bupropion65 plus Lorazepam64.
Various analogs and isomers of the foregoing drugs also advantageiously may be employed.
It should be noted that certain combination drugs, including some of the above-hsted combination drugs, also may be blended and packaged in a single tablet or capsule, when chemical interaction is not a problem.

The present invention also allows for the rapid production of different dosage medications using the same active ingredient, and aIlows for the development of medications with longer resident time.

APPENDIX
1. Omeprazole: 5-methoxy-2[[(4-methoxy-3,5-dimethyl-2-pyrindinly) methyl] sulfinyl]-1H-benziinidazole.

2. Valacyclovir: L-valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl ester, monohydrochloride.

3. Cimetidine: N"-cyano-N-methyl-N'-[2-[[(5-methyl-l-H-imidazol-4-yl) methyl]thio]-ethyl]-quanidine.

4. Probenecid: 4-[(dipropylamino) sulfonyl] benzoic acid (molecular weigh 285.36).

5. ' Enalapxil: (S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline, (Z)-2-butenedioate salt.

6. Hydralazine: 1-Hydrazinophthalazine monohydrochloride.

7. Prazosin HCI: hydrochoride salt of 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furoyl) piperazine.

8. Digoxin:, 3B-[(o-2,6-dideoxy-B-D-ribo-hexopyranosyl-(lrj4)-0-2, 6-dideoxy-B-D-ribo-hexopyranosyl - (1jI4)-2,6-dideoxy -B-D-ribo-hexopyranosyl) oxy] -12B, 14-dihydroxy-5B-card-20(22) enolide.

9. Ketocanozole: CIS -1- acetyl - 4[4 -[[2,4-dicheorophenyl -2-(1H-imidazol-1-ylmethyle) -1,3-dioxolan-4-yl] methocy] phenyl] piperazive.
10. Clarithoromycin:6-0-methylerythromycin.

11. Tamoxifen: (Z)2-[4=(1,2-diphenyl-l-butenyl)phenoxy]-N, N-dimethylethanaxnine 2 hydroxy-1,2,3-propanetricarboxylate.
12. Isotretinoin: 13-cis-retinoic acid.

13. Metformin: N,N-dimethylimidodcarbonimidic diamide hydrochloride.
14. Sulfonylurea: 1-[[P-[2-(5-chloro-o-anisamido) ethyl] phenyl] sulfonyl-]-3-cyclohexylure.

15. Dichlorophenamide: 4,5-dichloro-1,3- benzenedisulfonamide.

16. Furosemide: 4-chloro-N-furfuryl-5-sulfamoylanthranilic acid.

17. Aldactone:17-hydroxy-7aliha-mercapto-3-oxo-l7a4L)k-pregn-4-ene-21-carboxylic acid ag mma-lactone acetate.

18. Hydrochlorthiazide: 6-chloro-3, 4-dihydro-2H-1, 2, 4-benzothiadiazine-7-sulfonamide 1,1-dioxide.

19. Chlorthalidone:2-Chloro-5-(2,3-dihydro-l-hydroxy-3-oxo-lH-isoindol-1-yl)benzenesulfonanmide.
, 20. Spirolactone:17-hydroxy-7alpha-mercapto-3-oxo-l7atpha-pregn-4-ene-21-carboxylic acid ag mma -lactone acetate.

21. Enalapril maleate: (S)-1-[N-[1-(ethoxycarbonyl) -3-phenylpropyl]-L-alanyl] -L-proline, (Z)-2-butenedioate salt (1:1).

22. Fosinopril sodium: L-proline, 4-cyclohexyl-l-[[[2-methyl-l-(1-oxopropoxy) propoxyl](4-phenylbutyl) phosphinyl]acetyl]-,sodium salt, trans-.

23: Lisinopril: (S)-1=[N2-(1-Carboxy-3- phenylpropyl)-L-lysyl]-L-proline dihydrate.

24. Losartan=potassium.:2-butyl-4-chloro-1[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-methanol monopotassium salt.

25. Valsartan: as N (1-oxopentyl)-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L valine.

26. Bioprolol fumarate: ( )-1-(4-((2-(1-Methylethoxy)ethoxy)methyl)phenoxy)-3-((1 methylethyl)amino)-2-propanol (E)-2-butenedioate (2:1) (salt).

27. Metoprolol succinate: (t)1-(isopropylamino)-3-[p-(2 methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt).

28. Amlodipine: (R.S.) 3-ethyl-5-methyl-2-(2-am.inoethoxymethyl)-4-(2 chlorophenyl)-1,4-dihyxo-6-methyl-3,5-pyridinedicarboxylate benzenessulphonate.

29. Nifedipine: 3,5-pyridinedicarboxylic acid,1,4-dihydro-2,6-dimethyl-4- =
(2-nitrophenyl)-,dimethyl ester.

' Trademark 30. Methyldopa: levo-3-(3,4- dihydroxyphenyl)-2-methylalanine sesquihydrate.

31. Clonidine HCL: (2,6-dichlorophenylamino)-2- imidazoline hydrochloride.

32. Glucotrol:1-cycloli.exyl-3-[[p-(2-(5-methylpyrazinecarboxamido) ethyl]phenyl]sulfonyl]urea.

33. Rosiglitazone maleate: ( )-5-[[4-[2-(methyl-2-pyridinylamino)ethoxy]phenyl]methyl]- 2,4-thiazolidinedione,(Z)-2-butenedioate.

34. Cerivastatin: [S-[ R*, S'-( E)] -7-[ 4-(4-b fluorophenyl)-5-methoxymethyl)- 2,6bis(1-met ylethyl) 3-pyridinyll-3,5-dihydroxy+
heptenoate.

35. Siunvastatin:2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro=4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S'E [1a,3a,7b,8b(2S';4S); 8ab]].

36. Atorvastatin: [R-(R*,R*)]-2-(4-fluorophenyl)-b,s-dihydroxy-5-(1-methylethyl)-3-phenyl-4 [(phenylamino)carbonyl]-1H-pyrrole-l-heptanoic acid, calcium salt (2:1) trihydrate.

37. Pravastatin:l-Naphthalene-heptanoic acid, 1,2,6,7,8,8a-hexahydro-b, d,6-trihydroxy-2-methyl -8-(2-methyl -1- oxobutoxy)-, monosodium salt,[1S-[1a(bS*, d S*),2a,6a,8b(R*),8aa]]-.

38. Colestipol hydrochloride: diethylenefriamine and 1 chloro-2,3-epoxypropane.

39. Gemfibrozil: 5- (2,5-dimethylphenoxy)-2,2-dinnethylpentanoic acid.

40. Loratadine: ethyl4-(8-chloro-5,6-dihydro-11H benzo(5,6]cydohepta[1,2 b]pyridin-ll-ylidene)-1-piperidinecarboxylate.

41. Montelukast: [R-(E)]-I-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-l-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt, 42. Naratriptin HCL: N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethanesulfonamide monohydrochloride.

43. Sumatriptan: 3-[2-(dimethylamino)ethyl]-N-methyl indole -5-methanesulfonamide succinate (1:1).

44. Doperidol:1-(1-[3-(p-fluorobenzoyl)propyl]-1,2,3,6-tetrahydro-4-pyridyl)-2-benzimidazolinone.

45. Dexamethasone: 9-fluoro-1l P,17,21-trihydroxy-l6a-methylpregna-1,4-diene-3,20-dione.

46. Famotidine: N'-(arninosulfonyl)-3-[[[2= [(diaminomethylene)amino]-4-thiazolyl]methyl]thio]propanimidamide.

47. Prozac": ( )-N-methyl-3-phenyl-3-[(a,a,a-trifluoro p-tolyl)-oxy]propylamine hydrochloride.

48. Buptopion: (t)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride.

49. Cxixivari is [1(1S,2R),5(S)]-2,3,5-trideoxy-N-(2,3-dihydro-2- hydroxy-1H-inden-1-yl)-5-[2-[ [ (1,1-dimethylethyl) amino] carbonyl]-4-(3-pyridinylmethyl)-1-piperazinyl]-2-(phenylmethyl)-D-erythro-pentonamide sulfate (1:1) salt.

50. Sustiva (S)-6-chloro-4=(cyclopropylethynyl)-1,4-clihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin 2-one.

51. Ziduvudine: 3'-azido-3'-deoxythymidine.

52. Azidothymidine:3'-azido-3'-deoxythymidine.

53. Cyclosporine: [R-[R.R*(E)}] cyclic(L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dirnethyl-L-2-?imino-6-octenoyl-Is-a-amino-butyryl-N-methylglycyl-N-rnethyl-L-leucyl-L-valyl-N-methyl Irleucyl).

54. Prednisone: pregna-1,4-diene-3,11,20-trione, 17,21-dihydroxy.

55. Isoniazid: isonicotinic acid hydrazide.

56. .Pyrazinarnide: pyrazinecarboxamide.

57. Rifampin:3-(4-methyl-l-piperazinyl-iminomethyl)-rifamycin.
~ Trademark .58. Gabapentin 1-(aminomethyl)cyclohexanacetic add.

59. Div-alproex Sodium: sodiuin hydrogen bis (2-propylpentanoate).
60. Alprazolam 8-Chloro-].-mefihyl-6-phenyl-4H-s-triazolo [4,3-a] [1,4]
benzodiazepine.

61. Celecoxib: 4-[5-(4-methylphenyl)-3- (trifluoromethyl)-1H pyrazol=1-yl]
benzenesulfonamide.

62. Naproxen: 2-naphthaleneacetic acid, 5 methoxy- a-methyl-,(+).

63. Paroxetine available as Immediate-Release Tablets and Oral Suspension as:
(-)-trans-4R-(4' fluorophenyl)-3S-[(3',4'-methylenedioxyphenoxy) methyl] piperidine hydrochloride heniihydrate and as Controlled-Release Tablets as: (-) - (3S,4R)-4-[(p-fluorophenyl)-3-[(3,4-methylenedioxy) phenoxy]methyl]piperidine hydrochloride hemihydrate.

64. Lorazepa.m:7-chloro-5-(0-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzo-d.iazepin-2-one.

65. Bupropion: (f)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride.

Claims (4)

1. A pharmaceutical delivery package comprising two or more active pharmaceuticals (a) combined in a single delivery package, and (b) segregated from one another, wherein said single delivery package comprises an unitary structure for repeatable administration of fixed quantities of said two or more active ingredients to the user, wherein said pharmaceuticals are encapsulated within inert coatings, and wherein said two or more active ingredients comprise Ketoconazole and testosterone; Valacylovir and one or both of Cimetidine and Probenecid; Enalapril and a beta adrenergic-blocking agent, methyldopa, nitrate, a calcium blocking agent, hydrazine, Prazosin or Digoxin; Omeprazole and B 12;
of Omeprazole and Clarithoromycin; Tamoxifen and a diuretic; Isotretinoin and an oral contraceptive; Metformin HCl and Solfonylurea; a diuretic and an Angiotensin converting enzyme inhibitor (ACE inhibitor); a diuretic and an Angiotensin II Receptor Antagonist; a Beta Adrenergic Blocking Agent; a diuretic and a Calcium channel block; a diuretic and a Periferal Adrenergic Blocking Agent; a diuretic and an Adrenergic central stimulant; a diuretic and Endothelin A;
an ACE inhibitor and a beta blocker; a biguanide and a sulfonylurea; a biguanide and a thiazolidinedione; Metaformin and an alpha glucosidase inhibitor; a short acting oral insulin with a sustained release oral insulin; an HMG-CoA
reductase inhibitor with a bile acid sequestrant; an HMG-CoA reductase inhibitor with a niacin compound; an HMG-CoA reductase inhibitor with a hypolipidemia agent;
an HMG-CoA reductase inhibitor, a niacin compound and a hypolipidemia agent;
digitalis plus an ACE inhibitor; digitalis plus an ACE inhibitor and a diuretic;
digitalis plus an ACE inhibitor, a diuretic and a beta blocker; a rapid onset anti-histamine plus a sustained release anti-histamine; an antihistamine plus a Leukotriene modifier; a rapid acting 5-HT 1 receptor agonist plus a long acting 5-HT1 receptor agonist; an anti-nausea plus a steroid; a quick onset H blocker plus a proton pump inhibitor; a selective serotonin reuptake inhibitor (SSRI) fluoxetine and an Aminoketon; a protease inhibitor plus a nuclear reverse transcriptase inhibitor plus 2nd NRTI-Ziduvudine or Azidothymidine; cyclosporine plus a steroid; cyclosporine plus a steroid, plus a PPI/H2; Isoniazid, Pyrazidamide and Rifampin; a Calcium channel block plus a vasodilator; a Gamma Aminobutyric analog or a Gamma Aminobutyric stimulator plus a Benzodiazepine; an opioid and a non-opioid analgesic; an opioid and an antiemetic; an opioid and a bowel softener or evacuant; a cyclooxygenase-2 inhibitor plus Omeprazole; an anti-inflammatory plus Omeprazole; prednisone plus testosterone; prednisone plus estrogen; a selective serotonin reuptake inhibitor plus a benzodiazepinel; and an aminoketone plus Lorazepam.

2. A pharmaceutical delivery package according to claim 1, characterized by comprising a combination of Ketoconazole and testosterone; or a combination of Valacylovir and one or both of Cimetidine and Probenecid; or a combination of Enalapril and a beta adrenergic-blocking agent, methyldopa, nitrate, a calcium blocking agent, hydrazine, Prazosin or Digoxin; or a combination of Omeprazole and B12; or a combination of Omeprazole and Clarithoromycin; or a combination of Tamoxifen and a diuretic; or a combination of Isotretinoin and an oral contraceptive; and a combination of Metformin HCl and Solfonylurea; or a combination of a diuretic and an Angiotensin converting enzyme inhibitor (ACE inhibitor); or a combination of a diuretic and an Angiotensin II Receptor Antagonist; or a combination of a diuretic and a Beta Adrenergic Blocking Agent; and a combination of a diuretic and a Calcium channel block.

3. A pharmaceutical delivery package according to claim 1, characterized by comprising a combination of Ketoconazole and testosterone; or a combination of Valacylovir and one or both of Cimetidine and Probenecid; or a combination of Enalapril and a beta adrenergic-blocking agent, methyldopa, nitrate, a calcium blocking agent, hydrazine, Prazosin or Digoxin; or a combination of Omeprazole and B12; or a combination of Omeprazole and Clarithoromycin; or a combination of Tamoxifen and a diuretic; or a combination of Isotretinoin and an oral contraceptive; and a combination of a diuretic and a Periferal Adrenergic Blocking Agent; or a combination of a diuretic and an Adrenergic central stimulant; or a combination of a diuretic and Endothelin A;
or a combination of an ACE inhibitor and a beta blocker; or a combination of a biguanide and a sulfonylurea.

4. A pharmaceutical delivery package as claimed in any of claims 1-3, and further including digitalis.