Aspirin + Nitroglycerin
Combination Medication Patent
The invention in this patent describes formulating a single dosage form comprising of both, aspirin and nitroglycerin, providing rapid onset of their respective pharmacological actions. This innovative formulation can tremendously benefit patients with cardiovascular diseases.
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Dosage Forms for Administering Combination of Aspirin and Nitroglycerin
FIELD OF THE INVENTION
The present field of the invention pertains to heart related patients who are required to always carry on their person both nitroglycerin as well as aspirin which is available in various embodiments as detailed within this Provisional Patent. These vital medications are administered during a heart related event. It is therefore the objective of this invention to enable a heart patient rather than remembering to always carry separate nitroglycerin as well as an aspirin on their person, to simply carry just one combined nitroglycerin and aspirin embodiment. The patent describes various embodiments of the combination of the nitroglycerin and aspirin.
Typically, a heart patient must always remember to carry both nitroglycerin and a separate aspirin on their person in the event of a heart episode, since their chances of survival are significantly reduced when either medication is omitted, and potential damage to the heart is increased. It is therefore the objective of this invention to eliminate the need for heart patients to locate both the nitroglycerin and an aspirin when leaving their home, as opposed to simply carrying just one combined nitroglycerin and aspirin embodiment. There will always be heart patients who for various reasons will forget either their nitroglycerin or their aspirin. This innovative combined embodiment of nitroglycerin and aspirin will inevitably save lives, reduce heart attacks, strokes, heart damage, and deaths, since during a heart problem, the two most critical medications to be administered are nitroglycerin and aspirin.
There are approximately 5.7 million adults in the United States diagnosed with heart disease, and the costs exceeds an estimated $30.7 billion for treatment, which excludes the cost for foreign heart patients. The revenues which the combined nitroglycerin and aspirin will generate, will continue to increase exponentially. This increase is due to the “Patent Pending” status, first to market, foreign patent rights, and the aversion of pharmaceutical companies to introduce a competing product with the knowledge that a patent is classified as “Patent Pending”.
BACKGROUND OF THE INVENTION
Typically, heart patients with a history of angina, angina pectoris, coronary microvascular disease, and severe heart conditions such as heart attack (myocardial infarction), heart failure, or rhythm abnormalities that can cause sudden cardiac death, are prescribed nitroglycerin and aspirin by their cardiologist, and always carry it on their person in the form of a chewable tablet (aspirin), and sublingual tablet or spray form (nitroglycerin). It is recommended to take nitroglycerin sublingually (0.4 – 0.8 mg) as tablet or spray. It should not be chewed or swallowed. Nitroglycerin tablets can further be taken every 5 minutes until the symptoms are relieved; however not more than 3 tablets/3 sprays must be taken in total within 15 minutes. Nitroglycerin is commonly used as a coronary vasodilator, which dilates the coronary arteries in the heart to improve blood flow, and thus, reduces the load on the heart and also lowers the blood pressure. Most importantly, nitroglycerin dilates the coronary arteries, as narrowing of the latter results in angina. Chest pain or "angina pectoris" is a signal that the heart muscle is not receiving sufficient blood flow and oxygen due to the narrowing or blockage in the coronary arteries. Typically, one experiences relief within two to three minutes after taking a nitroglycerin pill or spray under the tongue, or the nitroglycerin spray under the tongue.
Additionally, cardiologists also recommend that a heart patient must always carry aspirin as well as nitroglycerin in the event of a heart problem. Aspirin prevents blood from clotting in a blocked or partially blocked artery. It helps by inhibiting platelets, which makes them less likely to clot. Additionally, aspirin helps reduce blood clotting, which could cause blockage in the blood vessels. If users take an aspirin within the first hour of a suspected heart attack, it increases their chances of survival and minimizes muscle damage to the heart. During a heart issue, for maximum results, cardiologists recommend to chew 1 uncoated aspirin tablet (adult-strength: 325 mg) or 4 baby aspirins (81 mg each). As the clot grows minute by minute, time is of the essence regarding how quickly an aspirin should be taken during a heart problem. It is strongly recommended that during a heart issue, the user must chew aspirin as opposed to swallowing it, which inhibits platelet activity that could block arteries during an attack.
Based upon the facts stated above regarding a heart problem, the user should always carry both nitroglycerin and aspirin to increase their chances of survival. The nitroglycerin dilates the coronary arteries in the heart to improve blood flow, which reduces how hard the heart must work, whereas an aspirin taken during a suspected heart attack helps reduce blood clotting, which could cause blockage in the blood vessels. Although each medication pharmacologically performs different functions to increase the chance of survival, taking just nitroglycerin without aspirin, or aspirin without nitroglycerin will decrease the probability of survival, and increase potential damage to the heart. However, the two medications when taken together at the right time can aid in subsiding the symptoms of heart issue till the person can actually be hospitalized. However, currently the heart patients have to carry them in separate containers as no combination dosage form for the two drugs is available. Thus, there is tendency of low patient compliance with this treatment strategy as the patient may easily forget to carry the two containers with them all the time.
The invention in this patent describes formulating a single dosage form comprising of both, aspirin and nitroglycerin, providing rapid onset of their respective pharmacological actions. In addition to the formulation, a novel design for packaging of the combined dosage form as well as additional nitroglycerin dosage (required only in case the pain does not subside after the first or second dose has also been elaborated. Different dosage forms for the combination can be designed) for administration via different routes that include but are not limited to oral chewable and sublingual combined tablets, sublingual (tablet, film, spray, powder), and nasal (solution, suspension, spray, gel, ointment, cream).
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a representation of the present invention;
FIG. 2 is a representation of the present invention;
FIG. 3a is a representation of the present invention;
FIG. 3b is a representation of the present invention;
FIG. 3c is a representation of the present invention.
DETAIL DESCRIPTIONS OF THE INVENTION
All illustrations of the drawings are for the purpose of describing selected versions of the present invention and are not intended to limit the scope of the present invention.
The present inventor proposes formulating a combination of aspirin and nitroglycerin in a sublingual form, preferably as a tablet or film. Sublingual nitroglycerin is already commercially available as tablet, spray and powder for the emergency situations of heart attack. Aspirin is recommended to be taken as a chewable tablet (325 mg or 4 baby aspirin: 81 mg each) along with sublingual nitroglycerin (0.4-0.8 mg), but the former is currently not available commercially in the sublingual form by itself.
Formulation of nitroglycerin and other drugs in sublingual formulation have been well-justified as sublingual drug delivery is the preferred and most favorable route of oral delivery for drugs that provides quick onset of pharmacological action. It has been reported that sublingual drug absorption is about 3-10 times greater than oral absorption. The superior absorption capabilities of the sublingual route can be attributed to greater permeability than the other three oral mucosas (buccal, palatal, and gingival) as it is stratified non-keratinized squamous epithelium. While much of this greater permeability can be explained by the non-keratinization of the sublingual epithelium, another main feature which contributes to rapid sublingual absorption is the thickness of the sublingual mucosa. The latter is about 100-200 µm as compared to 200, 250 and 500-600 µm in case of buccal, gingival, and palatal, respectively. Furthermore, the area below the tongue is highly vascularized that contributes to quick absorption, and thus, onset of drug action. Other advantages include increased patient compliance, and ease of self-administration. Rapidly dissolving sublingual tablets are highly effective for the emergency treatment of angina. Similarly, in order to expedite the pharmacological effect of aspirin as well, delivering it in the sublingual form with nitroglycerin would be highly beneficial, especially as the combination is needed for an emergency situation and we intend the drugs to act in just few minutes. As stated above, nitroglycerin is commercially available in sublingual formulations already, but aspirin is not. However, some studies in literature have demonstrated feasibility of sublingual administration of aspirin that would result in its faster absorption and reduced probability of gastric issues associated with its oral administration as well. A patent demonstrating feasibility of formulating sublingual aspirin tablets containing its dose varying from 50-145 mg [U.S. Pat. No. 4866046A] has been reported in literature. There are several other patents describing formulation of sublingual aspirin tablets (U.S. Pat. No. 4,206,209 and U.S. Pat. No. 4,539,315). In addition to tablets, aspirin capsules for sublingual drug delivery have also been patented (U.S. Pat. No. 20100255086A1). As the rate and extent of aspirin absorption via sublingual route will be significantly faster than the peroral route, the dose required to produce the pharmacological effect shall also be reduced. However, a combination of nitroglycerin and aspirin has not been formulated or patented in any kind of sublingual dosage form previously. Thus, the novelty here is to formulate such a combination of aspirin and nitroglycerin as both the drugs are required to be taken in case of an emergency of heart attack.
The present inventor proposes formulating a fixed-dose combination (FDC) containing two active ingredients (nitroglycerin and aspirin) in a single tablet designed for sublingual administration. FDCs provide multiple mechanistic actions of active pharmaceutical ingredients acting on different therapeutic targets which leads to better clinical outcomes and improving patient compliance by reducing pill burden. A single layer monolithic tablet as depicted in Fig 1 can be formulated. In this design, aspirin and nitroglycerin will be mixed and compressed into one tablet. Chemical compatibility of the actives and the formulation composition should be studied in this design. Monolithic formulation will make it feasible to obtain smaller FDC tablets, as compared to multi-layer or core tablet-in-tablets making them more practical for sublingual delivery. The same principles as for tablet formulations govern the process and selection of ingredients. Components such as lactose and silicified microcrystalline cellulose can be used for the formulation base.
Fig 1. Monolithic fixed-dose combination of aspirin and nitroglycerin for sublingual administration (red: drug 1, yellow: drug 2)
In addition to tablets, formulation of sublingual films can also be investigated. Thin sublingual films are more stable, durable and quick dissolving than other conventional dosage forms. Sublingual films of nitroglycerin are not commercially available as of now. However, different designs have been presented in literature (U.S. Patent No. 20100215774A1) that demonstrate the feasibility of developing the same for nitroglycerin. As aspirin is more water soluble (3 mg/mL, log P: 1.2) than nitroglycerin (1 mg/mL, log P: 2.1), formulation of films for aspirin should be feasible using the commonly available hydrophilic polymers. Wide variety of polymers can be possibly employed for such films, including but not limited to pullulan, pectin, starch, gelatin, maltodextrins, sodium alginate, polymerized Rosin, sodium carboxy methyl cellulose, hydroxy propyl methyl cellulose, ethylene oxide, hydroxy propyl cellulose, poly vinyl pyrrolidone, polyvinyl alcohol. The other additives include plasticizers (examples include, glycerol, low molecular weight polyethylene glycols, propylene glycol, phthalate derivatives like dimethyl, diethyl and dibutyl phthalate, citrate derivatives such as tributyl, triethyl, acetyl citrate, triacetin and castor oil), sweetening agents (sucrose, dextrose, liquid glucose, isomaltose, sorbitol, fructose, glucose, mannitol, isomalt, saccharin, aspartame and cyclamate, acesulfame-k, sucralose, alitame and neotame), flavoring agents (vanillin, chocolate or fruit essence like apple, cherry, raspberry, cherry) and colorants (natural coloring agents and natural juice concentrates, pigments such as titanium dioxide, zinc oxide, silicon dioxide and custom pantone matched colors)
As guidelines suggest, after the initial administration of 0.4 mg nitroglycerin and 325 mg aspirin, further nitroglycerin tablets (up to two additional doses) can be taken every 5 minutes to control the angina pectoris syndrome, but not more than three in total within 15 minutes. In this case the regular nitroglycerin tablet should be distinguishable from the proposed combination dosage. FIG. 2 shows a proposed packaging design for dispensing combination dosage forms of aspirin and nitroglycerin along with two additional nitroglycerin without the aspirin. This can be achieved by making designs of the blister and using guides such as colors and numbers to further increase patient compliance. This packaging design can also be applied in case of other dosage forms such as films, powder, and capsules.
Fig. 2 Proposed packaging design for dispensing combination dosage forms of aspirin and nitroglycerin alongwith additional nitroglycerin alone.
Combination of aspirin and nitroglycerin in an oral dosage form as a fixed dose combination tablet of sublingual nitroglycerin and chewable aspirin designed as bilayer, core tablet-in-tablet, or two-sided tablet as described below can also be investigated:
Bi-Layer Tablets: The bi-layer FDC tablet, as shown in FIG. 3a shall consist of two distinct layers of active pharmaceutical ingredients (aspirin and nitroglycerin) and compaction process would require two feeding systems. This formulation can be utilized in case of chemical incompatibility among the actives and the need for different release rates. The present inventor proposes that a chewable tablet can act as one layer after the sublingual release and absorption of nitroglycerin from the first layer. Ingredients will be selected to provide desired plastic and brittle properties. Lubricant concentration in the formulation can influence the adhesion strength of the layers. Various types of tablet press can be utilized in the manufacturing process. Single sided tablet press is the simplest design producing two individual layers of a tablet. It utilizes two chambers fed with different type of powders. However, the exact weight of the individual medicament cannot be achieved. Double sided tablet press utilizes an individual filling station. Each layer undergoes a pre- and a main compression. Bi-layer tablet press with displacement monitoring offers a control system sensitive to the pre-compression force but not on the operation point which can result in a better yield and less chance of capping.
Core Tablet-In-Tablet: FIG. 3b shows a proposed core tablet-in-tablet which shall consist of a tablet core formulation (aspirin) surrounded by a second outer formulation (nitroglycerin). In the manufacturing process, pre-compressed cores are guided into the specific dye and are remained in the center of the dye cavity. The upper punch is lowered, pushing core tablet down into the tablet.
Two-Sided Tablet: FIG. 3c shows a proposed hypothetical two-sided tablet in which two medications will be loaded individually on each half of the tablet making it easy and distinguishable for the patient to administer the required medication based on need. In this design, a combination can be taken by breaking the tablet in half with the Nitro part being used as a sublingual tablet and the aspirin part to be chewed after.
Fig 3. Design of suggested FDC tablets combining aspirin (yellow) and nitroglycerin (red)
Other sublingual dosage forms consisting of combination of aspirin and nitroglycerin may also be designed. These can include but may not be limited to, capsules, powder, or spray. A sublingual soft gel capsule can be designed with the same rationale as tablets containing both medications. Further, sublingual spray of nitroglycerin has been reported to be more effective than the tablet form in relieving angina pain. Also, nitroglycerin is already available in the metered dose spray form in the market. However, formulation of combination of aspirin and nitroglycerin in the spray form may also be investigated. The spray formulation shall comprise of the following ingredients, but not limited to propellants, penetration enhancers, solvents, sweeteners, antioxidants, hydrophilic polymers, flavoring agents, acidifying agents, preservatives, and co-solvents. Some penetration enhancers suitable for inclusion in the spray form include surfactants such as sodium lauryl sulfate, bile salts, fatty acids such as oleic acid, and azone (1-dodecylazacycloheptan- 2-one). Propellants include but are not limited to hydrofluorocarbon ones such as volatile chlorofluorocarbons (e.g. propellant 12), volatile hydrofluoroalkanes (e.g. 1,1,1,2,3,3,3-heptafluoro-n-propane and 1,1,1,2-tetrafluoroethane) and volatile alkanes (e.g. propane, butane). Formulation of sublingual powder, comprising of combination of nitroglycerin and aspirin can also be investigated. Nitroglycerin is available in the powdered form for sublingual administration. However, for aspirin, micronized collagen co-grinded powdered aspirin formulations for sublingual administration have been patented previously [U.S. Patent No. 102015000079955].
Combination of aspirin and nitroglycerin in a nasal dosage form is also proposed. The possible dosage forms for the same may include, but not limited to:
Intranasal administration of aspirin and nitroglycerin may also result in their rapid absorption and onset of pharmacological action and can thus, be explored as well. Feasibility of development of intranasal solution as well as spray for administration of nitroglycerin has been demonstrated previously in literature.
Interestingly, novel nasal dosage forms for administration of aspirin such as solution, ointment, suspension, and gels have also been patented (U.S. Patent No. WO1990001322A1) that demonstrate achievement of desirable bioavailability of aspirin via the nasal route as well. Nasal administration has been claimed as a convenient and non-invasive route for delivering aspirin that avoids first-pass metabolism, is safe as well as inexpensive, does not require a skilled clinician and yet results in high systemic concentrations of intact aspirin.
However, combination of the two drugs in the nasal dosage form has not been available till date. But, the individual studies for the two drugs in the nasal form provide affirmation to the possibility of formulating the same for the combination as well. Different intranasal dosage forms that may be formulated for the combination of nitroglycerin and aspirin include but are not limited to, solution (to be used as spray or drops), suspension, cream or ointment, and nasal gel. Solutions, suspensions and gels may be the preferred dosage forms that contain a major amount of water, in addition to the active ingredient. Other ingredients that may be included in minor amounts include pH adjusters (e.g., bases such as sodium hydroxide), emulsifiers or dispersing agents (e.g., Tween 20), preservatives, buffering agents, gelling agents (e.g., ethylcellulose), and wetting agents.
FIG. 1 is a monolithic fixed-dose combination of aspirin and nitroglycerin for sublingual administration (red: drug 1, yellow: drug 2). FIG. 2 shows a proposed packaging design for dispensing combination dosage forms of aspirin and nitroglycerin along with two additional nitroglycerin without the aspirin. FIG 3. shows a design of suggested FDC tablets combining aspirin (yellow) and nitroglycerin (red).
Although the invention has been explained in relation to its preferred embodiment, it is to be understood that many other possible modifications and variations can be made without departing from the spirit and scope of the invention.
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