Tri-oxy active agents (drugs having at least three different oxygen-containing groups) such as guaifenesin, codeine and hydrocodone are used to treat cold and cough as well as other related symptoms.  Often, cold, cough, allergies, and other similar conditions can require treatment with multiple active agents in order to simultaneously alleviate multiple symptoms.  For example, combinations of active agents such as codeine or hydrocodone with a mucolytic or a decongestant or an anti-tussive have been used for management of cold, cough and flu symptoms.  However, these combinations are primarily available as inconvenient liquids which are prone to dosing errors and which require frequent dosing in order to provide consistent and continuous symptom relief.  Commercially available combination products tend to be short-acting and often require dosing every four, six or eight hours.  The need for frequent dosing and the re-emergence of symptoms between doses often make sleeping difficult, which in turn can delay the recovery process.  Moreover, the combination dosage forms must meet each active agent's own unique pharmacokinetic requirement for symptom or co-symptom relief. 
Guaifenesin (glyceryl guaiacolate, GGE) is a widely used expectorant that assists in loosening phlegm (mucus) and thins bronchial secretions to make cough more productive.  The structure of guaifenesin is generally shown as:
Guaifenesin is thought to act by increasing the volume and reducing the viscosity of secretions in the trachea and bronchi.  It is also reported to stimulate the flow of respiratory tract secretions allowing ciliary movement to carry the loosened secretions upward toward the pharynx.  Guaifenesin has a plasma half-life of about one hour.  GGE is commonly available as an immediate release tablet (200 mg and 400 mg strengths) requiring frequent dosing such as once every four hours. 
Codeine (3-methylmorphine) is an opiate used widely for its antitussive (cough suppression) and analgesic properties.  Its structure is generally shown as:
Codeine helps in temporary control of cough caused by minor throat and bronchial irritation as occurs with common cold or inhaled irritants.  The recommended antitussive codeine dose in adults and children 12 years of age and above is 10 to 20 mg codeine administered every 4 to 6 hours not to exceed 120 mg/day.  The reported a plasma half-life for codeine is about 2.5-3 hours.  It is more commonly available as immediate release dosage form that requires frequent dosing. 
Hydrocodone is a narcotic pain reliever and a cough suppressant and its structure is generally shown as:
Hydrocodone is an opioid derived from codeine and is recognized as both an effective analgesic and antitussive agent.  It is generally considered to be one of the potent and effective antitussive drugs and is believed to act, at least in part, by a direct depressant effect on a cough center in the medulla and to a lesser degree the respiratory center.  The recommended adult hydrocodone bitartrate dosage for the symptomatic relief of cough is 5 mg (as hydrocodone bitartrate) every 4 to 6 hours as needed, not to exceed 30 mg in 24 hours.  Children 6 to 12 years of age should be administered ½ the adult dose, not to exceed a total of 15 mg drug in 24 hours.  It is reported to have a plasma half-life of about 3.8 to 6 hours.  It is more commonly available as immediate release dosage form that requires frequent dosing. 
Pseudoephedrine is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes.  It is found as a hydrochloride or sulfate salt in many over-the-counter preparations more commonly as a single ingredient formulation.  It is generally indicated for temporary relief of nasal and/or sinus congestion due to the common cold, hay fever or other upper respiratory allergies.  The typical dose for adults and children 12 years of age is 60 mg to 120 mg. 
Chlorpheniramine is a propylamine antihistamine (H1-receptor antagonist) that also possesses anticholinergic and sedative activity.  It prevents released histamine from dilating capillaries and causing edema of the respiratory mucosa. 
Chlorpheniramine maleate is commonly available in immediate release dosages as an over-the-counter anti-allergy drug.  Following oral administration of chlorpheniramine the peak plasma concentration is reached in 2-3 hours and its duration of effect lasts for 4-6 hours, therefore requiring frequent dosing.  The oral dose in adults and children 12 years of age and older is typically 4 mg chlorpheniramine maleate every 4 to 6 hours. 
Dextromethorphan hydrobromide monohydrate (C18H25NO.HBr. H2O) is a centrally acting antitussive agent which elevates the threshold for coughing.  It has no analgesic or addictive properties.  Its dose is 10 to 30 mg every 4 to 8 hours.  Dextromethorphan exerts its effect in 15 to 30 minutes after oral administration and its duration of action is for approximately three to six hours, hence requiring frequent dosing. 
Phenylephrine is a potent decongestant agent commonly used for temporary relief of nasal congestion associated with allergy or head colds symptoms, etc.  Following oral administration, phenylephrine exerts its effect in 15 to 30 minutes and its effect persists for up to 4 hours, therefore requiring frequent dosing.  The usual adult dose of phenylephrine is 10 to 20 mg orally every 4 hours as needed. 
Most long acting oral dosage forms currently available to treat the above-recited conditions contain only one active agent, and typically require coating or bi-layering to enable various controlled or sustained release including biphasic release of the active. 
Oxyl-containing polymers (having oxygen-containing groups) such as methacrylates, carbomers, hypromellose (HPMC), etc.  have been used to enable slow release dosage forms having a single tri-oxy or non-tri-oxy active.  As reported for a single-layer matrix tablet of a non-tri-oxy active such as chlorpheniramine, an HPMC polymer (Methocel K4M) to active ratio of about 1:1 provides a time to 50% in vitro drug release of about 3.5 hours.  However, such very slow release profile is unsuitable for a 12 hour dosing therapy of tri-oxy actives to allow sleeping through the night and without excessive daytime grogginess. 
Use of oxyl-containing non-ionic hydrophilic polymers (e.g. HPMC) have also been reported to formulate a single di-oxy active (having two different oxygen-containing groups) such as propranolol HCl into a matrix tablet, wherein a HPMC (Methocel K4M) to active agent ratio is 1:0.3 by weight, and which provides a time to 50% drug release in vitro of about 4 hours.  However, such a slow release profiles for tri-oxy actives is unsuitable for a 12 hour dosing therapy. 
Due to tremendous safety liability associated with deviations from acceptable peak blood concentrations, many tri-oxy active agents, such as narcotics like codeine and hydrocodone, require stable blood levels upon oral dosing.  For a solid dosage form (tablet, capsules etc.)  containing multiple actives with a hydrophilic polymer, the design and management of the dosage form performance for a given intended use becomes increasingly challenging.  This is especially true with regards to efficacy, release, and pharmacokinetic requirements, which can be further complicated for each active due to its distinct physiochemical and biological properties.  Additionally, food interactions with an oral dosage form upon ingestion can produce unacceptable higher blood concentrations of actives, especially from a longer acting product which has higher active strength per dosage unit relative to an immediate release dosage form.  It is noteworthy that regulatory concerns related to food effects of a bilayer tablet containing ionic polymer of guaifenesin and codeine have been reported in the literature. 
To date, there appear to be no known teachings that enable a combination matrix tablet containing at least one tri-oxy active, such as guaifenesin or a codone, that upon single administration of the combination tablet of two pharmacologically different actives are released in an optimal manner, individually and collectively, and that enables optimal blood levels of each active as required for twice-a-day dosing therapy for regulatory approval purposes.