DOSE PACKAGING SYSTEM FOR LOAD-DOSE TITRATION ADMINISTRATION OF A LIQUID FORMULATION

Abstract

The invention generally relates to a dose packaging system for the administration of a liquid formulation to a patient requiring load-dose titration therapy of a pharmaceutically active drug, such as steroid therapy. More particularly, the invention relates to a dose packaging system for administering titration therapy of liquid formulations to a patient which eliminates the disadvantages that are associated with cups, dosing spoons, calibrated oral syringes and bottles.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to and benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application Ser. No. 60/783,401 filed Mar. 20, 2006, the disclosure of which is expressly incorporated herein by reference in its entirety.

BACKGROUND

1. Field of the Invention

The invention generally relates to a dose packaging system for the administration of a liquid formulation to a patient requiring load-dose titration therapy of a pharmaceutically active drug, such as steroid therapy. More particularly, the invention relates to a dose packaging system for administering titration therapy of liquid formulations to a patient which eliminates the disadvantages that are associated with cups, dosing spoons, calibrated oral syringes and bottles.

2. Related Art

Administration of liquid medication is a common practice, especially among children, for a variety of conditions. While administration of liquid oral medication has many benefits, there are drawbacks as well, which may vary the efficacy and safety of the medications.

For example, asthma is the most common chronic illness affecting children. At least one-third of the 24.7 million people diagnosed with asthma are children under the age of 18. Asthma is the third leading cause of hospitalization among children under age 15 and leads to 14 million days of missed school each year. This condition can also negatively affect children's academic performance because of doctor visits during school hours, lack of concentration while at school because of nighttime attacks, and decreased attentiveness or involvement at school because of the side effects of some medications.

Since children may have difficulty swallowing a tablet, oral steroids are often administered as treatment for children afflicted with asthma. Oral corticosteroids may be given early during an acute asthma exacerbation (i.e., within 45 minutes of the onset of symptoms) to reduce the likelihood of hospital admission. In addition, oral corticosteroids may be more effective than inhaled or nebulized corticosteroids in children hospitalized with severe acute asthma. Repeated short courses of oral corticosteroids, at a dose of 1 mg per kg per day, in the treatment of acute flares of asthma do not appear to cause any lasting changes in bone metabolism, bone mineralization, or adrenal function. There is no evidence that intravenous corticosteroids are any more effective than oral corticosteroids in children with an intact and functioning digestive tract.

Administering oral medications to children, however, is often very difficult. Pediatric liquid medicines may be given with a variety of dosing instruments: plastic medicine cups, hypodermic syringes without needles, oral syringes, oral droppers, and cylindrical dosing spoons. Whether the dosing instruments measure teaspoons, tablespoons, ounces, or milliliters, these dosing instruments are preferable to using regular tableware to administer medicines because one type of tableware teaspoon may differ substantially in size from another. However, there are several disadvantages associated with these dosing instruments: (1) the numbers on the sides of the dosing instruments are often small and difficult to read, which may result in the child receiving an inaccurate dose; (2) droppers tend drip, thus the liquid formulation must be administered quickly to the child otherwise, the child will not receive the proper dose; and (3) while dosage cup may be convenient for children who can drink from a cup, the dosage cup may spill.

SUMMARY OF THE INVENTION

The invention satisfies the above needs by providing a dose packaging system including pre-filled ampoules for accurate load-dose titration administration of oral steroids to children afflicted with a condition, such as asthma.

In one aspect of the invention, a dose packaging system for administering load-dose titration therapy to a patient afflicted with a condition. The packaging system includes a plurality of ampoules containing a pharmaceutically effective dose of a liquid formulation and a backing card. In particular, the ampoule may be a blow-fill seal vial and may be fabricated from plastic. The backing card may include two or more sections containing an appropriate number of ampoules such that each section of the backing card corresponds to a daily dose of the liquid formulation to be administered to the patient and furthermore, at least one of the sections has a different number of ampoules than at least one other section.

In a further aspect, the package system may further include a cover sheet to retain the ampoules onto the backing card. The cover sheet may transparent, opaque, or UV resistant. The cover sheet may be a skin package or the cover sheet may be a shrink package.

In another aspect, the backing card may have a weakened portion along the perimeter of the ampoules. The weakened portion may be a perforated region. Moreover, the backing card may be composed of cardboard.

In yet a further aspect, the load-dose titration therapy is load-dose upward titration therapy. Alternatively, the load-dose titration therapy is load-dose downward titration therapy. The load-dose therapy may be a 5 day, 6 day, 7 day, 8 day, 9 day, 10 day, 20 day or 30 day regimen. Specifically, the load-dose therapy is a 5 day regimen. More specifically, the load dose therapy is a 6 day therapy regimen.

According to an aspect of the invention, the liquid formulation includes an effective amount of prednisolone. The ampoules may be filled with about 5 ml of a liquid formulation. Moreover, the ampoules may be filled with about 2.5 ml of a liquid formulation. The patient may be afflicted with a condition such as asthma, acute lower respiratory tract infection, pneumonia, infant respiratory distress syndrome, adult respiratory distress syndrome, croup, bronchitis, and pertussis.

Additional features, advantages, and embodiments of the invention may be set forth or apparent from consideration of the following detailed description, drawings, and claims. Moreover, it is to be understood that both the foregoing summary of the invention and the following detailed description are exemplary and intended to provide further explanation without limiting the scope of the invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are included to provide a further understanding of the invention, are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the detailed description serve to explain the principles of the invention. No attempt is made to show structural details of the invention in more detail than may be necessary for a fundamental understanding of the invention and various ways in which it may be practiced.

FIG. 1 is a schematic showing a dose packaging system of the invention containing a 5 day load dose downward titration of a liquid formulation of prednisolone, according to principles of the invention.

FIG. 2 is a schematic showing a dose packaging system of the invention containing a 5 day load dose upward titration of a liquid formulation of prednisolone, according to principles of the invention.

FIG. 3 is a schematic showing a dose packaging system of the invention containing a 6-day load-dose downward titration of a liquid formulation of prednisolone, according to principles of the invention.

FIG. 4 is a front view of a skin or shrink ampoule package.

FIG. 5 is a sectional view of FIG. 4.

DETAILED DESCRIPTION OF THE INVENTION

It is understood that the invention is not limited to the particular methodology, protocols, and reagents, etc., described herein, as these may vary as the skilled artisan will recognize. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only, and is not intended to limit the scope of the invention. It also is be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include the plural reference unless the context clearly dictates otherwise. This, for example, a reference to “a construct” is a reference to one or more constructs and equivalents thereof known to those skilled in the art.

Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which the invention pertains. The embodiments of the invention and the various features and advantageous details thereof are explained more fully with reference to the non-limiting embodiments and/or illustrated in the accompanying drawings and detailed in the following description. It should be noted that the features illustrated in the drawings are not necessarily drawn to scale, and features of one embodiment may be employed with other embodiments as the skilled artisan would recognize, even if not explicitly stated herein.

Any numerical values recited herein include all values from the lower value to the upper value in increments of one unit provided that there is a separation of at least two units between any lower value and any higher value. As an example, if it is stated that the concentration of a component or value of a process variable such as, for example, osmolality, temperature, pressure, time and the like, is, for example, from 1 to 90, specifically from 20 to 80, more specifically from 30 to 70, it is intended that values such as 15 to 85, 22 to 68, 43 to 51, 30 to 32 etc., are expressly enumerated in this specification. For values which are less than one, one unit is considered to be 0.0001, 0.001, 0.01 or 0.1 as appropriate. These are only examples of what is specifically intended and all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application in a similar manner.

Moreover, provided immediately below is a “Definition” section, where certain terms related to the invention are defined specifically. Particular methods, devices, and materials are described, although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention. All references referred to herein are incorporated by reference herein in their entirety.

Definitions

The terms “active agent,” “drug” and “pharmacologically active agent” are used interchangeably herein to refer to a chemical material or compound which, when administered to an organism (human or animal) induces a desired pharmacologic effect. Included are derivatives and analogs of those compounds or classes of compounds specifically mentioned that also induce the desired pharmacologic effect.

By “pharmaceutically acceptable carrier” is meant a material or materials that are suitable for drug administration and not biologically or otherwise undesirable, i.e., that may be administered to an individual along with an active agent without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical formulation in which it is contained.

Similarly, a “pharmacologically acceptable” salt, ester or other derivative of an active agent as provided herein is a salt, ester or other derivative that is not biologically or otherwise undesirable.

By the terms “effective amount” or “therapeutically effective amount” of an agent as provided herein are meant a nontoxic but sufficient amount of the agent to provide the desired therapeutic effect. The exact amount required will vary from subject to subject, depending on the age, weight, and general condition of the subject, the severity of the condition being treated, the judgment of the clinician, and the like. Thus, it is not possible to specify an exact “effective amount.” However, an appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using only routine experimentation.

The terms “treating” and “treatment” as used herein refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, and improvement or remediation of damage. Thus, for example, the present method of “treating” asthma, as the term “treating” is used herein, encompasses both prevention of asthma in a predisposed individual and treatment of asthma in a clinically symptomatic individual.

The terms “condition,” “disease” and “disorder” are used interchangeably herein as referring to a physiological state that can be prevented or treated by administration of a pharmaceutical formulation as described herein. Exemplary diseases and conditions may include, but not limited to, asthma, acute lower respiratory tract infection, pneumonia, infant respiratory distress syndrome, croup, bronchitis, and pertussis.

The term “patient” as in treatment of “a patient” refers to a mammalian individual afflicted with or prone to a condition, disease or disorder as specified herein, and includes both humans and animals.

The term “ampoule” as used herein generally refers to a container for aseptic or sterile compositions in the pharmaceutical and biological industries. Product information such as batch number and expiration date may be printed on the ampoule directly, or on a paper or plastic label which is then affixed to the body of the ampoule surface. Additionally, the term “ampoule” as used herein may generally refer to a blow-fill seal vial.

The invention relates to a dose packaging system for administration of liquid formulations to a patient which eliminates the disadvantages that are associated with cups, spoons and bottles. The dose packaging system of the invention may include pre-filled blow ampoules containing the desired liquid formulation thereby eliminating the need to measure and preventing spilling and inaccuracy in dose amount administered to the patient. Additionally, ampoules included in the dose packaging system of the invention may be disposable thereby providing a more sterile administration of the liquid formulation.

According to an embodiment of the invention, a dose packaging system is provided which defines a course of therapy to be administered to a patient. In particular, the dose packing system of the invention may define a course of therapy such as load-dose titration therapy of a pharmaceutically effective amount of a drug in a liquid formulation to a patient afflicted with a disease requiring load dose titration therapy. The liquid formulation may be in the form of syrup, an aqueous solution or a reconstituted powder in a water solution which may include a buffer to regulate the pH of the solution and a complexing agent to prevent the formation of insoluble complexes of the drug.

FIG. 1, which illustrates an embodiment of the invention, shows a load-dose downward titration of a liquid formulation, such as prednisolone. FIG. 1 shows package 10 containing sections 20, 21, 22, 23, and 24 accommodating a varying number of blow-filled ampoules 30. Furthermore, package 10 may be flexible and may provide one or more chambers inside each of section 20-24 to accommodate ampoules 30. The chambers may be compressed to allow the ampoule to be released from the package.

Ampoules 30 may be pre-filled with a particular amount of a liquid formulation containing the pharmaceutically active drug. For example, ampoules 30 may be pre-filled with 5 ml of prednisolone or 2.5 ml of prednisolone. The liquid formulations suitable for load-dose titration therapy provided in ampoules 30 will vary according to factors such as the active ingredient or ingredients, amount of time the formulation will be stored, conditions under which it will be stored and used, including the dosage form of the composition, and the particular patient population to which it may be administered. Adjustments to the formulation by adjusting constituents of the formulations and their relative concentrations, including the amounts of the drug, may be made as needed according to the needs of the formulator, administrator or patient.

Turing back to FIG. 1, each individual section 20-24 and the ampoules contained within each section may correspond to the daily dose of a liquid formulation that may be administered to the patient requiring load-dose titration therapy. For example, section 20, containing 4 ampoules, may correspond to the dose to by administered to the patient on day 1; section 21, containing 4 ampoules, may correspond to the dose to be administered to the patient on day 2; section 22, containing 3, ampoules may correspond to the dose to be administered on day 3; section 23, containing 2 ampoules, may correspond to the dose to be administered on day 4; and section 24, containing 1, ampoule may correspond to the dose to administered on day 5.

The regimen course of the load-dose titration therapy should not be construed to be limited to the five day regimen illustrated in FIG. 1. The course of load-dose titration therapy defined by dose packaging system of the invention may vary according to factors such as the pharmaceutically active drug included in the liquid formulation contained within the ampoule, and the particular patient population to which it may be administered. Adjustments to the therapy regimen may be made according to the needs of the formulator, administrator or patient. For example, the dose packing system of the invention may define a 5 day, 6, day, 7 day, 8 day, 9 day, 10 day, 20 day, and 30 day course of therapy, for example. Additionally, the titration therapy defined by the dose packaging system of the invention may include load-dose downward titration as well as load-dose upward titration or a combination of load dose upward and load dose downward titration.

FIG. 2 illustrates an example of an upward load-dose titration therapy. Here, each individual section 40-44 and the ampoules 50 contained within each section may correspond to the daily dose of a liquid formulation that may be administered to the patient requiring load-dose titration therapy. For example, section 40, containing 1 ampoule, may correspond to the dose to by administered to the patient on day 1; section 41, containing 2 ampoules, may correspond to the dose to be administered to the patient on day 2; section 42, containing 3, ampoules may correspond to the dose to be administered on day 3; section 43, containing 4 ampoules, may correspond to the dose to be administered on day 4; and section 44, containing 5, ampoules may correspond to the dose to administered on day 5.

Another embodiment of the invention is illustrated in FIG. 3. FIG. 3 is a schematic showing a box configuration 300 for a 6 day load-dose downward titration. In particular, each individual compartment 304, 306, 308, 310, 312, and 314 and the ampoules 302 contained within each compartment may correspond to the daily dose of a liquid formulation that may be administered to the patient requiring load-dose titration therapy. For example, compartment 304, containing 4 ampoules 302, may correspond to the dose to by administered to the patient on day 1; compartment 306, containing 4 ampoules 302, may correspond to the dose to be administered to the patient on day 2; compartment 308, containing 3 ampoules 302 may correspond to the dose to be administered to the patient on day 3; compartment 310, containing 3 ampoules 302, may correspond to the dose to be administered to the patient on day 4; compartment 312, containing 2 ampoules 302, may correspond to the dose to be administered to the patient on day 5, and compartment 314, containing 1 ampoule 302, may correspond to the dose to be administered to the patient on day 6.

The ampoules of the invention may be made from glass, plastic, or any other suitable material known by those of skill in the art. Specifically, the ampoules may be plastic blow-fill seal vial. More specifically, the ampoules may be mounted on a backing card with a cover sheet. The backing card may be cardboard, for example, and may provide a surface area on which to display product information. For example, product name, manufacturer, batch number and product expiration date can be readily printed on the peripheral flange portion surrounding the ampoule, and the instruction for opening the package or using the contents can be printed on the front or rear side of the backing card. Additionally, the backing card may be manufactured in strips with a scored or perforated weakened section between adjacent packages. The cover sheet may be transparent so that the user can conveniently inspect the appearance of the ampoule contents. If the ampoule contents are light sensitive, an opaque or ultraviolet absorbing cover sheet material may be used. In the packaging arts, the package containing the ampoule would generally be referred to as a skin, shrink, or blister package.

In one embodiment, skin packaging may be employed. Skin packaging generally refers to a package comprising an air pervious backing card upon which the ampoule may be supported by a relatively thin thermoplastic film which is softened by heating. Suction may be drawn through the backing card to draw the heat softened film into a sheath or “skin” about the ampoule and into contact with the backing card. The cover sheet can be attached to the backing card by an adhesive material or heat sealing.

In another embodiment, shrink packaging may be used as a substitute for skin packaging when the active ingredient is heat sensitive. Shrink packaging generally refers to the technique where the plastic film is first stretched, while hot, to form a relatively large cavity to accommodate the ampoule. After the ampoule has been positioned in the cavity the film is heated to shrink it into tight abutment with the product. This method may be used to skin packaging if the pharmaceutical composition in the ampoule is heat sensitive.

A blister or bubble package generally includes a cup which may be molded from a relatively heavy plastic film and is contoured to the shape of the article. This cup, known as a bubble or blister, provides a preformed cavity of sufficient size to receive the ampoule. The bubble is formed with a peripheral flange so that it can be attached to the backing card by an appropriate means, such as heat fusion or a heat-sealed coating.

FIGS. 4 and 5 show an ampoule 402 in a skin or shrink package 400, according to an embodiment of the invention. Here, the package includes a backing card 500 and a pliable transparent cover sheet 502 which forms a sheath over the ampoule. The ampoule is filled with a solution containing the desired active ingredient 504 and includes a container portion 506 and a tip portion 508. In a specific embodiment, the backing card may be perforated along the perimeter of the ampoule so the ampoule may be easily removed from the package for use by the caregiver or patient.

Exemplary compounds for use in the invention, may include but not limited to, alprazolam; amoxapine; atropine; bumetanide; buprenorphine; butorphanol; clomipramine; donepezil; hydromorphone; loxapine; midazolam; morphine; nalbuphine; naratriptan; olanzapine; paroxetine; pramipexole; prochlorperazine; quetiapine; rizatriptan; sertraline; sibutramine; sildenafil; sumatriptan; tadalafil; vardenafil; venlafaxine; zolpidem; apomorphine HCl; celecoxib; ciclesonide; eletriptan; parecoxib; valdecoxib; fentanyl; citalopram; escitalopram; clonazepam; oxymorphone; albuterol; sufentanyl; and remifentanyl.

Additionally, the active compounds which may be applicable for load-dose titration therapy, for example, may include substances selected from the groups of anti-inflammatory compounds, anti-allergics, glucocorticoids, anti-infective agents, antibiotics, antifungals, antivirals, mucolytics, antiseptics, vasoconstrictors, wound healing agents, local anaesthetics, peptides, and proteins.

Examples of potentially useful anti-inflammatory compounds that may be applicable for load-dose titration therapy may include glucocorticoids and non-steroidal anti-inflammatory agents such as betamethasone, beclomethasone, budesonide, ciclesonide, dexamethasone, desoxymethasone, fluoconolone acetonide, flucinonide, flunisolide, fluticasone, icomethasone, rofleponide, triamcinolone acetonide, fluocortin butyl, hydrocortisone, hydroxycortisone-17-butyrate, prednicarbate, 6-methylprednisolone aceponate, mometasone furoate, elastane, prostaglandin, leukotriene, bradykinin antagonists, non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, indometacin, including any pharmaceutically acceptable salts, esters, isomers, stereoisomers, diastereomers, epimers, solvates or other hydrates, prodrugs, derivatives, or any other chemical or physical forms of active compounds comprising the respective active moieties.

Examples of potentially useful antiallergic agents applicable for load-dose titration therapy may include glucocorticoids, nedocromil, cetrizin, loratidin, montelukast, roflumilast, ziluton, omalizumab, heparinoids and other antihistamins, Azelastine, Cetirizin, Desloratadin, Ebastin, Fexofenadin, Levocetirizin, Loratadin.

Examples of anti-infective agents, whose class or therapeutic category is herein understood as comprising compounds which are effective against bacterial, fungal, and viral infections, i.e. encompassing the classes of antimicrobials, antibiotics, antifungals, antiseptics, and antivirals, that may be suitable for load-dose titration therapy may include penicillins, including benzylpenicillins (penicillin-G-sodium, clemizone penicillin, benzathine penicillin G), phenoxypenicillins (penicillin V, propicillin), aminobenzylpenicillins (ampicillin, amoxycillin, bacampicillin), acylaminopenicillins (azlocillin, mezlocillin, piperacillin, apalcillin), carboxypenicillins (carbenicillin, ticarcillin, temocillin), isoxazolyl penicillins (oxacillin, cloxacillin, dicloxacillin, flucloxacillin), and amiidine penicillins (mecillinam); cephalosporins, including cefazolins (cefazolin, cefazedone); cefuroximes (cerufoxim, cefamdole, cefotiam), cefoxitins (cefoxitin, cefotetan, latamoxef, flomoxef), cefotaximes (cefotaxime, ceftriaxone, ceftizoxime, cefmenoxime), ceftazidimes (ceftazidime, cefpirome, cefepime), cefalexins (cefalexin, cefaclor, cefadroxil, cefradine, loracarbef, cefprozil), and cefiximes (cefixime, cefpodoxim proxetile, cefuroxime axetil, cefetamet pivoxil, cefotiam hexetil), loracarbef, cefepim, clavulanic acid/amoxicillin, Ceftobiprole; synergists, including beta-lactamase inhibitors, such as clavulanic acid, sulbactam, and tazobactam; carbapenems, including imipenem, cilastin, meropenem, doripenem, tebipenem, ertapenem, ritipenam, and biapenem; monobactams, including aztreonam; aminoglycosides, such as apramycin, gentamicin, amikacin, isepamicin, arbekacin, tobramycin, netilmicin, spectinomycin, streptomycin, capreomycin, neomycin, paromoycin, and kanamycin; macrolides, including erythromycin, clarythromycin, roxithromycin, azithromycin, dithromycin, josamycin, spiramycin and telithromycin; gyrase inhibitors or fluroquinolones, including ciprofloxacin, gatifloxacin, norfloxacin, ofloxacin, levofloxacin, perfloxacin, lomefloxacin, fleroxacin, garenoxacin, clinafloxacin, sitafloxacin, prulifloxacin, olamufloxacin, caderofloxacin, gemifloxacin, balofloxacin, trovafloxacin, and moxifloxacin; tetracyclins, including tetracyclin, oxytetracyclin, rolitetracyclin, minocyclin, doxycycline, tigecycline and aminocycline; glycopeptides, including vancomycin, teicoplanin, ristocetin, avoparcin, oritavancin, ramoplanin, and peptide 4; polypeptides, including plectasin, dalbavancin, daptomycin, oritavancin, ramoplanin, dalbavancin, telavancin, bacitracin, tyrothricin, neomycin, kanamycin, mupirocin, paromomycin, polymyxin B and colistin; sulfonamides, including sulfadiazine, sulfamethoxazole, sulfalene, co-trimoxazole, co-trimetrol, co-trimoxazine, and co-tetraxazine; azoles, including clotrimazole, oxiconazole, miconazole, ketoconazole, itraconazole, fluconazole, metronidazole, tinidazole, bifonazol, ravuconazol, posaconazol, voriconazole, and omidazole and other antifungals including flucytosin, griseofluvin, tonoftal, naftifin, terbinafin, amorolfin, ciclopiroxolamin, echinocandins, such as micafungin, caspofungin, anidulafungin; nitrofurans, including nitrofurantoin and nitrofuranzone;—polyenes, including amphotericin B, natamycin, nystatin, flucocytosine; other antibiotics, including tithromycin, lincomycin, clindamycin, oxazolindiones (linzezolids), ranbezolid, streptogramine A+B, pristinamycin aA+B, Virginiamycin A+B, dalfopristin/qiunupristin (Synercid), chloramphenicol, ethambutol, pyrazinamid, terizidon, dapson, prothionamid, fosfomycin, fucidinic acid, rifampicin, isoniazid, cycloserine, terizidone, ansamycin, lysostaphin, iclaprim, mirocin B17, clerocidin, filgrastim, and pentamidine; antivirals, including aciclovir, ganciclovir, birivudin, valaciclovir, zidovudine, didanosin, thiacytidin, stavudin, lamivudin, zalcitabin, ribavirin, nevirapirin, delaviridin, trifluridin, ritonavir, saquinavir, indinavir, foscamet, amantadin, podophyllotoxin, vidarabine, tromantadine, and proteinase inhibitors; plant extracts or ingredients, such as plant extracts from chamomile, hamamelis, echinacea, calendula, papain, pelargonium, essential oils, myrtol, pinen, limonen, cineole, thymol, mentol, alpha-hederin, bisabolol, lycopodin, vitapherole; wound healing compounds including dexpantenol, allantoin, vitamins, hyaluronic acid, alpha-antitrypsin, anorganic and organic zinc salts/compounds, interferones (alpha, beta, gamma), tumor necrosis factors, cytokines, interleukins.

Examples of potentially useful mucolytics that may be useful for load-dose titration therapy may be DNase, P2Y2-agonists (denufosol), heparinoids, guaifenesin, acetylcysteine, carbocysteine, ambroxol, bromhexine, lecithins, myrtol, and recombinant surfactant proteins.

Examples of potentially useful local anaesthetic agent which may be suitable for load-dose titration therapy may include benzocaine, tetracaine, procaine, lidocaine and bupivacaine.

Additionally drugs to treat pulmonary hypertension, such as prostacycline analogs, iloprost, remodulin, phosphodiesterase inhibitors, such as sildenafil, vardenafil, endothelian recector antagonists, such as bosentane, virustatics, including podophyllotoxine, vidarabine, tromantadine, zidovudine; ribavirin, may be applicable for load-dose titration therapy.

Also, immunmodulators may be suitable for load-dose titration therapy may include methotrexat, azathioprine, cyclosporine, tacrolimus, sirolimus, rapamycin, mofetil, cytotatics and metastasis inhibitors, alkylants, such as nimustine, melphanlane, carmustine, lomustine, cyclophosphosphamide, ifosfamide, trofosfamide, chlorambucil, busulfane, treosulfane, prednimustine, thiotepa; antimetabolites, e.g. cytarabine, fluorouracil, methotrexate, mercaptopurine, tioguanine; alkaloids, such as vinblastine, vincristine, vindesine; antibiotics, such as alcarubicine, bleomycine, dactinomycine, daunorubicine, doxorubicine, epirubicine, idarubicine, mitomycine, plicamycine; complexes of secondary group elements (e.g. Ti, Zr, V, Nb, Ta, Mo, W, Pt) such as carboplatinum, cis-platinum and metallocene compounds such as titanocendichloride; amsacrine, dacarbazine, estramustine, etoposide, beraprost, hydroxycarbamide, mitoxanthrone, procarbazine, temiposide; paclitaxel, iressa, zactima, poly-ADP-ribose-polymerase (PRAP) enzyme inhibitors, banoxantrone, gemcitabine, pemetrexed, bevacizumab, ranibizumab.

In a further embodiment other active ingredient that may used in load-dose titration therapy may include, proteinase inhibitors, such as a-anti-trypsin; antioxidants, such as tocopherols, glutathion; pituitary hormones, hypothalamic hormones, regulatory peptides and their inhibiting agents, corticotropine, tetracosactide, choriogonandotropine, urofolitropine, urogonadotropine, saomatotropine, metergoline, desmopressine, oxytocine, argipressine, omipressine, leuproreline, triptoreline, gonadoreline, busereline, nafareline, goselerine, somatostatine; parathyroide gland hormones, calcium metabolism regulators, dihydrotachysterole, calcitonine, clodronic acid, etidronic acid; thyroid gland therapeutics; sex hormones and their inhibiting agents, anabolics, androgens, estrogens, gestagenes, antiestrogenes; anti-migraine drugs, such as proxibarbal, lisuride, methysergide, dihydroergotamine, ergotamine, clonidine, pizotifene; hypnotics, sedatives, benzodiazepines, barbiturates, cyclopyrrolones, imidazopyridines, antiepileptics, zolpidem, barbiturates, phenytoin, primidone, mesuximide, ethosuximide, sultiam, carbamazepin, valproic acid, vigabatrine; antiparkinson drugs, such as levodopa, carbidopa, benserazide, selegiline, bromocriptine, amantadine, tiapride; antiemetics, such as thiethylperazine, bromopride, domperidone, granisetrone, ondasetrone, tropisetrone, pyridoxine; analgesics, such as buprenorphine, fentanyl, morphine, codeine, hydromorphone, methadone, fenpipramide, fentanyl, piritramide, pentazocine, buprenorphine, nalbuphine, tilidine; drugs for narcosis, such as N-methylated barbiturates, thiobarbiturates, ketamine, etomidate, propofol, benzodiazepines,droperidol, haloperidol, alfentanyl, sulfentanyl; antirheumatism drugs including tumor necrosis factor-alfa, nonsteroidal antiinflammatory drugs; antidiabetic drugs, such as insulin, sulfonylurea derivatives, biguanids, glitizols, glucagon, diazoxid; cytokines, such as interleukines, interferones, tumor necrosis factor (TNF), colony stimulating factors (GM-CSF, G-CSF, M-CSF); proteins, e.g. epoetine, and peptides, e.g. parathyrin, somatomedin C; heparine, heparinoids, urokinases, streptokinases, ATP-ase, prostacycline, sexual stimulants, or genetic material.

Additional constituent elements of the liquid formulations of the invention may include water, a buffer, a pH-adjusting agent, a surfactant or anti-adsorbant, a wetting agent, a gelling agent, a drying agent, an osmolality adjusting agent, or virtually any other additive or carrier, depending upon the desired dosage form.

The liquid formulations may be modified to accommodate the particular pharmaceutically effective drug and the particular patient population the liquid formulation is administered to. Formulation characteristics that may be modified include, for example, the pH and the osmolality. Additionally, polymeric excipients may be useful in the liquid formulations of the invention, for among other things, to obtain slow release profile of the drug, such as chitosan, hydroypropylmethylcellulose, dextrans, and kollidon.

Buffers may be useful in the invention for, among other purposes, manipulation of the total pH of the liquid formulation. A variety of buffers known in the art may be used in the formulation of the invention, such as various salts of organic or inorganic acids, bases, or amino acids, and including various forms of citrate, phosphate, tartrate, succinate, adipate, maleate, lactate, acetate, bicarbonate, or carbonate ions. The pH of the formulation changes according to the amount of buffer used. Depending upon the dosage form it may alternatively be advantageous to use buffers in different concentrations or to use other additives to adjust the pH of the formulation to encompass other ranges. Useful pH ranges for formulations of the invention include a pH of about 4.0 to a pH of about 7.0.

It may also be advantageous to employ surfactants in the liquid formulations of the invention. Surfactants or anti-adsorbants that prove useful include polyoxyethylenesorbitans, polyoxyethylenesorbitan monolaurate, polysorbate-20, such as Tween-20™, polysorbate-80, hydroxycellulose, and genapol, vitamin E-TPGS and lecithins or lecithin constituents.

Additional useful additives are readily determined by those of skill in the art, according to particular needs or intended uses of the compositions and formulator. One such particularly useful additional substance is sodium chloride, which is useful for adjusting the osmolality of the formulations to achieve the desired resulting osmolality. Particularly preferred osmolalities for administration of the liquid formulations of the invention are in the range of about 200 to about 400 mOsm/kg.

The description and examples given above are merely illustrative and are not meant to be an exhaustive list of all possible embodiments, applications or modifications of the invention. Thus, various modifications and variations of the described methods and systems of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in the pharmaceutical sciences or related fields are intended to be within the scope of the appended claims.

The disclosures of all references and publications cited above are expressly incorporated by reference in their entireties to the same extent as if each were incorporated by reference individually.

Claims

1. A dose package system for administering a load-dose titration therapy to a patient afflicted with a condition, said system comprising:

a plurality of ampoules containing a pharmaceutically effective dose of a liquid formulation;

a backing card; and

wherein said backing card includes two or more sections containing an appropriate number of ampoules such that each section of said backing card corresponds to a daily dose of the liquid formulation to be administered to the patient and wherein at least one of said sections has a different number of ampoules than at least one other of said section.

2. The package system of claim 1, further comprising a cover sheet to retain said ampoules onto said backing card.

3. The package system of claim 2, wherein said cover sheet is transparent.

4. The package system of claim 2, wherein said cover sheet is a skin package.

5. The package system of claim 2, wherein the cover sheet is a shrink package.

6. The package system of claim 1, wherein said backing card has a weakened portion along a perimeter of said ampoules.

7. The package system of claim 3, wherein the weakened portion is a perforated portion.

8. The package system of claim 1, wherein said backing card is cardboard.

9. The package system of claim 1, wherein the load-dose titration therapy is load-dose upward titration therapy.

10. The package system of claim 1, wherein the load-dose titration therapy is load-dose downward titration therapy.

11. The package system of claim 1, wherein the load-dose titration therapy is a 5-day regimen.

12. The package system of claim 1, wherein the load-dose titration therapy is a 6-day regimen.

13. The package system of claim 1, wherein the ampoule is a blow-fill seal vial.

14. The package system of claim 13, wherein the blow-fill seal vial is fabricated from plastic.

15. The package system of claim 1, wherein the liquid formulation includes an effective amount of prednisolone.

16. The package system of claim 1, wherein said ampoules are pre-filled with about 5 ml of a liquid formulation.

17. The package system of claim 1, wherein said ampoules are filled with about 2.5 ml of a liquid formulation.

18. The package system of claim 1, wherein the patient is afflicted with at least one condition selected from the group consisting of asthma, acute lower respiratory tract infection, pneumonia, infant respiratory distress syndrome, adult respiratory distress syndrome, croup, bronchitis, and pertussis.

19. The package system of claim 1, wherein the patient is a child.

20. The package system of claim 1, wherein the packaging system is a box.