JP2004520358A - Sustained-release pharmaceutical compositions containing beta-lactam antibiotics with improved therapeutic efficacy - Google Patents

Abstract

The present invention discloses a sustained release oral pharmaceutical composition comprising at least one β-lactam antibiotic that releases the drug for a long time after administration. The pharmaceutical compositions are useful for maintaining a desired therapeutically effective blood level of the active ingredient for an extended period of time, and are thus useful in meeting the requirements for effective management of infectious diseases. The pharmaceutical compositions take the form of tablets, capsules or in the form of dry syrups to be reconstituted at the time of administration, and release the active ingredient in the initial and maintenance amounts at a specific rate. The present invention also relates to a method for preparing a sustained release pharmaceutical composition comprising a β-lactam antibiotic.

Description

【Technical field】
[0001]
The present invention discloses an oral pharmaceutical composition for sustained release of the active ingredient. At least one of the active ingredients is a β-lactam antibiotic for drug release that is site-specifically absorbed upon oral administration. The pharmaceutical compositions are useful for maintaining a therapeutically desirable blood level of the active ingredient for an extended period of time, and thus are effective for the management of certain infections with minimal dosing frequency and patient intervention. Useful for meeting requirements. The present invention also relates to a method for preparing said pharmaceutical composition.
[0002]
The oral pharmaceutical composition of the present invention is a polymer matrix in the form of a tablet, capsule or reconstituted dry syrup upon administration containing at least one β-lactam antibiotic together with other excipients and additives.
[Background Art]
[0003]
The discovery of penicillin by Alexander Flemming in 1929 has changed the concept and treatment of infectious diseases caused by bacteria and other microorganisms. Today, many complex antibiotics are being developed for the treatment of infections caused by various microorganisms. Among the various types, β-lactam occupies a visible position. β-lactams act with an ideal therapeutic index against a wide range of infections, but have very short biological half-lives and require frequent administration to elicit the desired therapeutic response. In addition, site-specific gastrointestinal absorption may limit therapeutic applications. Moreover, it is a known fact that contact with various β-lactams damages the intestinal flora (see, for example, Non-Patent Documents 1 to 3). The aforementioned poor and detrimental effects of bioavailavility can be overcome by using prodrugs of the respective compounds. However, the prodrug approach also did not result in full bioavailability.
[0004]
Recent studies have shown that the antibiotic activity of β-lactam is solely dependent on the time of exposure to microorganisms above the minimum inhibitory concentration (MIC) rather than the maximum plasma / serum concentration (eg, non- Patent Document 4). This is achieved by continuous infusion requiring hospitalization and continuous monitoring.
[0005]
Therefore, the selection of an appropriate alternative drug administration mode is a primary goal. This is because the efficacy of a drug is highly dependent on the time above the minimum inhibitory concentration (MIC). The choice should be based on pharmacokinetic and pharmacodynamic parameters.
[0006]
In antibiotics, the relationship between pharmacokinetics and pharmacodynamics is dependent on three parameters: pathogen, host and specific antimicrobial. The post-antibiotic effect of a drug is another pharmacodynamic parameter to consider in determining optimal dosing regimen.
[0007]
Based on the foregoing, oral sustained release formulations of β-lactam antibiotics that maintain low but effective concentrations for extended periods of time may be a suitable mode of administration for long-term treatment.
[0008]
Alanshibia et al. Studied the bioavailability of amoxicillin after oral administration of a controlled release tablet, found that in 8 cases no drug was detected after 8 hours in each case, and the dosage form was reduced to a conventional dosage form. It has been concluded that there is no advantage (for example, see Non-Patent Document 5).
[0009]
Uchiba et al. Described a method for preparing amoxicillin microcapsules using ethylcellulose (for example, see Non-Patent Document 6). These microcapsules exhibited a controlled release pattern when administered to beagle dogs. However, such effects were expected. The pH of the dog stomach tested is significantly higher than the pH of the human stomach (beagle dog has a pH of about 6, while human pH is about 2). Preliminary experiments on amoxicillin have revealed that microcapsules are less suitable for pH 6 than for pH 2 (see, for example, Non-Patent Document 7). It is expected that very fast drug release will be obtained if the same microcapsules are administered to humans. Therefore, they do not appear to be relevant to human studies.
[0010]
Martin et al. Studied the effects of co-administration of clavulanic acid with amoxicillin and found that its bioavailability and subsequent therapeutic response were improved over conventional oral dosage forms (e.g., patents Reference 1). However, the production of products containing clavulanic acid requires controlled environmental conditions, which increases production costs.
[0011]
Hilton and Daisy described a floating tablet of amoxicillin trihydrate (see, for example, Non-Patent Document 8). This tablet is buoyant for 6 hours and has good in vitro sustained release, but lacks bioavailability at doses of 500 mg compared to conventional capsules.
[0012]
Hilton and Daisy also described a controlled release tablet of amoxicillin containing hydroxypropyl methylcellulose acetate succinate as a matrix carrier (see, for example, Non-Patent Document 9). This polymer slows the release of amoxicillin at gastric pH, but does not increase the release in the proximal duodenum and jejunum of the small intestine, where maximum absorption is believed to occur. In addition, studies of single doses in vivo in fasting subjects showed that the tablets had a relative bioavailability of 64.4%. This is probably due to poorer drug absorption from the distal jejunum and ileum than from the duodenum and proximal jejunum.
[0013]
Katzendler discloses pharmaceutical compositions for controlled release of β-lactam antibiotics using various types of cellulose and acrylic polymer derivatives (see, for example, US Pat. According to the present invention, 30.0 hours after administration of the dosage form, 50.0% of the drug is initially released, followed by drug release for up to 8 hours. In addition, the author noted that the free drug did not come into contact with the gut flora because the drug was embedded in the matrix, and therefore the drug was not degraded until absorbed. However, these descriptions contradict each other. Beyond the end of the jejunum, β-lactam absorption is a non-carrier mediated mechanism and therefore does not result in complete drug absorption, resulting in reduced bioavailability and continued intestinal free drug release. Presence causes damage to the gastrointestinal flora.
[Patent Document 1] U.S. Patent No. 5,851,550 [Patent Document 2] International Publication WO98 / 122091 Pamphlet [Non-Patent Document 1] Nord and Edlund., J. Chemother. 2,218,1990.
[Non-Patent Document 2] Pien FD., Antimicrobial Agents and Chemother. 24, 856, 1983.
[Non-Patent Document 3] Fleisher et al., Antimicrobial Agents and Chemother. 24, 679, 1983.
[Non-Patent Document 4] Drusano and Craig, J. Chemother., 9, 38, 1998.
[Non-Patent Document 5] Arancibia et al. Int. J. Clin. Pharmacol. Ther. Toxicol., 25, 97, 1987.
[Non-Patent Document 6] Uchida et. Al. Chem. Pharm. Bull., 37, 3416, 1989.
[Non-Patent Document 7] Tsuji et.al., J. Pharm. Sci., 67, 1059, 1978.
[Non-Patent Document 8] Hilton and Deasy Int. J. Pharm., 86, 79, 1992.
[Non-Patent Document 9] Hilton and Deasy J. Pharm. Sci., 82, 737, 1993.
DISCLOSURE OF THE INVENTION
[Problems to be solved by the invention]
[0014]
In view of the above, we aimed to develop oral sustained release formulations that optimize the therapeutic response of various drugs belonging to β-lactam antibiotics such as penicillin and cephalosporin. A promising approach to accomplish this is to optimize the drug release so as to release all the drug in the dosage form while passing through the absorption window. The advantages of such a formulation are: (a) improving patient compliance by minimizing the frequency of drug administration once or twice daily; and (b) reducing damage to the gastrointestinal flora. It is to avoid.
[Means for Solving the Problems]
[0015]
The present invention is based on the finding that the in vitro antibiotic isolation profile from a sustained release composition comprising an antibiotic or a prodrug thereof, when administered orally to humans for the treatment of infectious diseases, results in a longer therapeutic concentration over a longer period of time. Based on our findings to provide good patient compliance. The composition is coated with a modified release polymer that maintains the integrity of the dosage form even at various pH conditions of the gastrointestinal tract, compressed into tablets, filled into gelatin capsules, Alternatively, it is a dried syrup for reconstitution. The present invention provides pre-programmed, unattended, drug delivery at therapeutically required rates and times. Such drug delivery systems minimize patient intervention and maximize compliance with a given medication regimen.
[0016]
The present invention relates to a pharmaceutical composition in the form of a sustained release oral drug delivery system. The pharmaceutical composition comprises an active ingredient, such as, for example, a β-lactam antibiotic, which has a specific absorption site in the gastrointestinal tract, in combination with a polymeric substance that forms a matrix with other pharmaceutically acceptable excipients. In the pharmaceutical composition, at least 25% of the active antibiotic is released from the matrix within 0.5-1.0 hours after oral administration, and a sufficient amount of the remaining active ingredient is released between 2 hours and 5 hours after administration. Released over a long period of time. This facilitates complete absorption of the active ingredient prior to crossing the "absorption window" where active carrier-mediated transport across the gastrointestinal tract occurs. The idea of the present invention can be effectively applied to any pharmaceutical formulation having an "absorption window".
BEST MODE FOR CARRYING OUT THE INVENTION
[0017]
The drug granules according to the invention comprise at least one β-lactam antibiotic, together with a release-modifying polymer comprising other pharmaceutically acceptable additives, plasticizers and anti-adherents. The pharmaceutical composition of the present invention can take any of the following dosage forms (a) to (c).
(A) Tablets containing drug granules, diluents or fillers, and lubricants.
(B) Capsules containing drug granules, fillers and lubricants.
(C) Dry syrups suitable for reconstitution and oral administration, including granules mixed with additives such as, for example, sweeteners, flavors (flavors).
[0018]
Accordingly, a primary object of the present invention is to provide a novel sustained release pharmaceutical composition comprising an antimicrobial specifically selected from β-lactam antibiotics that is effective in treating infectious diseases.
[0019]
It is another object of the present invention to provide a novel sustained release pharmaceutical composition comprising a longer acting antibiotic as compared to conventional immediate release pharmaceutical compositions.
[0020]
Yet another object of the present invention is to provide an initial dose of the active substance to be absorbed immediately, i.e. within 0.5-1.0 hours, with a range sufficient to maintain a therapeutically effective drug concentration. It is to provide a novel pharmaceutical composition which is therapeutically effective over a long period of at least 10 to 14 hours, which releases at a rate a sufficient amount of the remaining active substance for a desired period of time.
[0021]
Accordingly, the present invention relates to an antibiotic, comprising a drug in the form of a tablet, capsule, or dry syrup for reconstitution, made from drug granules coated with a modified release polymer composition, which is effective in treating infectious diseases. A novel oral sustained release pharmaceutical composition comprising: The formulation also contains the necessary excipients.
[0022]
In another embodiment, the present invention also provides a method for preparing a pharmaceutical composition as described above.
[0023]
In a sustained release pharmaceutical composition comprising a β-lactam antibiotic capable of providing a required initial amount of the active substance of the present invention followed by a sustained release of the remaining drug, the active substance is selected from penicillin or cephalosporin. Is done.
[0024]
In one example of the sustained release pharmaceutical composition, the β-lactam antibiotic is, for example, penicillin V, penicillin G, amoxicillin, ampicillin, cloxacillin, oxacillin, penicillins such as nalcillin and derivatives thereof, or cefadroxyl, cefixime (cefixime). ), Cefuroxime axetil, cefadroxil, cefaclor and derivatives thereof and the like. The amount of the drug used is, for example, 500.0 to 900.0 mg, more preferably 550.0 to 800.0 mg, per 1 g of the drug granule.
[0025]
The polymer used in the present invention is, for example, cellulose acetate phthalate, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose derivatives such as ethylcellulose, or, for example, poly (methacrylic acid, methyl methacrylate) (1: 1) And methacrylic acid derivatives such as poly (methacrylic acid, ethyl methacrylate) (1: 1) (Eudragid L100 and Eudragg L100-55). The amount of the polymer used is, for example, about 20.0 mg to 400.0 mg, more preferably 25.0 mg to 250.0 mg, per 1 g of the drug granule.
[0026]
The plasticizer is, for example, a phthalate derivative such as diethyl phthalate, dipropyl phthalate, dioctyl phthalate, dibutyl phthalate, or, for example, propylene glycol, a glycol derivative such as polyethylene glycol having a molecular weight of 200 to 6000, or It is selected from triethyl citrate or triacetin or a mixture thereof, for example, in an amount of about 10.0% to about 30.0% by weight of the polymer. The anti-adhesion agent used is selected from talc, magnesium stearate, calcium carbonate, magnesium carbonate, and the amount is, for example, from about 10.0% to about 30.0% by weight of the polymer.
[0027]
Granular matrices are formulated in tablet or capsule unit dosage form, or as a dry syrup dosage form to be reconstituted upon administration. The tablets and capsules include, for example, diluents such as starch, lactose, microcrystalline cellulose, dibasic calcium phosphate or mixtures thereof, and, for example, talc, hydrogenated castor oil, magnesium stearate, stearic acid, calcium stearate, stearin. Includes excipients selected from lubricants such as zinc acid or mixtures thereof. The amount of the diluent is, for example, 20.0 to 500.0 mg, more preferably 50.0 to 400.0 mg, per 1 g of the drug granule. The amount of the lubricant is, for example, 5.0 to 50.0 mg, more preferably 10.0 to 40.0 mg, per 1 g of the drug granules.
[0028]
The dosage unit of the dried syrup is, for example, a sweetener such as sucrose, glucose, aspartame, saccharin sodium, N-methylglycerresinate (fructose), and the like; for example, pineapple, strawberry, banana, vanilla, orange, mango, raspberry, and the like. Coloring agents such as titanium dioxide, erythrosine, brilliant blue, indigo carmine, tartrazine, Ponceau 4R, sunset yellow, quinoline yellow, red iron oxide, yellow iron oxide; and the like; for example, methylparaben, propylparaben and the like. Preservatives such as sodium salts; buffers such as citric acid, sodium citrate and the like; seasonings; eg, sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium benzoate, butyric acid Hydroxytoluene toluene, a pharmaceutically acceptable additive selected from antioxidants, such as butylated hydroxy anisole.
[0029]
According to another embodiment, the present invention also provides a method for preparing a pharmaceutical composition as described above, comprising i) to iii) below.
i) Prepare granules containing the drug.
ii) Coat the granules with a polymer dissolved in a mixture of organic solvents together with a plasticizer and an anti-adhesion agent.
iii) The granules are formulated into tablets, capsules or dry syrup for reconstitution with appropriate excipients.
[0030]
Based on the above, the present invention provides a method for preparing granules by dry granulation or wet granulation using a polymer solution of an organic solvent or a mixed solvent. The granules are further coated with a modified release polymer composition in a mixture of organic solvents such as, for example, acetone, ethyl alcohol, isopropyl alcohol, methylene chloride.
[0031]
The granules are mixed with a diluent and a lubricant and subsequently compressed into tablets by a rotary compressor or filled into hard gelatin capsules by a capsule filling machine. Dried syrups are prepared by mixing the granules with sweeteners, flavors, colorings, preservatives, antioxidants and buffers and seasonings.
[0032]
Complete release of antibiotics before they cross the controlled absorption window, together with improved therapeutic response, maximizes bioavailability, minimizes local side effects, reduces medication frequency, and improves patient compliance. Become.
[0033]
The dosage forms described herein provide a controlled entry of the drug through the gastrointestinal tract and into the systemic circulation. The dosage form has advantages over conventional systemic therapeutic dosage forms. The principle of such dosage forms is based on the ability to maintain a blood drug concentration in a range that selectively elicits the desired therapeutic effect over a longer period of time as compared to conventional dosage forms.
[0034]
(Superiority)
1) Long-term therapeutic response compared to conventional oral formulations.
2) Reduced dosing frequency.
3) Improve patient compliance.
4) Avoidance of intestinal flora damage.
[0035]
Hereinafter, the present invention will be described in detail with reference to examples, but these are for explanation, and do not limit the scope of the present invention.
Embodiment 1
[0036]
(Stage 1)
Composition: mg / g
Ampicillin trihydrate 900.00
Hydroxyprolyl methylcellulose phthalate 60.00
Diethyl phthalate 18.00
Talc 22.00
Isopropyl alcohol QS (sufficient amount)
Acetone QS
Hydroxyprolyl methylcellulose was dissolved in a mixture of isopropyl alcohol and acetone along with diethyl phthalate and dispersed talc. Compact granules of ampicillin trihydrate were coated with the polymer composition and dried at 50 ° C.
[0037]
(Stage 2)
Composition: mg / g
Coated ampicillin granules 560.00
Ampicillin granules 145.00
Starch 180.00
Microcrystalline cellulose powder 95.00
Talc 10.00
Magnesium stearate 10.00
The coated ampicillin granules were mixed with ampicillin trihydrate granules, starch and microcrystalline cellulose powder and lubricated with talc and magnesium stearate. The lubricated granules were compressed with a rotary compression press into tablets.
Embodiment 2
[0038]
(Stage 1)
Composition: mg / g
Cefadroxil monohydrate 925.00
Poly (methacrylic acid, methyl methacrylate) 45.00
Triethyl citrate 14.00
Talc 16.00
Isopropyl alcohol QS
Acetone QS
Poly (methacrylic acid, methyl methacrylate) was dissolved in a mixture of isopropyl alcohol and acetone with triethyl citrate and dispersed talc. Compact granules of cefadroxil monohydrate were coated with the polymer composition and dried at 50 ° C.
[0039]
(Stage 2)
Composition: mg / g
Coated Cefadroxil Granules 520.00
Cefadroxil granules 140.00
Starch 180.00
Microcrystalline cellulose powder 140.00
Magnesium stearate 20.00
The coated cefadroxil granules were mixed with cefadroxil granules, starch and microcrystalline cellulose powder and lubricated with magnesium stearate. The lubricated granules were compressed with a rotary compression press into tablets.
Embodiment 3
[0040]
(Stage 1)
Composition: mg / g
Cloxacillin sodium 800.00
Cellulose acetate phthalate 70.00
Hydroxypropyl methylcellulose 90.00
Diethyl phthalate 19.50
Talc 24.00
Isopropyl alcohol QS
Methylene chloride QS
Cellulose acetate phthalate was dissolved in a mixture of isopropyl alcohol and methylene chloride with diethyl phthalate and dispersed talc. Compact cloxacillin sodium granules containing hydroxypropyl methylcellulose were coated with the polymer composition and dried at 50 ° C.
[0041]
(Stage 2)
Composition: mg / g
Cloxacillin coated granules 540.00
Cloxacillin sodium granules 160.00
Starch 115.00
Dicalcium phosphate 70.00
Microcrystalline cellulose powder 95.00
Magnesium stearate 20.00
Starch, calcium diphosphate and crystalline cellulose powder were mixed and granulated with starch paste. The not yet dried mass was passed through 14 # and then dried at 65 ° C. The coated cloxacillin granules were mixed with the dried granules together with cloxacillin sodium granules and lubricated with magnesium stearate. The lubricated granules were filled into hard gelatin capsules with a capsule filling machine.
Embodiment 4
[0042]
(Stage 1)
Composition: mg / g
Cefuroxime Axetil 920.00
Hydroxyprolyl methylcellulose phthalate 54.00
Diethyl phthalate 10.80
Talc 15.20
Isopropyl alcohol QS
Acetone QS
Hydroxyprolyl methylcellulose was dissolved in a mixture of isopropyl alcohol and acetone, along with diethyl phthalate and dispersed talc. Compact granules of cefuroxime axetil were coated with the polymer composition and dried at 50 ° C.
[0043]
(Stage 2)
Composition: mg / g
Coated cefuroxime granules 450.00
Cefuroxime Axetil granules 150.00
Sodium carboxymethylcellulose 40.50
Sodium citrate 16.00
Sodium benzoate 39.00
Quinoline Yellow 1.00
Sunset Yellow 1.50
Pineapple dry flavor 10.00
Orange DC116 flavoring 6.00
Strawberry DC109 Flavor 2.60
Vanilla DC110 Flavor 2.80
Colloidal silicon dioxide 25.00
Sucrose 2500.00
The sucrose was milled to purification grade, mixed with the other ingredients previously sieved with 30 #, and finally the cefuroxime granules were mixed. The dry mixture was filled into a unit dose pack.

Claims (10)

A sustained release pharmaceutical composition comprising at least one β-lactam antibiotic, comprising from about 50.0% to about 90.0% by weight of a β-lactam antibiotic in the form of a granular matrix; From about 1.0% to about 40.0% by weight of the polymer and from about 1.0% to about 20.0% by weight of the pharmaceutically acceptable inert component, wherein the granular matrix comprises a film-forming polymer and Further coated with a polymer composition containing other coating aids, about 25% of the active ingredient is released one hour after oral administration and the remaining active ingredient is released at a controlled rate before crossing the absorption window. A sustained-release pharmaceutical composition characterized by being released. β-lactam antibiotics are penicillin V, penicillin G, amoxicillin, ampicillin, cloxacillin, oxacillin, penicillins such as narcillin and derivatives thereof, or cefadroxyl, cefixime, cefuroxime axetil, cefadroxil, cefaclor and the like. The sustained-release pharmaceutical composition according to claim 1, which is selected from cephalosporins such as derivatives. The sustained release pharmaceutical composition of a β-lactam antibiotic according to claim 1, which provides a therapeutically effective blood drug concentration for a long period of 8 to 12 hours. The granular matrix is coated with about 1.0% to about 20.0%, by weight of the granular matrix, of a polymer composition, wherein the polymer composition comprises about 40.0% to about 80.0%, by weight. The polymer of claim 1, comprising from about 10.0% to about 30.0% by weight of a plasticizer and from about 10.0% to about 30.0% by weight of an anti-adhesion agent. A sustained release pharmaceutical composition of a lactam antibiotic. The polymer used for the preparation of the granular matrix and the film may be a cellulose derivative such as cellulose acetate phthalate, hydroxypropylmethylcellulose and hydroxypropylmethylcellulose phthalate, or poly (methacrylic acid, methyl methacrylate) (1: 1) The β-lactam according to claim 1, wherein the β-lactam is selected from methacrylic acid derivatives such as and poly (methacrylic acid, ethyl methacrylate) (1: 1), the amount of which is 2% to about 40% by weight of the drug granules. Sustained release pharmaceutical compositions of antibiotics. The plasticizer used for the film coating of the granular matrix is diethyl phthalate, dipropyl phthalate, dioctyl phthalate, dibutyl phthalate, propylene glycol, polyethylene glycol having a molecular weight of 200 to 6000, triethyl citrate, triacetin, or From about 10.0% to about 30.0% by weight of the polymer and the anti-adhesion agent used is talc, magnesium stearate, calcium carbonate, carbonate The sustained release pharmaceutical composition for a β-lactam antibiotic according to claim 1, wherein the composition is selected from magnesium, and the amount is, for example, from about 10.0% to about 30.0% by weight of the polymer. The sustained-release β-lactam antibiotic of claim 1, wherein the granular matrix is formulated as a tablet or capsule unit dosage form, or a dry syrup reconstituted upon administration. Pharmaceutical composition. The unit dosage form of the tablet or capsule further comprises from about 5.0% to about 50.0% by weight of a diluent or disintegrant such as starch, lactose, microcrystalline cellulose and dibasic calcium phosphate, and talc, hydrogen. And about 0.5% to about 4.0% by weight of a lubricant, such as castor oil, magnesium stearate, stearic acid, calcium stearate, and zinc stearate. 8. A sustained-release pharmaceutical composition for a β-lactam antibiotic according to any one of claims 1 to 7. The dry syrup dosage unit may further comprise sweeteners such as sucrose, glucose, aspartame, saccharin sodium, N-methylglycerresinate (fructose); flavorants such as pineapple, strawberry, banana, vanilla, orange, mango, raspberry, Colorants such as titanium dioxide, erythrosine, brilliant blue, indigo carmine, tartrazine, Ponceau 4R, sunset yellow, quinoline yellow, red iron oxide, yellow iron oxide; methyl paraben, propyl paraben and their sodium salts, etc. Preservatives; buffers such as citric acid and sodium citrate and seasonings; sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium benzoate, butylated hydroxytoluene, butylated hydride Sustained-release pharmaceutical composition β- lactam antibiotics according to any crab of claims 1-7 containing an additive pharmaceutically acceptable chosen from antioxidants such Kishianisoru. The sustained-release pharmaceutical preparation of a β-lactam antibiotic according to claim 1, wherein the preparation method comprises the following steps i) to iii).
i) Prepare granules containing the drug.
ii) Coat the granules with a polymer dissolved in a mixture of organic solvents together with a plasticizer and an anti-adhesion agent.
iii) The granules are formulated into tablets, capsules or dry syrup for reconstitution with appropriate excipients.