CA1302261C - Buccal drug dosage form - Google Patents
Buccal drug dosage formInfo
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- CA1302261C CA1302261C CA000529319A CA529319A CA1302261C CA 1302261 C CA1302261 C CA 1302261C CA 000529319 A CA000529319 A CA 000529319A CA 529319 A CA529319 A CA 529319A CA 1302261 C CA1302261 C CA 1302261C
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/006—Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Dental Preparations (AREA)
Abstract
ABSTRACT
Buccal dosage forms for transmucosal administration of drugs comprise a pharmaceutical compound dispersed in an erodible matrix comprising from about 20 to about 75 percent by weight of a polyethylene glycol component having a low molecular weight of from about 100 to about 4000, from about 2 to about 54 percent by weight of a polyethylene glycol component having a medium to high molecular weight of from about 6000 to about 20,000, and from about 1 to about 40 percent by weight of a polyethylene oxide having a high molecular weight of from about 100,000 to 5,000,000.
Buccal dosage forms for transmucosal administration of drugs comprise a pharmaceutical compound dispersed in an erodible matrix comprising from about 20 to about 75 percent by weight of a polyethylene glycol component having a low molecular weight of from about 100 to about 4000, from about 2 to about 54 percent by weight of a polyethylene glycol component having a medium to high molecular weight of from about 6000 to about 20,000, and from about 1 to about 40 percent by weight of a polyethylene oxide having a high molecular weight of from about 100,000 to 5,000,000.
Description
2~L
TITLE: BVCCAL DRUG DOSAGE FORM
BACKGROUND OF THE INVENTION
Field of the Invention:
This invention relates to dosage forms for administration of drugs and more particularly to buccal dosage forms havin~ a polymeric matrix for controlled release of a drug.
i DescriPtion of the Prior Art:
Administration of drugs by absorption through the oral mucosa has been found to be an efficient and convenient method of supplying to the body a drug which is not well adapted to administration via the intestinal route. Some drugs are poorly absorbed from the gastrointestinal tract; others are rapidly metabolized in the liver and do not reach the target organ.
Y Transmucosal administration, which introduces the drug directly ( ~
into the bloodstream, avoids the problems of poor absorption or rapid metabolism.
However, because the continuous secretion of saliva rapidly washes dissolved drugs out of the oral cavity, ~ublingual and buccal administration of drugs have been most useful for drugs, such as nitroglycerin, which are very rapidly absorbed through the oral mucosa. In order to keep a drug in contact with the oral mucosa for a longer period of time, sustained release dosage forms especially adapted for transmucosal administration of drugs have been developed. These have generally comprised a drug disper~ed in a matrix which ~lowly releases the drug by diffusion -I -Z~
from the matrix or by slow dissolution or erosion of the matrix. In order to retain ~he dosage form within the mouth, it may be bonded to an adhesive patch or the dosage form itself may be provided with an adhesive layer which adheres to the mucosa.
Alternatively, the dosage form itself may adhere to the mucosa and slowly dissolve, releasins the drug contained therein.
For example, Zaffaroni, U. S. Patent 3,598,122, discloses an adhesive buccal device having an impermeable backing layer and a drug-cvntaining ~dhesive matrix layer which adheres to the oral mucosa, allowing the drug to diffuse through the mucosa over a period of time. This device has the drawback that it must be removed from the mouth after the drug has been dispensed.
Another adherent dosage form comprising an impervious backing material coated with an adhesive which adheres to the mucosa and having a drug reservoir matrix comprised of a mixture of low molecular weight polyethylene glycol and polyvinyl-pyrrolidone is disclosed in Tsuk, U. S. Patent 3,972,995.
Evidently this dosage form suffers from the same problems as that of Zaffaroni.
Another approach is exemplified by Nagai, U. S. Patent 4,250,163, who discloses a totally soluble adhesive buccal dosage form which adheres to the oral mucosa and releases the medication over a period of 10-40 minutes. The dosage form is a lamella having the drug dispersed in a matrix comprised of 50-95 ~ of a cellulose ether and 5-50% of ~n acrylic polymer. These dosage forms are prepared by compression molding of a mixture of ingredients in powder form, which sometimes presents problems in obtaining uniform distribution of the drug in th~ matrix.
A buccal dosage form comprising a strip of gauze or paper impreg~ated with a drug in a matrix of a mixture of polyethylene glycol~ is disclosed in Applezweigr U.S. Patent 3,536,809. This 22~.
TITLE: BVCCAL DRUG DOSAGE FORM
BACKGROUND OF THE INVENTION
Field of the Invention:
This invention relates to dosage forms for administration of drugs and more particularly to buccal dosage forms havin~ a polymeric matrix for controlled release of a drug.
i DescriPtion of the Prior Art:
Administration of drugs by absorption through the oral mucosa has been found to be an efficient and convenient method of supplying to the body a drug which is not well adapted to administration via the intestinal route. Some drugs are poorly absorbed from the gastrointestinal tract; others are rapidly metabolized in the liver and do not reach the target organ.
Y Transmucosal administration, which introduces the drug directly ( ~
into the bloodstream, avoids the problems of poor absorption or rapid metabolism.
However, because the continuous secretion of saliva rapidly washes dissolved drugs out of the oral cavity, ~ublingual and buccal administration of drugs have been most useful for drugs, such as nitroglycerin, which are very rapidly absorbed through the oral mucosa. In order to keep a drug in contact with the oral mucosa for a longer period of time, sustained release dosage forms especially adapted for transmucosal administration of drugs have been developed. These have generally comprised a drug disper~ed in a matrix which ~lowly releases the drug by diffusion -I -Z~
from the matrix or by slow dissolution or erosion of the matrix. In order to retain ~he dosage form within the mouth, it may be bonded to an adhesive patch or the dosage form itself may be provided with an adhesive layer which adheres to the mucosa.
Alternatively, the dosage form itself may adhere to the mucosa and slowly dissolve, releasins the drug contained therein.
For example, Zaffaroni, U. S. Patent 3,598,122, discloses an adhesive buccal device having an impermeable backing layer and a drug-cvntaining ~dhesive matrix layer which adheres to the oral mucosa, allowing the drug to diffuse through the mucosa over a period of time. This device has the drawback that it must be removed from the mouth after the drug has been dispensed.
Another adherent dosage form comprising an impervious backing material coated with an adhesive which adheres to the mucosa and having a drug reservoir matrix comprised of a mixture of low molecular weight polyethylene glycol and polyvinyl-pyrrolidone is disclosed in Tsuk, U. S. Patent 3,972,995.
Evidently this dosage form suffers from the same problems as that of Zaffaroni.
Another approach is exemplified by Nagai, U. S. Patent 4,250,163, who discloses a totally soluble adhesive buccal dosage form which adheres to the oral mucosa and releases the medication over a period of 10-40 minutes. The dosage form is a lamella having the drug dispersed in a matrix comprised of 50-95 ~ of a cellulose ether and 5-50% of ~n acrylic polymer. These dosage forms are prepared by compression molding of a mixture of ingredients in powder form, which sometimes presents problems in obtaining uniform distribution of the drug in th~ matrix.
A buccal dosage form comprising a strip of gauze or paper impreg~ated with a drug in a matrix of a mixture of polyethylene glycol~ is disclosed in Applezweigr U.S. Patent 3,536,809. This 22~.
- 3 - 70557-~5 dosage form also has the drawback that the supporting gauze or paper must be re~oved from the mouth after the medicine has been exhausted.
DeFoney, in U.S. Patents 3,911,099 and 4,039,653, discloses a dosage form comprising a tablet or similar article formed of a sustained release matrix of polyvinylpyrrolidone containing an odor masking substance which is retained in the oral cavity by means of an adhesive layer on one side of the tablet.
Hence a need has continued to exist for a buccal dosage form which adheres to the oral mucosa, provides for administration of medication over a controlled period of time, has a very uniform distribution of the drug in the matrix, and which completely dissolves in the mouth.
SUMMARY OF THE INVENTION
The invention herein comprises an injection moldable erodible composition sui-table for use as a controlled release matrix for a bioactive compound comprising from about 20 to about 75 percent by weight of a polyethylene glycol component having a low molecular weight of from about 100 to about 4000, from about 2 to about 54 percent by weight of a polyethylene glycol eomponent having a medium to high molecular weight of from about 6000 to about 20,000, and from about 1 to about 40 percent by weight of a polyethylene oxide having a high molecular weight of from about 100,000 to 5,000,000.
The invention further comprises a controlled release composition for a buccal dosage form comprising a pharmaceutical compound or a pharmaceutically acceptable salt or derivative thereof dispersed in a non-crystalline polymeric matrix comprising from about 20 to about 75 percent by weight of a polyethylene glycol component having a low molecular weight of from about 100 to about 4000, from about 2 to about 54 percent by weight of a polyethylene glycol component having a medium to high molecular weight of from about 6000 to about 20,000, and from about 1% to about 40% by weight of a polyethylene oxide having a high molecular weight of from about 100,000 to 5,000,000.
The inventlon also comprises an injection molded dosage ; form comprising a pharmaceutical compound or a pharmaceutically acceptable salt or derivative thereof dispersed in a non-crystalline polymeric matrix comprising from about 20 to about 75 percent by weight of a polyethylene glycol component, having a low molecular weight of from about 100 to about 4000, from about 2 to about 54 percent by weight oE a polyethylene glycol component having a medium to high molecular weight of from about 6000 to about 20,000, and from about 1~ to about 40~ by weight of a polyethylene oxide having a high molecular weight of from about 100,000 to 5,000,000.
DETAILED DESCRIPTION OF T~E INVENTION AND PREFERRED EMBODIMENTS
The b~ccal dosage form of this invention is a blend of ingredients chosen to provide the proper physical properties in manufacture and use. The injection moldable matrix should have a melting poin-t which is high enough to prevent fusion of packaged dosage forms during storage in a reasonably temperate environmen-t, yet low enough to permit mixing of the active pharmaceutical ingredient with the molten matrix without causing significant decomposition of the pharmaceutical compound. The molten matrix should also have a viscosity suitable for mixing the active ingredient and for injection molding to form buccal dosage forms. The solidified buccal dosage form may also require special properties. For example, in some cases, it may be 2~
DeFoney, in U.S. Patents 3,911,099 and 4,039,653, discloses a dosage form comprising a tablet or similar article formed of a sustained release matrix of polyvinylpyrrolidone containing an odor masking substance which is retained in the oral cavity by means of an adhesive layer on one side of the tablet.
Hence a need has continued to exist for a buccal dosage form which adheres to the oral mucosa, provides for administration of medication over a controlled period of time, has a very uniform distribution of the drug in the matrix, and which completely dissolves in the mouth.
SUMMARY OF THE INVENTION
The invention herein comprises an injection moldable erodible composition sui-table for use as a controlled release matrix for a bioactive compound comprising from about 20 to about 75 percent by weight of a polyethylene glycol component having a low molecular weight of from about 100 to about 4000, from about 2 to about 54 percent by weight of a polyethylene glycol eomponent having a medium to high molecular weight of from about 6000 to about 20,000, and from about 1 to about 40 percent by weight of a polyethylene oxide having a high molecular weight of from about 100,000 to 5,000,000.
The invention further comprises a controlled release composition for a buccal dosage form comprising a pharmaceutical compound or a pharmaceutically acceptable salt or derivative thereof dispersed in a non-crystalline polymeric matrix comprising from about 20 to about 75 percent by weight of a polyethylene glycol component having a low molecular weight of from about 100 to about 4000, from about 2 to about 54 percent by weight of a polyethylene glycol component having a medium to high molecular weight of from about 6000 to about 20,000, and from about 1% to about 40% by weight of a polyethylene oxide having a high molecular weight of from about 100,000 to 5,000,000.
The inventlon also comprises an injection molded dosage ; form comprising a pharmaceutical compound or a pharmaceutically acceptable salt or derivative thereof dispersed in a non-crystalline polymeric matrix comprising from about 20 to about 75 percent by weight of a polyethylene glycol component, having a low molecular weight of from about 100 to about 4000, from about 2 to about 54 percent by weight oE a polyethylene glycol component having a medium to high molecular weight of from about 6000 to about 20,000, and from about 1~ to about 40~ by weight of a polyethylene oxide having a high molecular weight of from about 100,000 to 5,000,000.
DETAILED DESCRIPTION OF T~E INVENTION AND PREFERRED EMBODIMENTS
The b~ccal dosage form of this invention is a blend of ingredients chosen to provide the proper physical properties in manufacture and use. The injection moldable matrix should have a melting poin-t which is high enough to prevent fusion of packaged dosage forms during storage in a reasonably temperate environmen-t, yet low enough to permit mixing of the active pharmaceutical ingredient with the molten matrix without causing significant decomposition of the pharmaceutical compound. The molten matrix should also have a viscosity suitable for mixing the active ingredient and for injection molding to form buccal dosage forms. The solidified buccal dosage form may also require special properties. For example, in some cases, it may be 2~
5 - i desirable for the bu~cal dosage form to adhere to the oral mucosa, so that it is retained in the oral cavity for a period of time while slowly releasing the active ingredient. While the compositions of the invention are specially adapted for use as buccal dosage forms, they may also be used as conventional oral dosage forms which are swallowed and deliver their medication via the gastrointestinal tract.
The desired c~mbination oP properties in the buccal dosage form of this invention is achieved by proper choice of the proportions of the three basic components of the matrix.
The first component of the buccal matrix of the invention i~
a low molecular weight polyethylene glycol (PEG) component which may be a single PEG or a mixture of low molecular weight PEG's.
For purposes of this invention, low molecular wei~ht P~G' 5 are those having a molecular weight not greater than about 4000 daltons. The proportion of low molecular weight PEG component may range from about 20 % t~ ab~ut 75 % by wei~ht of the matrix. The proportion of low molecular weight PEG component affects the rate at which the matrix is eroded by saliva and therefore the rate of release of the drug and the duration of its action. In general, greater amounts of low molecular weight PEG
component increase the rate of erosion. The relative amounts of the low molecular weight PEG component and the medium or high molecular weight co~ponent determine the melting point of the kuccal matrix of the inventlon. Mixtures of low molecular weight PEG's can be used to attain a desired average ~olecular weight and the desired effect on the properties of the matrix. A
preferred low molecular weight PEG component comprise~ a mixture of PEG 1000, PEG 1450 and PEG 3350, where the numbers signify the molecular weight as is conventionalO Another preferred low ~olecular weight PEG component ~omprises a mixture of PEG 1450 and PEG 3350.
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The medium to high molecular weight polyethylene glycol component has a molecular weight in the range from about 6000 daltons to about 20,000-daltons, Its prop~rtion in the matrix may ran~e from about 2 % to about 65 % by weight. Greater amounts of the medium to high molecular weight comp~nent tend to increase the mel~ing point of the mixture, and favsr the noncrystalline character of the matrixO
The viscosity of the molten material should be low enough to provide for easy mixing of the active ingredient into the matrix and also for conforming to the final molded shape. This includes the ability to flow freely into thin layers when la~ellae or disks are to be prepared by casting, and the abili.ty to flow freely through the sprues of a multiple form injection mold.
The buccal dosage form matrix should also be non-hygroscopic for ease in handling the dosage forms and should have good mold-release properties to facilitate manufacture by injection molding.
The third ingredient of the buccal dosage matrix of the invention i~ a high molecular weight polymer introdùced to adiust the properties of the matrix, parti~ularly the melt v~scosity and the molding proper~ies of the molten matrix and the adhesion of the dosage form to the oral mucosa. The proportion of ~he third ingredient ranges from about 1 ~ to about 40 % by weight of the matrix. Suitable high molecular weight polymers include poly-vinylpyrrolidone tPVP), polyethylene oxide (PEO), poly(acrylic acid ) (PAA), sodium alginate and carboxymethyl cellulose.
Preferred high molecular weight polymers include polyvinylpyr-rolidone and polyethylene oxide. Both of these polymers provide the matrix with water activatea adhesive properties ~or good adhesion to the oral mucosa . They also influence the melt ~;, ~ viscosity of the molten matrixO The PEO used in the matrix may ~3~22~
have a molecular weight from about 100~000 to about 5,000,000 daltons. The PVP may have a molecular weight from about 30,000 to about 90,000 daltons.
In a preferred matrix of the invention the auxiliary polymeric ingr~dient is polyvinylpyrrolidone in a proportion of about 25 % to about 40 % by weight of the matxix. ~hi~ dosage form rapidly disintegrates and dissolves after being placed in the buccal pouch, in a period of about 60 seconds, leaving no noticeable residue, but rather a coating of the matrix ingredients which adhere to a relatively large area of the mucosa surrounding the site where the dosage form was placed. The presence of this thin coating is unnoticeable to the patient, but it continues to dispense the drug through the mucosa until such time as the drug is used up or the matrix dissolves in the mouth fluids. Thus, the drug is typically dispensed over a period of 10-30 minutes via transmucosal absorption directly into the bloodstream.
Additional ingredients in minor amounts may be incorporated into the buccal matrix of the invention to provide desirable physi~al properties or modify the properties of the matrix. For example, a plasticizer such as propylene glycol, may be added in amounts up to about 5 ~ by weight of the matrix.
The buccal dosage form of the invention is prepared by mixing the ingredients at a temperature such that the PEG's are molten and can serve as a solvent ~or the auxiliary high molecular weight polymeric ingredients, for any additional auxiliary ingredients and for the active pharmaceutical ingredient. In general~ the PEG's are melted and mixed in a vessel equipped with a stirrer and a heating device, ~uch as a heating mantle or steam jacket. Such melting usually occurs at about 60-80C and the viscosity and plasticity adjustin~
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ingredients, e. 9., polyethylene oxide or polyvinylpyrrolidone, any auxiliary ingredients and the pharmaceutically active ingredient are added while stirring. After the blending is complete, buccal dosage forms are prepared by conventional procedures, such as cas~ing a thin layer of the composition on a flat surface, allowing it ~o harden and cutting the layer so prepared into dosage forms, or by injection molding.
Formulation of the compositions of the invention in the molten state has a number of advantages over the conventional method of formula~ion by mixing of powdered or granulated ingredients in the solid state. The mixing equipment needed for mixing of li~uid ingredients is generally simpler than that used for solid materials. The fact that the ingredients are actually dissolved in the matrix makes for more uniform distribution of the active ingredients in the composition and a more uniform rate of release as the dosage form dissolves in the oral cavity. The use of a molten matrix for formulating the romp~sition also permits the use of injection molding to prepare the dosage forms themselves.
Injection molding of pharmaceutical dosage forms has a number of advantages over conventional tabletting. Injection molding allows a greater uniformity in size and density, a greater range of shapes for the dosage forms, and a greater uniformity of distribution of the drug within the matrix.
Handling and metering of a molten matrix composition is also much simpler than for powdered or granulated compositions.
Any drug suitable for transmucosal administration may be incorporated into the buccal dosage form of this invention. Such drugs may include locally or systemically acting drugs, 5ut in most cases will be systemically acting drugs. The drugs may be selected from among any group ~herein a transmucosal ~0226~
g administration of the drug over a period ranging from a few minutes to several minutes is desired. The drug may be selected from among analgesic, anorexic, antiarthritic. antibacterial, an~ibiotic, anticonvulsan~, anti-depressant, antidiabetic, anti-fungal, antihistaminic, anti-hypertensive, anti-inflammatory, anti-neoplastic, antiparkinsonism, antipyretic, ~nticholinergic, anesthetic, antimicrobial, antiviral, anti-ulcer, bronchodilator, cardiovascular, contraceptive, central nervous system affecting, inotropic, vasodilator, vasoconstrictor, decongestant, diuretic, hypoglycemic, hormone, hypnotic, hematinic, electrolyte supplement, germicidal, muscle relaxant, parasympathetolytic, parasympathetomimetic, tranquilizer, ophthalmic, psychostimulant, vitamin, and the like drugs.
Preferred ~rugs for incorporation into the buccal dosage fotm of this invention include estrogens in general, e. 9.
estradiol and esters thereof such as the valerate ester, ethinylestradiol, progestins including norethindrin, gonadotropin releasing hormone (GNRH), human growth hormone, insulin, nicotin~, phenylephrine, desmopressin (DDA~P), oxytscin9 vasopressin, epinephrine, peptides useful in the treatment of patients with Paget's disease or other calcium deficiency ~yndromes, such as calcitonin and the like, ni~roqlycerin, isosorbide dinitrate, scopolamine, verapamil, oxymetazoline, tamoxifen and the like.
The proportion of active ingredient in the buccal dosage form of the invention will vary according to the potency of the drug and the needs of the patient, as will be understood by those skilled in the art. The active ingredient will generally comprise from about 0.01 percent by weight to about 10 percent by weight, typically 0.1 percent to 1 percent by weight, the remainder of the composition being the matrix. ~he concentration 22~;1 i of the drug in the composition will also vary with the size of the dosage ~orm prepared, since as will be understood by those skilled in the art, the amount of drug delivered in a single dose will depend on both the concentration of the drug in the matrix and the size of the buccal do~age form~
A particularly preferred buccal dosage form of the invention incorporates an estrogen, a progestin or preferably both, to prepare a dosage form useful as an oral contraceptive or a post-menopausal estrogen supplement. An oral contraceptive dosage form according to the invention will typically contain a progestin and an estrogen in amoun~s suitable for providing contraceptive activity. A typical contraceptive formulation will include 0.02 - 0.05 percent by weight of ethinylestradiol and 1.0 - 5.0 perc~nt by weight of norethindrone in a buccal matrix of the invention. A typical dosage form for post-menopausal estrogen supplement will contai~ 0.2 - 0.5 percent by weight of 17-beta-estradiol and 1.0 - 5.0 percent by weight of norethindrone in a buccal matrix of the invention.
The buccal dosage forms prepared from the composition of this invention may ha:ve any of the conventional shapes and sizes used for such dosage forms. For example a dosage form may be in the form of a lozenge, a lamella, a disk, a wafer, a tablet or the like. It should have dimensions which ~it conveniently into the buccal cavity or under the tongue. Suitable dimensions for the dosage form are a length of 5 to 10 mm, a width of 2 to 10 mm and a thickness of 0~2 to 3 mm. A preferred thickness is O.S to 1.5 mm. The total weight of the dosage form may be from about 10 to about 150 mg, preferably 50 to 100 mg.
; The invention will be illustrated by the following examples, which are not intended to be limiting. Parts and percentages in .~ ~30æ26~
the example6 are by weight unless otherwi~e specified.
Example 1 This example illustrates the preparation of a buccal dosage form of the invention.
A molten mixture was prepared by the procedur~ described above having ~he following composition PEG 1000 20 %
PEG 8000 3 %
Propylene glycol 3 Polyvinylpyrrolidone 33 ~
After the ingredients were melted together, the molten mixture was cast on a smooth flat surface and allowed to cool.
The film 50 formed was hard and somewhat flexible at room temperature. Dosage forms of a size to fit comfortably in the buccal pouch were cut from the film (about 1 cm x 3 cm). These lamellae dissolved rapidly when placed in the buccal pouch or sublingually.
Another dosage form was prepared by the same procedure except that a small amount of a dye was incorporated into the mat~ix. When the dosage form was placed in the buccal pouch, it dissolved in less than 60 seconds. ~owever~ it was observed from the dye pattern that the matrix adhered to an area of about 10 cm2 on the cheek and about 10 cm2 on the adjacent gum, and remained there for a period of 10-30 minutes.
~ ~3022~
Example 2 This example illustrates another formulation of a dosage form of this invention.
A molten mixture was prepared by the procedure described above having the following composition PEG 1000 J18 %
PEG 8000 3 %
Propylene glycol 5 %
Polyvinylpyrrolidone 33 ~
When tested by the procedure of Example 1, this formulation also was found to dissolve rapidly and to form a coating on the mucosa close to the site of application.
Example 3 A 10 g batch of the composition of Example 1 was prepared incorporating 20 mg of ~copolamineD The formulation was molded by injection molding to prepare a buccal dosage form containing 0.2 % of scopolamine useful for treating patients having motion sickness.
Example 4 A 10 g batch of the composition of Example 1 was prepared incorporating S % ~y weight of verapamil hydrochloride to prepare a buccal dosage form useful for treating cardiovascular conditions.
-~ ~3~2;~6~
Example 5 This example illustrates a buccal matrix composition of the invention.
By the general procedure outlined above a number of matrix formulations were prepared having the following c~mpositions:
A B C D
PEG 1000 71 ~ 60 ~ 60 % 61 ~
PEG 20, 000 11 ~ 15 ~ 20 ~ 22 %
PEO (MW 100,000) 18 % 25 3 20 ~ 17 %
In general all formulations exhibited satisfactory rates of erosion when us~d as buccal dosage forms.
A quantity of 20 mg of calcitonin was added to 10 9 of the molten composition A and a buc~al dosage form was prepared containing 0.2 ~ of calcitonin which was useful in treating patients with Paget's disease or other calcium deficiency syndromes.
A quantity of 10 mg of scopolamine was added to 10 9 of the molten composition A to for~ a pharmaceutîcal composition which was formed into a buccal dosage forms containing 0.1 %
scopolamine useful in treating patients having motion sickness.
Verapamil hydrochloride was mixed with the molten composition C in an amount equal to 5 % of the total composition, and the molten composition was molded into ~uccal dosage forms useful in treating patients having cardiac arrythmia or angina pectoris.
~ Z216~.
Verapamil (free base) was mixed with the molten compositi~n D in an amount equal to 10 % of the total composition. The composition was formed into buccal dosage forms useful for transmucosal administration of verapamil for treating cardiovascular conditions.
Examples 6 - 10 The examples illustrate dosage forms according to the invention incorporating other drugs.
An excipient composition is prepared haviny the composition of Example 5A. To separate portions of the composition are added amounts of the gonadotropin releasing hormone (~NRH), insulin, phenylephrine, desmopressin (DDAVP) and epinephrine to prepare pharmaceutical compositions containing effective amounts of each drug. Buccal dosage forms are prepared which are useful in treating patients in need of these drugs.
L3qll2~
15 -- ~
Example 11 This example illustrates the effect of varying proportions of polyethylene oxide on the buccal controlled release ~atrices of the invention.
By the general procedure outlined above a series of matrix formulations were prepared having the following aompositions A B C D
PEG 3350 49.0 % 48.0 % 4~.3 % 43.1 %
PEG 8000 19.6 % 19.4 % 18.6 % 17.2 %
PEG 20000 29.4 % 28.8 % ~7.7 % 25.9 %
PEO (MW 100,000)2.0 ~3.8 ~ 7.4 % 13.8 %
Formulations A and B exhibited good viscosity characteristics for mixing in a pharmaceutical compound:
formulation C was accepta~le; formulation D was difficult to US2 at 80C because it exhibited a relatively high viscosity and stringiness.
This example illustrates another buccal device of the invention.
A formulation was prepared by the general procedure described above having the following compositions PEG 3350 44.9 ~
PEG 8000 20.0 %
PEG 20000 30.0 %
PEO ~MW 100,000)5.0 %
Scopolamine HCl0.1 %
A buccal device was made from this composition which was useful in administration of scopolamine to patients suffering from mo~ion sickness.
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Example 13 This example illustrates another buccal matrix of this invention.
A formulation was prepared by the general procedure described above having the following cQmposition:
PEG 1000 S0.0 %
PEG 8000 24.9 %
PEO (MW S,000,000) 0.1 %
PVP (~W 30,000J20.0 ~
PVP (MW 90,000)5.0 %
This matrix was easy to mold but was somewhat hygroscopic.
Example 14 This example illustrate~ another buccal matrix of the invention.
A formulation was prepared by the general procedure described above having the following composition:
PEG 1000 24 %
PEG 1450 20 %
PEG 3350 10 %
PEG 8000 10 %
Propylene glycol3 %
PVP (MW 30,000)33 %
This composition yielded a solid matrix which rapidly dissolved in water but was ~omewhat hygroscopic.
~ 22~
Example 15 This example illustrates another buccal matrix of the invention.
A formulation was prepared by the general procedure described above having the following composition:
PEG 1000 18 ~
PEG 1450 38 %
PEG 8000 3 ~
Propylene glycol5 %
PVP (MW 30,000)33 %
Example_16 This example illustrates another buccal matrix of the invention.
A formulation was prepared by th2 general procedure described above having the following composition:
PEG 1450 10 ~
PEG 3350 58 %
PEG 8000 9 %
Propylene glycol 2 %
P~O (NW S,OOO,OOU) 1 .
~3~1~261 - 18 - i This example illustrates another buccal dosage form of the invention.
A formulation was prepared by ~he general procedure described above having the following composition:
PEG 3350 30.0 %
PEG 8000 64.8 %
PEO (MW 5,000,000) 5.0 %
Calcitonin 0.2 ~
This compo~ition exhibited excellent physical properties and could be easily molded into buccal dosage forms by in~ection molding.
~ his example illustrates another buccal matrix of the invention.
A formulation was prepared by the general procedure described above having the following composition:
PEG 1450 11.0 %
PEG 3350 25.4 ~
PEG 8000 60.6 %
PEO (MW 5~000,000~ 3.0 %
This formulation was used to prepare buccal dosage forms which dissolved slightly faster than those of ~xample 17.
L3~22/S~.
Example 19 This example illustrates a highly preferred buccal matrix of the invention.
A formulation was prepared by the general pr~cedure described above having the following com~osition:
PEG 1450 11.0 %
PEG 3350 25.0 ~
PEG 8000 5g.0 %
PEO (MW S,000,000) 5.0 %
Example 20 This exa~ple illustrates the preparation of dosage forms suitable for use as oral ~ontraceptives or post menopausal estrogen suppLements.
- A buccal dosage form matrix having the following composition is prepared by the procedure of ~xample 1.
PEG 1000 20 ~
PEG ~Hff~- 145~34 %
PEG 3350 8 %
PEG 8000 5 %
Propylene glycol 3 %
PVP (MW 30~000) 30 %
Into portions of this matrix are incorporated the following estrogens and progestins in the listed proportions A. 17-beta~estradiol 0O2 % by weight B. ethinylestradiol 0.02 % by weight ~3~2Z61 - 2~ -C. norethindrone2.0 % by weight D. ethinylestradiol 0~ 02 % by weight norethindrone2.0 % by weight E. 17-beta-estradiol 0.2 ~ ~y weight norethindrone 2.0 % by weight Formulation A through C are useful as components of a dosa~e regimen for contraception or estrogen supplement. Formulation D
is uitable for use as an oral contraceptive. Formulation E is suitable as a post-menopausal estrogen supplement.
Example 21 This exa~ple illustrates the superior bioavailability provided by transmucosal administration using the buccal dosage forms of this invention as compared with oral administration.
A buccal dosage form matrix baving the following composition was prepared by the procedure of Example 1.
PEG 1000 20 %
PEG 14S0 34 ~
PEG 3350 8 %
PEG B000 S %
Propylene glycol3 %
PVP (MW 30,000)30 %
Dosage forms were prepared from this matrix in the form of lozenges containing 192 micrograms of l~-beta-estradiol each.
The dosage forms were administered to a human volunteer by the buccal route (transmucosal absorption) and by the oral route (absorption from the gastrointestinal tract). Blood levels were ~0;22~
measured at various intervals after administration and the results for each method of administration are given below.
Oral administration Time af~er Plasma level administration ~minu~es) (micrograms/milliliter) o 10 ~
A~--~Ai~t~
Time after Plasma level administration (minutes) (micrograms/milliliter1 360 lE~
Inspection of the data reveals that the blood level attained via buccal ad~inistration is much greater than that attained by oral administration.
The invention having now been fully described, it should be understood that it may be embodied in other specific forms or variations without d~parting from its spirit or essential characteristics. Accordingly, the embodiments described above are to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the " ~L3~261 appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are intended to be embraced therein.
The desired c~mbination oP properties in the buccal dosage form of this invention is achieved by proper choice of the proportions of the three basic components of the matrix.
The first component of the buccal matrix of the invention i~
a low molecular weight polyethylene glycol (PEG) component which may be a single PEG or a mixture of low molecular weight PEG's.
For purposes of this invention, low molecular wei~ht P~G' 5 are those having a molecular weight not greater than about 4000 daltons. The proportion of low molecular weight PEG component may range from about 20 % t~ ab~ut 75 % by wei~ht of the matrix. The proportion of low molecular weight PEG component affects the rate at which the matrix is eroded by saliva and therefore the rate of release of the drug and the duration of its action. In general, greater amounts of low molecular weight PEG
component increase the rate of erosion. The relative amounts of the low molecular weight PEG component and the medium or high molecular weight co~ponent determine the melting point of the kuccal matrix of the inventlon. Mixtures of low molecular weight PEG's can be used to attain a desired average ~olecular weight and the desired effect on the properties of the matrix. A
preferred low molecular weight PEG component comprise~ a mixture of PEG 1000, PEG 1450 and PEG 3350, where the numbers signify the molecular weight as is conventionalO Another preferred low ~olecular weight PEG component ~omprises a mixture of PEG 1450 and PEG 3350.
æ26~L
The medium to high molecular weight polyethylene glycol component has a molecular weight in the range from about 6000 daltons to about 20,000-daltons, Its prop~rtion in the matrix may ran~e from about 2 % to about 65 % by weight. Greater amounts of the medium to high molecular weight comp~nent tend to increase the mel~ing point of the mixture, and favsr the noncrystalline character of the matrixO
The viscosity of the molten material should be low enough to provide for easy mixing of the active ingredient into the matrix and also for conforming to the final molded shape. This includes the ability to flow freely into thin layers when la~ellae or disks are to be prepared by casting, and the abili.ty to flow freely through the sprues of a multiple form injection mold.
The buccal dosage form matrix should also be non-hygroscopic for ease in handling the dosage forms and should have good mold-release properties to facilitate manufacture by injection molding.
The third ingredient of the buccal dosage matrix of the invention i~ a high molecular weight polymer introdùced to adiust the properties of the matrix, parti~ularly the melt v~scosity and the molding proper~ies of the molten matrix and the adhesion of the dosage form to the oral mucosa. The proportion of ~he third ingredient ranges from about 1 ~ to about 40 % by weight of the matrix. Suitable high molecular weight polymers include poly-vinylpyrrolidone tPVP), polyethylene oxide (PEO), poly(acrylic acid ) (PAA), sodium alginate and carboxymethyl cellulose.
Preferred high molecular weight polymers include polyvinylpyr-rolidone and polyethylene oxide. Both of these polymers provide the matrix with water activatea adhesive properties ~or good adhesion to the oral mucosa . They also influence the melt ~;, ~ viscosity of the molten matrixO The PEO used in the matrix may ~3~22~
have a molecular weight from about 100~000 to about 5,000,000 daltons. The PVP may have a molecular weight from about 30,000 to about 90,000 daltons.
In a preferred matrix of the invention the auxiliary polymeric ingr~dient is polyvinylpyrrolidone in a proportion of about 25 % to about 40 % by weight of the matxix. ~hi~ dosage form rapidly disintegrates and dissolves after being placed in the buccal pouch, in a period of about 60 seconds, leaving no noticeable residue, but rather a coating of the matrix ingredients which adhere to a relatively large area of the mucosa surrounding the site where the dosage form was placed. The presence of this thin coating is unnoticeable to the patient, but it continues to dispense the drug through the mucosa until such time as the drug is used up or the matrix dissolves in the mouth fluids. Thus, the drug is typically dispensed over a period of 10-30 minutes via transmucosal absorption directly into the bloodstream.
Additional ingredients in minor amounts may be incorporated into the buccal matrix of the invention to provide desirable physi~al properties or modify the properties of the matrix. For example, a plasticizer such as propylene glycol, may be added in amounts up to about 5 ~ by weight of the matrix.
The buccal dosage form of the invention is prepared by mixing the ingredients at a temperature such that the PEG's are molten and can serve as a solvent ~or the auxiliary high molecular weight polymeric ingredients, for any additional auxiliary ingredients and for the active pharmaceutical ingredient. In general~ the PEG's are melted and mixed in a vessel equipped with a stirrer and a heating device, ~uch as a heating mantle or steam jacket. Such melting usually occurs at about 60-80C and the viscosity and plasticity adjustin~
- - -2Z~
ingredients, e. 9., polyethylene oxide or polyvinylpyrrolidone, any auxiliary ingredients and the pharmaceutically active ingredient are added while stirring. After the blending is complete, buccal dosage forms are prepared by conventional procedures, such as cas~ing a thin layer of the composition on a flat surface, allowing it ~o harden and cutting the layer so prepared into dosage forms, or by injection molding.
Formulation of the compositions of the invention in the molten state has a number of advantages over the conventional method of formula~ion by mixing of powdered or granulated ingredients in the solid state. The mixing equipment needed for mixing of li~uid ingredients is generally simpler than that used for solid materials. The fact that the ingredients are actually dissolved in the matrix makes for more uniform distribution of the active ingredients in the composition and a more uniform rate of release as the dosage form dissolves in the oral cavity. The use of a molten matrix for formulating the romp~sition also permits the use of injection molding to prepare the dosage forms themselves.
Injection molding of pharmaceutical dosage forms has a number of advantages over conventional tabletting. Injection molding allows a greater uniformity in size and density, a greater range of shapes for the dosage forms, and a greater uniformity of distribution of the drug within the matrix.
Handling and metering of a molten matrix composition is also much simpler than for powdered or granulated compositions.
Any drug suitable for transmucosal administration may be incorporated into the buccal dosage form of this invention. Such drugs may include locally or systemically acting drugs, 5ut in most cases will be systemically acting drugs. The drugs may be selected from among any group ~herein a transmucosal ~0226~
g administration of the drug over a period ranging from a few minutes to several minutes is desired. The drug may be selected from among analgesic, anorexic, antiarthritic. antibacterial, an~ibiotic, anticonvulsan~, anti-depressant, antidiabetic, anti-fungal, antihistaminic, anti-hypertensive, anti-inflammatory, anti-neoplastic, antiparkinsonism, antipyretic, ~nticholinergic, anesthetic, antimicrobial, antiviral, anti-ulcer, bronchodilator, cardiovascular, contraceptive, central nervous system affecting, inotropic, vasodilator, vasoconstrictor, decongestant, diuretic, hypoglycemic, hormone, hypnotic, hematinic, electrolyte supplement, germicidal, muscle relaxant, parasympathetolytic, parasympathetomimetic, tranquilizer, ophthalmic, psychostimulant, vitamin, and the like drugs.
Preferred ~rugs for incorporation into the buccal dosage fotm of this invention include estrogens in general, e. 9.
estradiol and esters thereof such as the valerate ester, ethinylestradiol, progestins including norethindrin, gonadotropin releasing hormone (GNRH), human growth hormone, insulin, nicotin~, phenylephrine, desmopressin (DDA~P), oxytscin9 vasopressin, epinephrine, peptides useful in the treatment of patients with Paget's disease or other calcium deficiency ~yndromes, such as calcitonin and the like, ni~roqlycerin, isosorbide dinitrate, scopolamine, verapamil, oxymetazoline, tamoxifen and the like.
The proportion of active ingredient in the buccal dosage form of the invention will vary according to the potency of the drug and the needs of the patient, as will be understood by those skilled in the art. The active ingredient will generally comprise from about 0.01 percent by weight to about 10 percent by weight, typically 0.1 percent to 1 percent by weight, the remainder of the composition being the matrix. ~he concentration 22~;1 i of the drug in the composition will also vary with the size of the dosage ~orm prepared, since as will be understood by those skilled in the art, the amount of drug delivered in a single dose will depend on both the concentration of the drug in the matrix and the size of the buccal do~age form~
A particularly preferred buccal dosage form of the invention incorporates an estrogen, a progestin or preferably both, to prepare a dosage form useful as an oral contraceptive or a post-menopausal estrogen supplement. An oral contraceptive dosage form according to the invention will typically contain a progestin and an estrogen in amoun~s suitable for providing contraceptive activity. A typical contraceptive formulation will include 0.02 - 0.05 percent by weight of ethinylestradiol and 1.0 - 5.0 perc~nt by weight of norethindrone in a buccal matrix of the invention. A typical dosage form for post-menopausal estrogen supplement will contai~ 0.2 - 0.5 percent by weight of 17-beta-estradiol and 1.0 - 5.0 percent by weight of norethindrone in a buccal matrix of the invention.
The buccal dosage forms prepared from the composition of this invention may ha:ve any of the conventional shapes and sizes used for such dosage forms. For example a dosage form may be in the form of a lozenge, a lamella, a disk, a wafer, a tablet or the like. It should have dimensions which ~it conveniently into the buccal cavity or under the tongue. Suitable dimensions for the dosage form are a length of 5 to 10 mm, a width of 2 to 10 mm and a thickness of 0~2 to 3 mm. A preferred thickness is O.S to 1.5 mm. The total weight of the dosage form may be from about 10 to about 150 mg, preferably 50 to 100 mg.
; The invention will be illustrated by the following examples, which are not intended to be limiting. Parts and percentages in .~ ~30æ26~
the example6 are by weight unless otherwi~e specified.
Example 1 This example illustrates the preparation of a buccal dosage form of the invention.
A molten mixture was prepared by the procedur~ described above having ~he following composition PEG 1000 20 %
PEG 8000 3 %
Propylene glycol 3 Polyvinylpyrrolidone 33 ~
After the ingredients were melted together, the molten mixture was cast on a smooth flat surface and allowed to cool.
The film 50 formed was hard and somewhat flexible at room temperature. Dosage forms of a size to fit comfortably in the buccal pouch were cut from the film (about 1 cm x 3 cm). These lamellae dissolved rapidly when placed in the buccal pouch or sublingually.
Another dosage form was prepared by the same procedure except that a small amount of a dye was incorporated into the mat~ix. When the dosage form was placed in the buccal pouch, it dissolved in less than 60 seconds. ~owever~ it was observed from the dye pattern that the matrix adhered to an area of about 10 cm2 on the cheek and about 10 cm2 on the adjacent gum, and remained there for a period of 10-30 minutes.
~ ~3022~
Example 2 This example illustrates another formulation of a dosage form of this invention.
A molten mixture was prepared by the procedure described above having the following composition PEG 1000 J18 %
PEG 8000 3 %
Propylene glycol 5 %
Polyvinylpyrrolidone 33 ~
When tested by the procedure of Example 1, this formulation also was found to dissolve rapidly and to form a coating on the mucosa close to the site of application.
Example 3 A 10 g batch of the composition of Example 1 was prepared incorporating 20 mg of ~copolamineD The formulation was molded by injection molding to prepare a buccal dosage form containing 0.2 % of scopolamine useful for treating patients having motion sickness.
Example 4 A 10 g batch of the composition of Example 1 was prepared incorporating S % ~y weight of verapamil hydrochloride to prepare a buccal dosage form useful for treating cardiovascular conditions.
-~ ~3~2;~6~
Example 5 This example illustrates a buccal matrix composition of the invention.
By the general procedure outlined above a number of matrix formulations were prepared having the following c~mpositions:
A B C D
PEG 1000 71 ~ 60 ~ 60 % 61 ~
PEG 20, 000 11 ~ 15 ~ 20 ~ 22 %
PEO (MW 100,000) 18 % 25 3 20 ~ 17 %
In general all formulations exhibited satisfactory rates of erosion when us~d as buccal dosage forms.
A quantity of 20 mg of calcitonin was added to 10 9 of the molten composition A and a buc~al dosage form was prepared containing 0.2 ~ of calcitonin which was useful in treating patients with Paget's disease or other calcium deficiency syndromes.
A quantity of 10 mg of scopolamine was added to 10 9 of the molten composition A to for~ a pharmaceutîcal composition which was formed into a buccal dosage forms containing 0.1 %
scopolamine useful in treating patients having motion sickness.
Verapamil hydrochloride was mixed with the molten composition C in an amount equal to 5 % of the total composition, and the molten composition was molded into ~uccal dosage forms useful in treating patients having cardiac arrythmia or angina pectoris.
~ Z216~.
Verapamil (free base) was mixed with the molten compositi~n D in an amount equal to 10 % of the total composition. The composition was formed into buccal dosage forms useful for transmucosal administration of verapamil for treating cardiovascular conditions.
Examples 6 - 10 The examples illustrate dosage forms according to the invention incorporating other drugs.
An excipient composition is prepared haviny the composition of Example 5A. To separate portions of the composition are added amounts of the gonadotropin releasing hormone (~NRH), insulin, phenylephrine, desmopressin (DDAVP) and epinephrine to prepare pharmaceutical compositions containing effective amounts of each drug. Buccal dosage forms are prepared which are useful in treating patients in need of these drugs.
L3qll2~
15 -- ~
Example 11 This example illustrates the effect of varying proportions of polyethylene oxide on the buccal controlled release ~atrices of the invention.
By the general procedure outlined above a series of matrix formulations were prepared having the following aompositions A B C D
PEG 3350 49.0 % 48.0 % 4~.3 % 43.1 %
PEG 8000 19.6 % 19.4 % 18.6 % 17.2 %
PEG 20000 29.4 % 28.8 % ~7.7 % 25.9 %
PEO (MW 100,000)2.0 ~3.8 ~ 7.4 % 13.8 %
Formulations A and B exhibited good viscosity characteristics for mixing in a pharmaceutical compound:
formulation C was accepta~le; formulation D was difficult to US2 at 80C because it exhibited a relatively high viscosity and stringiness.
This example illustrates another buccal device of the invention.
A formulation was prepared by the general procedure described above having the following compositions PEG 3350 44.9 ~
PEG 8000 20.0 %
PEG 20000 30.0 %
PEO ~MW 100,000)5.0 %
Scopolamine HCl0.1 %
A buccal device was made from this composition which was useful in administration of scopolamine to patients suffering from mo~ion sickness.
- ~30~
Example 13 This example illustrates another buccal matrix of this invention.
A formulation was prepared by the general procedure described above having the following cQmposition:
PEG 1000 S0.0 %
PEG 8000 24.9 %
PEO (MW S,000,000) 0.1 %
PVP (~W 30,000J20.0 ~
PVP (MW 90,000)5.0 %
This matrix was easy to mold but was somewhat hygroscopic.
Example 14 This example illustrate~ another buccal matrix of the invention.
A formulation was prepared by the general procedure described above having the following composition:
PEG 1000 24 %
PEG 1450 20 %
PEG 3350 10 %
PEG 8000 10 %
Propylene glycol3 %
PVP (MW 30,000)33 %
This composition yielded a solid matrix which rapidly dissolved in water but was ~omewhat hygroscopic.
~ 22~
Example 15 This example illustrates another buccal matrix of the invention.
A formulation was prepared by the general procedure described above having the following composition:
PEG 1000 18 ~
PEG 1450 38 %
PEG 8000 3 ~
Propylene glycol5 %
PVP (MW 30,000)33 %
Example_16 This example illustrates another buccal matrix of the invention.
A formulation was prepared by th2 general procedure described above having the following composition:
PEG 1450 10 ~
PEG 3350 58 %
PEG 8000 9 %
Propylene glycol 2 %
P~O (NW S,OOO,OOU) 1 .
~3~1~261 - 18 - i This example illustrates another buccal dosage form of the invention.
A formulation was prepared by ~he general procedure described above having the following composition:
PEG 3350 30.0 %
PEG 8000 64.8 %
PEO (MW 5,000,000) 5.0 %
Calcitonin 0.2 ~
This compo~ition exhibited excellent physical properties and could be easily molded into buccal dosage forms by in~ection molding.
~ his example illustrates another buccal matrix of the invention.
A formulation was prepared by the general procedure described above having the following composition:
PEG 1450 11.0 %
PEG 3350 25.4 ~
PEG 8000 60.6 %
PEO (MW 5~000,000~ 3.0 %
This formulation was used to prepare buccal dosage forms which dissolved slightly faster than those of ~xample 17.
L3~22/S~.
Example 19 This example illustrates a highly preferred buccal matrix of the invention.
A formulation was prepared by the general pr~cedure described above having the following com~osition:
PEG 1450 11.0 %
PEG 3350 25.0 ~
PEG 8000 5g.0 %
PEO (MW S,000,000) 5.0 %
Example 20 This exa~ple illustrates the preparation of dosage forms suitable for use as oral ~ontraceptives or post menopausal estrogen suppLements.
- A buccal dosage form matrix having the following composition is prepared by the procedure of ~xample 1.
PEG 1000 20 ~
PEG ~Hff~- 145~34 %
PEG 3350 8 %
PEG 8000 5 %
Propylene glycol 3 %
PVP (MW 30~000) 30 %
Into portions of this matrix are incorporated the following estrogens and progestins in the listed proportions A. 17-beta~estradiol 0O2 % by weight B. ethinylestradiol 0.02 % by weight ~3~2Z61 - 2~ -C. norethindrone2.0 % by weight D. ethinylestradiol 0~ 02 % by weight norethindrone2.0 % by weight E. 17-beta-estradiol 0.2 ~ ~y weight norethindrone 2.0 % by weight Formulation A through C are useful as components of a dosa~e regimen for contraception or estrogen supplement. Formulation D
is uitable for use as an oral contraceptive. Formulation E is suitable as a post-menopausal estrogen supplement.
Example 21 This exa~ple illustrates the superior bioavailability provided by transmucosal administration using the buccal dosage forms of this invention as compared with oral administration.
A buccal dosage form matrix baving the following composition was prepared by the procedure of Example 1.
PEG 1000 20 %
PEG 14S0 34 ~
PEG 3350 8 %
PEG B000 S %
Propylene glycol3 %
PVP (MW 30,000)30 %
Dosage forms were prepared from this matrix in the form of lozenges containing 192 micrograms of l~-beta-estradiol each.
The dosage forms were administered to a human volunteer by the buccal route (transmucosal absorption) and by the oral route (absorption from the gastrointestinal tract). Blood levels were ~0;22~
measured at various intervals after administration and the results for each method of administration are given below.
Oral administration Time af~er Plasma level administration ~minu~es) (micrograms/milliliter) o 10 ~
A~--~Ai~t~
Time after Plasma level administration (minutes) (micrograms/milliliter1 360 lE~
Inspection of the data reveals that the blood level attained via buccal ad~inistration is much greater than that attained by oral administration.
The invention having now been fully described, it should be understood that it may be embodied in other specific forms or variations without d~parting from its spirit or essential characteristics. Accordingly, the embodiments described above are to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the " ~L3~261 appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are intended to be embraced therein.
Claims (91)
1. An injection moldable erodible composition suitable for use as a controlled release matrix for a bioactive compound comprising from about 20 to about 75 percent by weight of a polyethylene glycol component having a low molecular weight of from about 100 to about 4000, from about 2 to about 54 percent by weight of a polyethylene glycol component having a medium to high molecular weight of from about 6000 to about 20,000, and from about 1 to about 40 percent by weight of a polyethylene oxide having a high molecular weight of from about 100,000 to 5,000,000.
2. The composition of Claim 1 wherein said low molecular weight polyethylene glycol component is a mixture of low molecular weight polyethylene glycols.
3. The composition of Claim 2 wherein said mixture of low molecular weight polyethylene glycols comprises PEG 1000, PEG
1450 and PEG 3350.
1450 and PEG 3350.
4. The composition of Claim 1 wherein said low molecular weight polyethylene glycol component is present in a proportion of from about 355 to about 65% by weight of the total composition.
5. The composition of Claim 1 wherein said medium or high molecular weight polyethylene glycol component comprises PEG
8000.
8000.
6. The composition of Claim 1 wherein said medium or high molecular weight polyethylene glycol comprises PEG 20,0000
7. The composition of Claim 1 wherein said medium or high molecular weight component is a mixture of medium and high molecular weight polyethylene glycols.
8. The composition of Claim 7 wherein said mixture of medium and high molecular weight polyethylene glycols is a mixture of PEG 8000 and PEG 20,000.
9. The composition of Claim 1 wherein said polyethylene oxide has a molecular weight of about 100,000 and is present in an amount from about 2% to about 10% by weight.
10. The composition of Claim 1 additionally comprising a plasticizer.
11. The composition of Claim 10 wherein said plasticizer is propylene glycol.
12. The composition of Claim 10 wherein said plasticizer is present in a proportion of about 3 percent by weight.
13. A controlled release composition for a buccal dosage form comprising a pharmaceutical compound or a pharmaceutically acceptable salt or derivative thereof dispersed in a non-crystalline polymeric matrix comprising from about 20 to about 75 percent by weight of a polyethylene glycol component, having a low molecular weight of from about 100 to about 4000, from about 2 to about 54 percent by weight of a polyethylene glycol component, having a medium to high molecular weight of from about 6000 to about 20,000, and from about 1% to about 40% by weight of a polyethylene oxide having a high molecular weight of from about 100,000 to 5,000,000.
14. The composition of Claim 13 wherein said low molecular weight polyethylene glycol component is a mixture of low molecular weight polyethylene glycols.
15. The composition of Claim 14 wherein said mixture of low molecular weight polyethylene glycols comprises PEG 1000, PEG
1450 and PEG 3350.
1450 and PEG 3350.
16. The composition of Claim 13 wherein said low molecular weight polyethylene glycol component is present in a proportion of from about 35 % to about 65 % by weight of the total composition.
17 . The composition of Claim 13 wherein said medium or high molecular weight polyethylene glycol component comprises PEG
8000.
8000.
18. The composition of Claim 13 wherein said medium or high molecular weight polyethylene glycol comprises PEG 20,000.
19. The composition of Claim 13 wherein said medium or high molecular weight component is a mixture of medium and high molecular weight polyethylene glycols.
20. The composition of Claim 19 wherein said mixture of medium and high molecular weight polyethylene glycols is a mixture of PEG 8000 and PEG 20,000.
21. The composition of Claim 13 wherein said polyethylene oxide has a molecular weight of about 100,000 and is present in an amount from about 2% to about 10% by weight.
22. The composition of Claim 13 additionally comprising a plasticizer.
23. The composition of Claim 22 wherein said plasticizer is propylene glycol.
24. The composition of Claim 22 wherein said plasticizer is present in a proportion of about 3 percent by weight.
25. The composition of Claim 13 wherein said pharmaceutical compound is nitroglycerin.
26. The composition of Claim 13 wherein said pharmaceutical compound is scopolamine.
27. The composition of Claim 13 wherein said pharmaceutical compound is an estrogen.
28. The composition of Claim 27 wherein said estrogen is selected from the group consisting of 17-beta-estradiol and ethinylestradiol.
29. The composition of Claim 27 wherein said estrogen is present in proportion of from about 0.02 percent to about 0.05 percent by weight.
30. The composition of Claim 13 wherein said pharmaceutical compound is a progestin.
31. The composition of Claim 30 wherein said progestin is norethindrone.
32. The composition of Claim 30 wherein said progestin is present in a proportion of from about 1.0 percent to about 5.0 percent by weight.
33. The composition of Claim 13 wherein said pharmaceutical compound is a mixture of an estrogen and a progestin.
34. The composition of Claim 33 wherein said estrogen is present in a proportion of from about 0.02 percent to about 0.0 percent by weight and said progestin is present in a proportion of from about 1.0 percent to about 5.0 percent by weight.
35. The composition of Claim 33 wherein said estrogen is ethinylestradiol present in a proportion of about 0.02 percent by weight and said progestin is norethindrone present in a proportion of about 2.0 percent by weight.
36. The composition of Claim 33 wherein said estrogen is 17-beta-estradiol present in a proportion of about 0.2 percent by weight and said progestin is norethindrone present in a proportion of about 2.0 percent by weight.
37 . The composition of Claim 13 wherein said pharmaceutical compound is gonadotropin releasing hormone.
38 . The composition of Claim 13 wherein said pharmaceutical compound is human growth hormone.
39. The composition of Claim 13 wherein said pharmaceutical compound is insulin.
40. The composition of Claim 13 wherein said pharmaceutical compound is phenylephrine.
41. The composition of Claim 13 wherein said pharmaceutical compound is desmopressin.
42. The composition of Claim 13 wherein said pharmaceutical compound is oxytocin.
43. The composition of Claim 13 wherein said pharmaceutical compound is nicotine.
44. The composition of Claim 13 wherein said pharmaceutical compound is vasopressin.
45. The composition of Claim 13 wherein said pharmaceutical compound is verapamil.
46. The composition of Claim 13 wherein said pharmaceutical compound is isosorbide dinitrate.
47. The composition of Claim 12 wherein said pharmaceutical compound is oxymetazoline.
48. The composition of Claim 1 having the following composition PEG 1450 11.0% by weight PEG 3350 25.0% by weight PEG 8000 59.0% by weight PEO (MW 5,000,000) 5.0% by weight
49. An injection molded dosage form comprising a pharmaceutical compound or a pharmaceutically acceptable salt or derivative thereof dispersed in a non-crystalline polymeric matrix comprising from about 20 to about 75 percent by weight of a - polyethylene glycol component having a low molecular weight of from about 100 to about 4000, from about 2 to about 54 percent by weight of a polyethylene glycol component having a medium to high molecular weight of from about 6000 to about 20,000, and from about 1% to about 40% by weight of a polyethylene oxide having a high molecular weight of from about 100,000 to 5,000,000.
50. The dosage form of Claim 49 wherein said low molecular weight polyethylene glycol component is a mixture of low molecular weight polyethylene glycols.
51. The dosage form of Claim 50 wherein said mixture of low molecular weight polyethylene glycols comprises PEG 1000, PEG
1450 and PEG 3350.
1450 and PEG 3350.
52. The dosage form of Claim 49 wherein said low molecular weight polyethylene glycol component is present in a proportion of from about 35% to about 65% by weight of the total composition.
53. The dosage form of Claim 49 wherein said medium or high molecular weight polyethylene glycol component comprises PEG
8000.
8000.
54. The dosage form of Claim 49 wherein said medium or high molecular weight polyethylene glycol comprises PEG 20,0000.
55. The dosage form of Claim 49 wherein said medium or high molecular weight component is a mixture of medium and high molecular weight polyethylene glycols.
56. The dosage form of Claim 55 wherein said mixture of medium and high molecular weight polyethylene glycols is a mixture of PEG 8000 and PEG 20,000.
57. The dosage form of Claim 49 wherein said polyethylene oxide has a molecular weight of about 100,000 and is present in an amount from about 2% to about 10% by weight.
58. The dosage form of Claim 49 additionally comprising a plasticizer.
59. The dosage form of Claim 58 wherein said plasticizer is propylene glycol.
60. The dosage form of Claim 58 wherein said plasticizer is present in a proportion of about 3 percent by weight.
61. The dosage form of Claim 47 wherein said pharmaceutical compound is nitroglycerin.
62. The dosage form of Claim 49 wherein said pharmaceutical compound is scopolamine.
63. The dosage form of Claim 49 wherein said pharmaceutical compound is an estrogen.
64. The dosage form of Claim 63 wherein said estrogen is selected from the group consisting of 17-beta-estradiol and ethinylestradiol.
65. The dosage form of Claim 63 wherein said estrogen is present in proportion of from about 0.02 percent to about 0.05 percent by weight.
66. The dosage form of Claim 49 wherein said pharmaceutical compound is a progestin.
67. The dosage form of Claim 66 wherein said progestin is norethindrone.
68. The dosage form of Claim 66 wherein said progestin is present in a proportion of from about 1.0 percent to about 5.0 percent by weight.
69. The dosage form of Claim 49 wherein said pharmaceutical compound is a mixture of an estrogen and a progestin.
70. The dosage form of Claim 69 wherein said estrogen is present in a proportion of from about 0.02 percent to about 0.05 percent by weight and said progestin is present in a proportion of from about 1.0 percent to about 5.0percent by weight.
71. The dosage form of Claim 69 wherein said estrogen is ethinylestradiol present in a proportion of about 0.02 percent by weight and said progestin is norethindrone present in a proportion of about 2.0 percent by weight.
72. The dosage form of Claim 69 wherein said estrogen is 17-beta-estradiol present in a proportion of about 0.2 percent by weight and said progestin is norethindrone present in a proportion of about 2.0 percent by weight.
73. The dosage form of Claim 49 wherein said pharmaceutical compound is gonadotropin releasing hormone.
74. The dosage form of Claim 49 wherein said pharmaceutical compound is human growth hormone.
75. The dosage form of Claim 49 wherein said pharmaceutical compound is insulin.
76. The dosage form of Claim 49 wherein said pharmaceutical compound is phenylephrine.
77. The dosage form of Claim 49 wherein said pharmaceutical compound is desmopressin.
78. The dosage form of Claim 49 wherein said pharmaceutical compound is oxytocin.
79. The dosage form of Claim 49 wherein said pharmaceutical compound is vasopressin.
80. The dosage form of Claim 49 wherein said pharmaceutical compound is nicotine.
81. The dosage form of Claim 49 wherein said pharmaceutical compound is verapamil.
82. The dosage form of Claim 49 wherein said pharmaceutical compound is isosorbide dinitrate.
83. The dosage form of Claim 49 wherein said pharmaceutical compound is oxymetazoline.
84. The dosage form of Claim 49 having the following composition PEG 1450 11.0% by weight PEG 3350 25.0% by weight PEG 8000 59.0% by weight PEO (MW 5,000,000) 5.0% by weight
85. The dosage form of Claim 49 wherein said dosage form is a buccal dosage form.
86. The dosage form of Claim 49 wherein said dosage form is an oral dosage form.
87. The dosage form of Claim 49 wherein said dosage form is selected from the group consisting of a lozenge, a lamella, a disk, and a wafer.
88. The dosage form of Claim 49 wherein said dosage form is a buccal dosage form having a length of from about 5 mm to about 10 mm, a width of from about 2 mm to about 10 mm and a thickness of from about 0.2 mm to 3 mm.
89. The dosage form of Claim 88 wherein said thickness is from about 0.5 mm to about 1.5 mm.
90. The dosage form of Claim 49 wherein the total weight of said dosage is from about 10 mg to about 150 mg.
91. The dosage form of Claim 49 wherein the total weight of said dosage form is from about 50 mg to about 100 mg.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US06/827,615 US4764378A (en) | 1986-02-10 | 1986-02-10 | Buccal drug dosage form |
US827,615 | 1986-02-10 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1302261C true CA1302261C (en) | 1992-06-02 |
Family
ID=25249675
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000529319A Expired - Fee Related CA1302261C (en) | 1986-02-10 | 1987-02-09 | Buccal drug dosage form |
Country Status (8)
Country | Link |
---|---|
US (1) | US4764378A (en) |
EP (1) | EP0232877B1 (en) |
JP (1) | JPS62265235A (en) |
AT (1) | ATE68966T1 (en) |
CA (1) | CA1302261C (en) |
DE (1) | DE3774144D1 (en) |
ES (1) | ES2026469T3 (en) |
GR (1) | GR3003420T3 (en) |
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-
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- 1986-02-10 US US06/827,615 patent/US4764378A/en not_active Expired - Lifetime
-
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- 1987-02-09 EP EP87101727A patent/EP0232877B1/en not_active Expired
- 1987-02-09 ES ES198787101727T patent/ES2026469T3/en not_active Expired - Lifetime
- 1987-02-09 DE DE8787101727T patent/DE3774144D1/en not_active Expired - Lifetime
- 1987-02-09 AT AT87101727T patent/ATE68966T1/en not_active IP Right Cessation
- 1987-02-09 CA CA000529319A patent/CA1302261C/en not_active Expired - Fee Related
- 1987-02-10 JP JP62029481A patent/JPS62265235A/en active Pending
-
1991
- 1991-12-23 GR GR91402116T patent/GR3003420T3/en unknown
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EP0232877A2 (en) | 1987-08-19 |
JPS62265235A (en) | 1987-11-18 |
GR3003420T3 (en) | 1993-02-17 |
ES2026469T3 (en) | 1992-05-01 |
US4764378A (en) | 1988-08-16 |
EP0232877A3 (en) | 1987-12-02 |
DE3774144D1 (en) | 1991-12-05 |
EP0232877B1 (en) | 1991-10-30 |
ATE68966T1 (en) | 1991-11-15 |
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