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Gastroretentive Dosage Forms

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Title: Gastroretentive Dosage Forms


1
  • Gastroretentive Dosage Forms

2
Gastroretentive Dosage Forms
  • Oral administration is the most convenient mode
    of drug delivery and is associated with superior
    patient compliance as compared to other modes of
    drug intake.
  • However, oral administration has only limited use
    for important drugs, from various pharmacological
    categories, that have poor oral bioavailability
    due to incomplete absorption and/or degradation
    in the gastrointestinal (GI) tract.
  • Some of these drugs are characterized by a narrow
    absorption window (NAW) at the upper part of the
    gastrointestinal tract. This is because the
    proximal part of the small intestine exhibits
    extended absorption properties (including larger
    gaps between the tight junctions, and dense
    active transporters).

3
Gastroretentive Dosage Forms
  • Despite the extensive absorption properties of
    the duodenum and jejunum, the extent of
    absorption at these sites is limited because the
    passage through this region is rapid.
  • Enhancing the gastric residence time (GRT) of a
    NAW drug may significantly improve the net extent
    of its absorption.

4
Gastroretentive Dosage Forms
  • Extended release DDS possessing gastric retention
    properties may be potentially useful as the
    retention of oral dosage forms in the upper GIT
    causes prolonged contact time of drug with the GI
    mucosa, leading to
  • Higher bioavailability, and hence therapeutic
    efficacy
  • Reduced time intervals for drug administration
  • Potentially reduced dose size and thus improved
    patient compliance

5
Gastroretentive Dosage Forms
  • This issue was demonstrated in a seminal
    experiment by Levy (1976) that compared the
    bioavailability of riboflavin when taken with
    Coca Cola, light cola, or water. The GRT of
    riboflavin attained by the glucose together with
    phosphoric acid in the Coca Cola was considerably
    larger than that produced by phosphoric acid
    alone in the light cola, while the GRT following
    intake with water was the shortest. There was a
    direct correlation between the prolonged GRT and
    enhanced bioavailability.
  • To further increase the GRT of drugs, a
    gastroretentive dosage form (GRDF) can be
    developed.
  • It is quite complex to achieve extensive
    retention of the GRDF since the natural activity
    of the stomach is to evacuate its contents into
    the intestine.

6
Gastroretentive Dosage Forms
  • Drug Candidates for Gastric Retention
  • Gastroretentive DDSs exhibiting controlled drug
    release are significantly important for drugs
    which are
  • Acting locally in the stomach (e.g. antibiotics
    against Helicobacter Pylori, antacids and
    misoprostol)
  • Absorbed incompletely due to a relatively narrow
    window of absorption in the GIT, such as
    cyclosporin, ciprofloxacin, furosemide, L-DOPA,
    p-aminobenzoic acid and riboflavin.
  • Unstable in the intestinal or colonic environment
    such as captopril
  • Exhibit low solubility at high pH values such as
    verapamil HCl, diazepam and chlordiazepoxide

7
Gastroretentive Dosage Forms
  • Drug Candidates for Gastric Retention
  • Gastroretentive DDS, on the other hand, are not
    suitable for drugs
  • That may cause gastric lesions, e.g.,
    non-steroidal anti-inflammatory agents
  • Drug substances that are unstable in the strong
    acidic environment of the stomach.
  • In addition, gastroretentive systems do not offer
    significant advantages over conventional dosage
    forms for drugs which are absorbed throughout the
    gastrointestinal tract.

8
Approaches to Gastric Retention
  • The most important parameters affecting gastric
    emptying and, hence, the gastric retention time
    of oral dosage forms include
  • 1. Density, size and shape of the device.
  • 2. Concomitant ingestion of food and its nature,
    caloric content and frequency of intake.
  • 3. Simultaneous administration of drugs with
    impact on gastrointestinal transit time for
    example, drugs acting as anticholinergic agents
    (e.g. atropine, propantheline), opiates (e.g.
    codeine) and prokinetic agents (e.g.
    metoclopramide, cisapride).
  • 4. Biological factors such as gender, posture,
    age, sleep, body mass index, physical activity
    and disease states (e.g. diabetes, Crohn's
    disease).

9
Gastroretentive Dosage Forms
  • The main approaches that have been examined for
    gastroretentive drug delivery include
  • low density of the GRDF that causes buoyancy
    above gastric fluid
  • high density which retains the dosage form (DF)
    in the body of the stomach that is anatomically
    lower than the pyloric sphincter
  • concomitant administration of drugs or excipients
    which slow the motility of the gastrointestinal
    tract
  • bioadhesion to gastric mucosa
  • swelling to a large size which prevents emptying
    of the DF through the pyloric sphincter

10
Approaches to Gastric Retention
  • Controlled release (CR) dosage forms have been
    extensively used to improve therapy of many
    important medications. However, in the case of
    NAW drugs this pharmaceutical approach cannot be
    utilized since it requires sufficient colonic
    absorption of the drug (which is, by definition,
    not the case for NAW agents).
  • On the other hand, incorporation of the drug in a
    controlled release gastroretentive dosage forms
    (CR-GRDF) can yield significant therapeutic
    advantages due to a variety of pharmacokinetic
    (PK) and pharmacodynamic (PD) factors.

11
Pharmacokinetic Aspects
  • Absorption windowvalidation that the drug is
    within the category of NAW agents
  • Enhanced bioavailability
  • Enhanced first pass biotransformation
  • Improved bioavailability due to reduced
    P-glycoprotein (P-gp) activity in the duodenum
  • Reduced frequency of dosing
  • Targeted therapy for local ailments in the upper
    GI tract

12
Absorption windowvalidation that the drug is
within the category of NAW agents
  • Various experimental techniques permit us to
  • Verify the absorption properties of the tested
    molecule
  • To determine the mechanism of intestinal
    absorption
  • To elucidate the permeability at different
    regions of the GI tract.
  • In general, appropriate candidates for CR-GRDF
    are molecules that have poor colonic absorption
    but are characterized by better absorption
    properties at the upper parts of the GI tract.
  • In the case of absorption by active transporters
    that are capacity limited, the efficacy of the
    transport activity may increase following
    sustained presentation of the drug to the
    transporting enzymes in comparison to non-CR mode
    of administration (fear of saturation)

13
Enhanced bioavailability
  • Once it has been ascertained that the compound in
    question is defined as NAW, the possibility of
    improving bioavailability by continuous
    administration of the compound to the specific
    site should be tested.
  • For example certain bisphosphonates, including
    alendronate, are absorbed directly from the
    stomach. However, the magnitude of this pathway
    remains modest even in the case where the
    prolonged gastric retention of the bisphosphonate
    in rats is produced by experimental/surgical
    means.
  • On the other hand, the bioavailability of
    riboflavin and levodopa CR-GRDF is significantly
    enhanced in comparison to administration of
    non-GRDF CR polymeric formulations.

14
Enhanced bioavailability
  • It may be concluded that several different
    processes, related to absorption and transit of
    the drug in the gastrointestinal tract, act
    concomitantly and influence the magnitude of drug
    absorption.

15
Enhanced first pass biotransformation
  • In a similar fashion to increased efficacy of
    active transporters exhibiting capacity limited
    activity, the pre-systemic metabolism of the
    tested compound may be considerably increased
    when the drug is presented to the metabolic
    enzymes (cytochrome P450, in particular CYP3A4)
    in a sustained manner, rather than by a bolus
    input.

16
Improved bioavailability due to reduced
P-glycoprotein (P-gp) activity in the duodenum
  • In apparent contrast to the higher density of
    CYP3A4 at the upper part of the intestine, P-gp
    mRNA levels increase longitudinally along the
    intestine such that the highest levels are
    located in the colon.
  • Therefore, for drugs that are P-gp substrate and
    do not undergo oxidative metabolism, such as
    digoxin, CR-GRDF may elevate absorption compared
    to the immediate and CR dosage forms.

17
Reduced frequency of dosing
  • For drugs with relatively short biological
    half-life, sustained and slow input from CR-GRDF
    may result in a flip-flop pharmacokinetics and
    enable reduced dosing frequency.
  • This feature is associated with improved patient
    compliance, and thereby improves therapy

18
Targeted therapy for local ailments in the upper
GI tract
  • The prolonged and sustained administration of the
    drug from the GRDF to the stomach may be
    advantageous for local therapy in the stomach and
    the small intestine.
  • By this mode of administration, therapeutic drug
    concentrations may be attained locally while the
    systemic concentrations, following drug
    absorption and distribution, are minimal.

19
Pharmacodynamic aspects
  • Reduced fluctuations of drug concentration
  • Improved selectivity in receptor activation
  • Reduced counter-activity of the body
  • Extended time over critical (effective)
    concentration
  • Minimized adverse activity at the colon

20
Reduced fluctuations of drug concentration
  • Continuous input of the drug following CR-GRDF
    administration produces blood drug concentrations
    within a narrower range compared to the immediate
    release dosage forms.
  • Thus, fluctuations in drug effects are minimized
    and concentration dependent adverse effects that
    are associated with peak concentrations can be
    prevented.
  • This feature is of special importance for drugs
    with a narrow therapeutic index.

21
Improved selectivity in receptor activation
  • Minimization of fluctuations in drug
    concentration also makes it possible to obtain
    certain selectivity in the elicited
    pharmacological effect of drugs that activate
    different types of receptors at different
    concentrations.

22
Reduced counter-activity of the body
  • In many cases, the pharmacological response which
    intervenes with the natural physiologic processes
    provokes a rebound activity of the body that
    minimizes drug activity.
  • Slow input of the drug into the body was shown to
    minimize the counter activity leading to higher
    drug efficiency.

23
Extended time over critical (effective)
concentration
  • For certain drugs that have non-concentration
    dependent pharmacodynamics, such as beta-lactam
    antibiotics, the clinical response is not
    associated with peak concentration, but rather,
    with the duration of time over a critical
    therapeutic concentration.
  • The sustained mode of administration enables
    extension of the time over a critical
    concentration and thus enhances the
    pharmacological effects and improves the clinical
    outcomes.

24
Minimized adverse activity at the colon
  • Retention of the drug in the GRDF at the stomach
    minimizes the amount of drug that reaches the
    colon.
  • Thus, undesirable activities of the drug in colon
    may be prevented. This pharmacodynamic aspect
    provides the rationale for GRDF formulation for
    beta-lactam antibiotics that are absorbed only
    from the small intestine, and whose presence in
    the colon leads to development of microorganisms
    resistance.

25
Rationale
  • In most cases, due complexity of pharmacokinetic
    and pharmacodynamic parameters, in vivo studies
    are required to establish the optimal dosage form
    for a specific drug.
  • For a certain drug, interplay of its
    pharmacokinetic and pharmacodynamic parameters
    will determine the effectiveness and benefits of
    the CR-GRDF compared to the other dosage forms.

26
Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug
  • Metformin is glucose-lowering agent that is
    widely used for management of type 2 diabetes.
  • Metformin is absorbed mainly in the upper parts
    of the gastrointestinal tract and due to the fact
    that metformin molecule is ionized at physiologic
    pH, has tendency to adsorb to the intestinal
    epithelium thus affecting the drug absorption
    pattern and increasing the incidence of
    gastrointestinal adverse effects.
  • In addition to these unique pharmacokinetic
    properties, the pharmacodynamics of metformin is
    rather complex and does not follow a direct
    relationship between plasma drug concentration
    and magnitude of effect.

27
Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug
  • Previous studies confirmed that the colonic
    absorption of metformin is poor and produced poor
    and inconsistent glucose-lowering effects.
  • On the other hand, it was determined that most of
    the metformin absorption occurs in the upper
    parts of the gastrointestinal tract.
  • This fact, together with the findings that major
    sites of metformin action are located in the
    gastrointestinal tract and the liver, provides a
    clear rationale for a sustained and prolonged
    release of this drug from a CR-GRDF into the
    stomach and duodenum, since absorption from these
    sites would result in continuous input of
    metformin to the sites of action.

28
Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug
  • Two controlled release matrix based tablet
    formulations with different rates of metformin
    release in vitro were used CR tablets I (matrix
    tablets) and CR tablets II (matrix tablets with
    ethylcellulose coating).
  • The in vitro rate of drug release was assessed
    according to method stated in the USP
    Pharmacopoeia.

29
Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug
  • To enable simultaneous PK and PD assessment in
    vivo, streptozotocin-diabetic rats (male,
    200250 g, n56) received different modes of
    metformin administration in a crossover design.
  • The studied modes were CR tablets I or II at a
    dosage corresponding to 450 mg/kg metformin, or
    the same dose of the drug administered as a bolus
    oral solution or a constant rate intraduodenal
    infusion (duration of the infusion was 4 h).
  • Serial blood samples were collected from the tail
    artery and assayed for glucose and metformin.

30
Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug
  • The gastric retention of the tablets was assessed
    radiographically in a separate study applying
    radiopaque markers added to the tablet
    formulation.

31
Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug
  • The preclinical model of the diabetic rat used in
    this work enabled simultaneous assessment of the
    PK and PD outcomes following administration of
    different dosage forms of metformin, and
    determination of the possible advantages of GRDF
    for this drug.

32
Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug
  • The metformin blood concentrations versus time
    (PK data) and the glucose lowering effects (PD
    data) obtained for various modes of drug
    administration were determined.
  • No significant differences in the bioavailability
    and the extent of the glucose-lowering effect
    were found following administration of the GRDF,
    bolus oral administration, or slow infusion of
    metformin to the duodenum.

33
Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug
  • Plasma metformin concentrations following
    administration of metformin (450 mg kg-1) as PO
    bolus, duodenal infusion, and gastroretentive CR
    tablets (CR I or CR II) to the streptozotocin-diab
    etic rats

34
Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug
  • Glucose-lowering effects following administration
    of metformin (450 mg kg-1) as PO bolus, duodenal
    infusion, and gastroretentive CR tablets (CR I or
    CR II) to the streptozotocin-diabetic rats

35
Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug
  • The underlying reason for these PK and PD
    outcomes for the GRDF of metformin is apparently
    the high affinity of the drug to the negatively
    charged intestinal wall.
  • Due to the basic properties of the biguanide
    molecule (positive charge), it adsorbs to the
    intestinal wall, producing a natural sustained
    release system.
  • The adsorbed metformin is released from the
    intestinal wall in a sustained manner, producing
    a drug absorption profile similar to that of the
    CR formulation.
  • As a result, the pharmaceutical manipulations
    that modify the release rate do not seem to
    improve the extent of metformin absorption and
    the magnitude of glucose-lowering effect.

36
Assessment of PKPD rationale for CR-GRDF
formulations in a rat model metformin as a model
drug
  • Thus, due to this natural sustained release
    property, CR-GRDF of metformin does not seem to
    offer PK or PD advantages over immediate release
    formulations. This work demonstrates the need for
    a combined PK and PD assessment in vivo to
    determine whether a certain drug is a proper
    candidate for GRDF.

37
Formulation Technologies
  • The main approaches to prolonging the gastric
    residence time of pharmaceutical dosage forms
    include
  • bioadhesive delivery systems, which adhere to
    mucosal surfaces
  • devices that rapidly increase in size once they
    are in the stomach to retard the passage through
    the pylorus
  • density-controlled delivery systems, which float
    on or settles in gastric fluids.

38
Bioadhesive drug delivery systems
  • It involves the use of bioadhesive polymers that
    can adhere to the epithelial surface of the GIT.
  • A bioadhesive can be defined as a substance with
    the ability to interact with biological materials
    and is capable of being retained on the
    biological substrate for a period of time.

39
Bioadhesive drug delivery systems
  • Bioadhesive polymers are usually macromolecular,
    hydrophilic gelling substances with numerous
    hydrogen-bond forming groups (carboxyl, hydroxyl,
    amide and sulfate groups)
  • crosslinked polyacrylic acids, sodium
    carboxymethyl cellulose (CMC), sodium alginate
    and carrageenan.
  • Anionic polymers have been found to have better
    binding capacity than neutral or cationic
    polymers.

40
Bioadhesive drug delivery systems
  • The proposed mechanism of bioadhesion is the
    formation of hydrogen and electrostatic bonding
    at the mucus-polymer boundary.
  • Rapid hydration in contact with the
    muco-epithelial surface appears to favor adhesion.

41
Bioadhesive drug delivery systems
  • microspheres consisting of a drug and Carbopol
    934P dispersed within a waxy matrix of
    polyglycerol esters of fatty acids were proposed
    as muco-adhesive delivery system.
  • These systems were found to adhere to the stomach
    mucosa in rats and to prolong the drug's
    gastrointestinal residence time after oral
    administration.

42
Bioadhesive drug delivery systems
Carbopol General Formula
Carbopol 934 P is cross-linked with allyl sucrose
Polyglycerol
43
Bioadhesive drug delivery systems
  • The adherence can be attributed to the hydration
    and swelling of Carbopol in the microspheres upon
    contact with water.
  • Importantly, parts of the macromolecules remain
    within the microspheres, whereas the rest is
    anchored within the mucus layer.
  • When furosemide was administered to rats, and
    riboflavin to human volunteers, with the use of
    microspheres, enhanced levels in plasma were
    observed compared with the administration of
    furosemide or riboflavin suspensions.

44
Bioadhesive drug delivery systems
  • Extended gastric residence times of the
    positively charged ion-exchange resin
    cholestyraminedue to adhering to and coating of
    the gastric mucosa.
  • On the other hand, the oppositely charged
    exchange resin Amberlite IRP-69 did not possess
    the same characteristics

45
Bioadhesive drug delivery systems
  • The major challenge for bioadhesive drug delivery
    systems is the high turnover rate of the gastric
    mucus and the resulting limited retention times.
  • Furthermore, it is difficult to target
    specifically the gastric mucus with bioadhesive
    polymers.
  • Most bioadhesive polymers (Polycarbophil,
    Carbopol and chitosan) will stick to various
    other surfaces that they come into contact with.
    In addition, the possibility of oesophageal
    binding might present a challenge regarding
    safety aspects.

46
Size-increasing drug delivery systems
  • Another approach to retaining a pharmaceutical
    dosage form in the stomach is by increasing its
    size above the diameter of the pylorus .
  • However, owing to significant inter-individual
    variations, the cut-off size cannot be determined
    exactly.
  • Roughly, the dosage forms should be larger than
    13 mm, but even bigger units have been found to
    be emptied from the stomach.

47
Size-increasing drug delivery systems
  • In order to facilitate swallowing, it is highly
    desirable to design dosage forms with an
    initially small size that once in the stomach
    significantly increase in size.
  • The expanded state should be achieved rapidly in
    order to prevent premature emptying through the
    pylorus.
  • Conversely, the systems should also guarantee
    their clearance from the stomach after
    predetermined time intervals to avoid
    accumulation upon multiple administrations.
  • In addition, the dosage form should have no
    effect on gastric motility or emptying process.

48
Size-increasing drug delivery systems
  • The increase in the systems size can be based on
    several principles, including
  • Expansion due to swellable excipients in the
    stomach.
  • The expansion of this type of DDS is generally
    due to the presence of specific hydrogel formers,
    which after swallowing drastically increase in
    size upon contact with aqueous media.
  • unfolding and/ or shape modification (to complex
    geometric shapes) in the stomach.
  • These are non disintegrating geometric shapes
    moulded from silastic elastomer or extruded from
    polyethylene blends, which extend the gastric
    residence time depending on size, shape and
    flexural modulus of the drug delivery device

49
Size-increasing drug delivery systems
  • Deshpande et al. (Deshpande et al., 1997a
    Deshpande et al., 1997b) developed a
    controlled-release gastric retention system
    composed of
  • a swellable core, which consisted of the drug,
    chlorphenamine maleate or riboflavin 5'
    phosphate, and the expanding agents crosslinked
    polyvinyl pyrrolidone (PVP), Carbopol 934P and
    calcium carbonate.
  • The tablet core was coated with a permeable
    coating, consisting of blends of Eudragit RL 30
    D and NE 30 D in different ratios.
  • The tablets swelled to 2- 4 times their original
    volume, while releasing the drug in a controlled
    manner.
  • The optimal ratio of Eudragit RL 30 D NE 30 D
    was found to be 70 30, which was optimum for
    sufficient elasticity to withstand the pressure
    of expansion during the initial swelling phase,
    and allowing the breakdown of the tablet
    following release of the drug.

50
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51
Size-increasing drug delivery systems
  • Enzyme-digestible hydrogels, consisting of
    poly(vinyl pyrrolidone) cross-linked with
    albumin, were described as gastroretentive dosage
    form.
  • These specially designed hydrogels swell to a
    significant extent, which is a function of the
    albumin content and degree of albumin alkylation.
    The polymers are degraded in the presence of
    pepsin either via bulk or surface erosion.
  • With increasing albumin alkylation, pepsin
    digestion is diminished and bulk erosion becomes
    predominant.

52
Size-increasing drug delivery systems
  • In dogs, the gastric residence time exceeded
    24 h, even under fasted conditions. Such an
    enzyme-digestible swelling hydrogel formulation
    was used to deliver riboflavin to the upper small
    intestine of these animals. Importantly, the drug
    could be detected for up to 54 h after
    administration in the blood, indicating gastric
    retention of the hydrogel in the stomach.

53
Size-increasing drug delivery systems
  • Omidian et al. (Omidian et al., 2005 Omidian et
    al., 2006) developed superporous hydrogel
    hybrids, which are prepared by crosslinking a
    water-soluble or water-dispersible polymer to the
    formed superporous hydrogel.
  • Examples for hybrid agents are polysaccharides,
    such as sodium alginate, pectin, chitosan or
    synthetic water-soluble hydrophilic polymers,
    e.g. poly(vinyl alcohol).
  • Gröning et al (Gröning et al., 2007 Groning et
    al., 2006) developed gastroretentive dosage forms
    prepared from compressed collagen sponges.
  • The sponges were manufactured by freeze-drying a
    riboflavin-containing collagen solution. The
    precompressed collagen was transported into a
    tablet machine for tablet compression.
  • Following contact with aqueous fluids, the
    collagen sponge expanded to a large size. Both
    systems released the drug in a controlled manner.

54
Size-increasing drug delivery systems
55
Size-increasing drug delivery systems
  • Schematic presentation of the gastroretentive
    drug delivery system multilayer polymeric films
    consisting of (a)shielding (outer) layers (b)
    rigid (frame) strips (c) polymer-drug matrix
    and (d) anti-adhering layers (microcrystalline
    cellulose).

56
Size-increasing drug delivery systems
  • Effects of the mode of administration of 100 mg
    riboflavin-5-phosphate on the resulting (a) mean
    riboflavin plasma concentration and (b)
    cumulative amount of riboflavin absorbed in dogs
    (n6). DF, dosage form GRDF, gastroretentive
    dosage form.

57
Size-increasing drug delivery systems
  • In general, size-increasing drug delivery systems
    potentially present the hazard of permanent
    retention in the stomach and could lead to
    life-threatening effects upon multiple
    administration.
  • To avoid this risk, the systems should consist of
    biodegradable materials or have the ability to
    lose their integrity after a desired time
    period. However, the systems also need to be
    sufficiently resistant in order to withstand the
    powerful mechanical contractions within the
    stomach.
  • A major advantage of size-increasing systems is
    the independence of their performance on the
    filling state of the stomach.

58
Floating drug delivery systems
  • Drug delivery systems that float immediately upon
    contact with gastric fluids present promising
    approaches for increasing the bioavailability of
    drugs with absorption windows in the upper small
    intestine.
  • However, immediate floating can only be achieved
    if the density of the device is low at the very
    beginning.
  • Devices with an initially high density (which
    decreases with time) first settle down in the
    stomach and, thus, undergo the risk of premature
    emptying.
  • Inherent low density can, for example, be
    provided by the entrapment of air (e.g. hollow
    chambers) or by the (additional) incorporation of
    low-density materials (e.g. fatty substances or
    oils, or foam powder).

59
Floating drug delivery systems
60
High density drug delivery systems
  • These devices use their weight as a retention
    mechanism.
  • When the density of the system is larger than
    that of the gastric juice (1.004 g/cm³), the
    device settles down to the bottom of the stomach,
    and remains located below the pylorus.
  • This could be accomplished by including a heavy
    inert material such as zinc oxide, titanium
    dioxide, iron powder or barium sulphate into the
    drug containing core pellets or coating drug
    containing pellets with it.
  • These materials increase density by up to 1.52.4
    g/cm3

61
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
  • Levodopa, a NAW drug that is absorbed solely via
    a specific transporter in the small intestine, is
    used for the treatment of Parkinsons disease.
  • Sustained levodopa blood concentrations following
    continuous levodopa administration or
    administration of CR dosage forms provide a clear
    clinical advantage compared to conventional oral
    dosage forms in terms of improved pharmacological
    efficacy and reduced wearing off effect at the
    end of dose interval.

62
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
  • Based on the pharmacokinetic and pharmacodynamic
    properties of levodopa it is expected that a
    CR-GRDF would optimize the therapy for this drug.
  • After oral administration, such a CR-GRDF would
    be retained in the stomach and would release the
    drug there in a controlled and sustained manner,
    providing continuous supply of the drug to its
    absorption sites in the small intestine, and
    yielding a sustained and prolonged levodopa input
    to the systemic blood circulation

63
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
  • The CR-GRDFs were comprised of an inner layer
    composed of a polymerdrug matrix framed with
    rigid polymeric strips covered on both sides by
    two outer (shielding) layers.
  • The CR-GRDFs were folded before insertion into
    gelatin capsules (000). The dimensions, prior to
    folding, of the CR-GRDF (and of the shielding
    layers) were 5 cm2.5 cm.
  • Several types of the CR-GRDFs were prepared with
    different thickness and amount of levodopa
    compounded (CR-GRDF AC).

64
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
  • Novel unfolding CR-GRDFs of levodopa that were
    characterized by extended geometrical dimensions
    with enhanced rigidity were developed.

65
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
66
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
  • The in vitro release rate of levodopa from the
    DFs into simulated gastric fluid was conducted
    according to the method described in the USP
    Pharmacopoeia.

67
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
  • The absorption of levodopa following intragastric
    administration of the GRDFs was studied in Beagle
    dogs in a crossover design in comparison to the
    CR dosage form and drug solution.
  • Serial blood samples were collected, plasma was
    obtained and assayed for levodopa.
  • The anatomical location of the CR-GRDFs in the
    gastrointestinal tract was accomplished
    radiographically by incorporating the radiopaque
    threads in the dosage form.
  • The unfolding of the GRDFs was studied applying
    gastroscopic equipment.

68
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
  • The results of the in vitro drug release test
    showed that the CR-GRDFs released levodopa in a
    controlled manner. Levodopa release rate showed
    an inverse correlation to the ethylcellulose
    membrane thickness, and different types of the
    GRDFs were characterized by different release
    rates.

69
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
  • The in-vitro release kinetics of levodopa into
    acidic buffer (pH 1.2) from controlled release
    (CR) gastroretentive dosage forms (GRDFs) with
    different thicknesses of the drug-loaded
    polymeric matrix or non-gastroretentive
    CR-particles.

70
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
  • Levodopa release rate showed an inverse
    correlation to the ethylcelluloselevodopa
    membrane thickness.

71
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
  • Effect of the mode of levodopa administration on
    the plasma concentrations in beagle dogs (n6,
    meanS.E.M.) (a) different types of controlled
    release (CR) gastroretentive dosage forms
    (GRDFs) (b) CR-GRDF C in comparison to the two
    control modes of administration (oral solution
    and CR-particles).

72
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
  • As can be seen, while CR-GRDF A produced too low
    a concentration and CR-GRDF B had a short
    absorption phase, CR-GRDF C produced elevated
    levodopa concentrations (gt500 ng ml) for more
    than 9 h after drug administration.
  • This outcome is considerably different from the
    short-lasting elevation of levodopa
    concentrations produced by the non-gastroretentive
    oral modes of administration.

73
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
  • Effect of the mode of levodopa administration on
    the mean cumulative amount of drug absorbed over
    time in beagle dogs (n6) (a) different types of
    controlled release (CR) gastroretentive dosage
    forms (GRDFs) (b) CR-GRDF C in comparison to the
    two control modes of administration (oral
    solution and CR-particles).

74
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
  • As seen, the absorption from CR-GRDF A and
    CR-GRDF B terminated in less than 6 h.
  • In the cases of oral solution and CR-particles
    administration, the absorption process lasted for
    about 2 and 3 h, respectively.
  • The apparent rates of absorption for CR-particles
    and CR-GRDF C during the first few hours were
    slower than the absorption rate obtained
    following administration of the drug as an oral
    solution.

75
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
  • MDTs following administration of CR-GRDF A,
    CR-GRDF B and CR-GRDF C were 2.690.3, 1.20.07
    and 4.170.33 h, respectively.
  • A correlation between the percent levodopa
    released (in-vitro) and the percent levodopa
    absorbed can be made.
  • It can be seen that this relationship is similar
    for all the CR-GRDF types.

76
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
  • In-vitro in-vivo correlation presented as mean
    percent levodopa absorbed versus mean percent
    levodopa released of various controlled release
    (CR) gastroretentive dosage forms (GRDFs).

77
Evaluation of novel CR-GRDF formulation of
levodopa in dogs
  • Results of this investigation confirm that a
    combination of extended physical dimensions with
    compounding rigid constituents enhances the
    gastroretentivity of DFs in vivo.
  • Multilayer polymeric GRDFs with size5 cm2.1 cm
    that were characterized by high rigidity retained
    in the human stomach for more than 5 h.
  • On the other hand, the formulation with extended
    dimensions but lacking high rigidity did not
    retain in the stomach like the equivalent size
    GRDFs.
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