Biopharmaceutics of Non Oral Medications

1. Biopharmaceutics of Non Oral Medications Possible routes of drug administration are divided into two classes : 1- Enteral 2- Parenteral Enteral include , Sublingual or buccal, oral and rectal administration . Parenteral routes include, I.V, I.M, Subutaneous injections and topical application to the eyes or certain mucous membrane.

2. Skin and dermatological preparation Dermatological preparation are those which intended to act locally in the treatment of skin disorders. It is applied to the skin for systemic absorption to decrease some side effect of drugs such as topical application of glucocorticoids dramatically decrease their side effects. Anti- inflammatory drugs that have irritant effect on the stomach mucosa can be used topically on the skin for systemic absorption with decreasing its side effect .

3. Anatomy of Human Skin 1- Epidermis 2- Dermis 3- subcutaneous Fat The most superfacial layer of epidermis is the stratum corneum which is composed of several layers of dead keratinized cells. The Dermis or true skin is highly vascular region Drugs penetrating to this region are likely to reach the systemic circulation .

4. Per cutaneous Absorption Route of penetration: The molecules move from the environment to the intact skin of the living person through : -- folecular region Sweat glands Unbroken stratum corneum between these appendages . Hair follicles play a distinguished part in the penetration of particular substances. It found that absorption of hydrocortisone is rapid in region with large or numerous hair follicles ,as in scalp and forehead. Absorption is decreased in in some region of skin having thickened stratum corneum e.g. the foot.

5. Cuts ,diaper rash , inflammation, mild burns or any other condition in which the stratum corneum is injured promotes the absorption of drugs through the skin. Factors affecting the skin penetration : 1- Physicochemical properties of the drug. 2- Vehicle, PH and concentration. 3- Different physiological variation . Among these variables are : a- Condition of skin ,intact or injured. b- skin age c- The area of skin treated . d- The thickness of skin barrier phase. e- Species variation F- Hydration state of skin

6. Chemical form of drug and the vehicle in which the drug is incorporated can have an important influence on percutaneous absorption . • Example the efficacy of flucinoloneacetonidein inflammatory dermatosis (eczema and psoriasis Strongly depend on the vehicle . Cream containing 0.1% of hydrocortisone is more effective than several other commercial formulation containing 1% hydrocortisone . The percutaneous absorption of betamethzone 17-benzoate is more greater from gel than from cream.

7. Incorporation of certain chemicals ,such as DMSO (dimethylsulfoxide ) into topical formulation has been advocated to enhance penetration and percutaneous absorption of drugs . • Possibly by producing structural change of the skin ,such as swelling of stratum corneum . • Possibly by replacement of water as the continuous membrane phase of the skin barrier. • Absorption of hydrocortisone is increased during repeated administration whether it was applied in an acetone vehicle or an emulsion ointment base. • Long term aplication of hydrocortisone may alter the percutaneous barrier ,resulting in inhanced penetration.

8. Hexachlorophane and gama benzene hexachloride are absorbed from the skin. • The topical application of drugs intended for systemic absorption may be useful for : • 1- Drugs with low bioavailability after oral administration due to first pass effect. • 2- It may be useful for short acting drugs since percutaneous absorption tend to be slow and prolonged effect may be realized. • E.g. nitroglycerin ointment has longer duration of action when compared with sublingual one , it can be used as prophylactic in certain cases of angina . Ointment has slower onset of action than buccal medication so it is not used for acute attack .Nitroglycerin ointment is available in 0.2% strength in lanoline petrolatum base.

9. Rectal Administration • Suppositories are more frequently used in children than in adult. • Rectal administration of drugs intended for systemic effect is usually limited to those situation in which oral administration is difficult or contraindicated. There are many drugs that can be administered by this route ,e.g,aspirin ,acetaminophen, theophyllin, chlorpromazine ,promethazine,indomethacin and certain barbiturates. The drug absorption from rectum is often slow ,as rectum is devoid from villi and has a relatively small surface area but rectum has a good blood supply.

10. The following are general principles with respect to drug absorption following rectal administration to human: • 1- Absorption from rectum is more rapid and efficient when drugs are given in solution form(microenema ) than in suppository form . • 2- Absorption is more variable when drugs are administered in solution form rectally than orally. • 3- the presence of fecal matter in rectum retards absorption .so absorption is more rapid and efficient if a cleansing enema preceds drug administration.

11. 4- Some suppository base ,such as PEG are irritant to human rectum and to promote defecation and loss of drug. • 5- Bioavailability from suppositories may be poor because the drug is not released or is slowly released . • The extent of absorption of theophyllin after rectal administration of aqueous solution of drug was about 90% that found after oral administration. • Attempts to develop rectal dosage forms of tetracyclin and penicillin G have been unsuccessful because of poor absorption of these drugs across rectal mucosa .

12. The extent of absorption of rectal solution of antibiotic lincomycin in children and adults was only 50% that observed after oral administration of a syrup of a drug and was more variable., and only about one third that found with capsule given orally. • Rectal suppositories of acetaminophen produce an antipyretic effect almost equal to an oral elixir in febrile children ,ranging in age from 3 months to 6 years . • The absorption of non steroidal anti- inflammatory and analgesic drug naproxin after rectal suppositories • Is rapid and complete as after commercial oral tablets. • Indomethacin given orally as capsules or rectally as suppositories are equally effective in relieving morning symptoms inpatient with rheumatoid arthiritis.

13. It was found that bioavailability of diazepam from rectal suppositories is better than from I.V. injection and absorption of it from rectal solutions is far better than from suppositories, and the rate of absorption of drug from rectal solution is greater than from oral tablets . • So rectal solution of diazepam may be a suitable alternative to I.V. injection of convulsive disorders in young children.

14. Rectal suppositories of oxymorphone has been compared with I.V. injection of the drug in patients with postoperative pain ,rectal administration resulted in lower and delayed peak of analgesia and a slightly longer duration of effect than I.M injection. Rectal oxymorphone was found to be one tenth as potent as I.M.form. However since I.M oxymorphone is 9 to 10 times as potent as morphine 5 to 10 mg of oxymorphone by suppositories may be as effective as the usual injected doses of narcotic analgesics.

15. Rectal administration of analgesic meptazinol in healthy subjects resulted in more rapid and complete absorption than after oral administration . • The more rapid absorption may be the result of avoiding the gastric emptying seen after oral administration of the drug . The more complete absorption suggests that at least part of the rectal dose was absorbed directly into systemic circulation and not subject to pre systemic hepatic metabolism. • The mean bioavailability of lidocaine was considerably higher after rectal than after oral administration. This is due to the fact that about half of the rectal dose by passes the liver during absorption.

16. Intranasal Application • There is interest in the intranasal route for the systemic administration of drugs as: • 1- the nasal mucosa appear to be more permeable to drugs than the GIT mucosa . • 2- No local metabolism is known. • 3- dugs absorbed through the nasal mucosa go directly to blood stream and are not subject to first pass hepatic metabolism.

17. E.G. propranolol, Nitroglycerin(NTG). • NTG is rapidly absorbed when given intranasally ,it provide a safe , simple and effective method to attenuate the hypertensive response to laryngoscopy and tracheal intubation. • Factors Affecting absorption of the drug from the nasal mucosa: • 1- Lipid solubility of the drug . • 2- Molecular weight of the drug . • 3- Effect on the movement of the nasal cilia .

18. Posterior pituitary hormones and other related compounds such as oxytocin and desmopressin . Oxytocinis available as a nasal solution to stimulate lactation . • Desmopressin is a synthetic polypeptide , its acetate salt nasal solution is indicated for the prevention or control of polydipsia , polyuria and dehydration associated with diabetes insipidus caused by insufficient antidiuretic hormone.

19. Intranasal administration of buserelin in the treatment of patients with metastatic prostatic cancer was used in the form of a nasal spray delivering 100 ug of drug per inhalation . • Intranasal buserelin is an effective ,simple and safe way to achieve androgen deprivation in the treatment of advanced prostatic cancer . This treatment neither causes the psychological problems of castration nor is associated with morbidity of estrogen administration . • Nasal spray of this drug is more acceptable to patients than daily subcutaneous injection

20. The nasal absorption of other hormones such as insulin and calcitonin is limited and not sufficiently reproducible. • Nasal administration of insulin with promoter such as bile salts improves bioavailability . • Administration of insulin in a solution containing 5% sodium glycocholate increased absorption of the drug but this bile salt is clinically unacceptable .Why?

21. Buccal or Sublingual Administration • Buccal or sublingual route appears ideal for ; • 1- Lipid – soluble drug . • 2- Those drugs that are metabolized in the gastrointestinal or liver during absorption. Why? • The pH of saliva is usually about 6. Increasing the pH of fluid in the cavity promote the absorption of weak bases but reduces the absorption of weak acids. WHY?

22. Although similarities exist between gastrointestinal and buccal absorption of drugs , some important differences must also exist. • 1- A higher degree of lipid solubility may be required for good absorption from the buccal cavity than from the gastrointestinal tract. • 2- there are storage compartment in the buccal membrane . • This phenomenon may be responsible for the slow absorption of buprenorphineafter buccal administration.

23. The main advantages of sublingual nitroglycerin: • 1- A lack of tolerance. 2- Ease of administration • 3- Rapid ,consistent and complete absorption. • Nitroglycerine levels were variable after sublingual administration . The low and variable absorption of it may be related to : • 1- The patient inability to maintain the dose in the mouth without swallowing. • 2- Inadequate moisture in the mouth . As the sublingual mucosa must be sufficiently moist to facilitate the dissolution of sublingual tablets of nitroglycerin.

24. An oral nitroglycerine aerosol spray is marketed for the prevention and treatment of angina pectoris.It is sprayed onto or under tongue. Its effect appear after 2 min after use of spray. • There are many advantages of nitroglycerin spray over sublingual tablets : • 1- It is easier to use spray than a small sublingual tablets . • 2- Dry mouth can delay the dissolution of sublingual nitrate tablets . • 3- The aerosol droplets may be better absorbed in some patients. • 4- The spray has shelf life 3-years, so it is more stable than sublingual tablets which have a shelf life of one year under ideal conditions.

25. Rapid and effective bronchodilator (fenoterol)was obtained by directing the jet of the aerosol onto the buccal mucosa .This technique could prove useful in the treatment of young children who can not use an aerosol dosage in the recommended manner . • Alprazolamis an anxiolytic agent for the treatment of panic disorder . Sublingual administration may be a useful alternative for panic disorder patients who can not swallow tablets or those who do not have access to water .Its absorption is rapid after sublingual administration and may prove to be preferable to oral administration of alprazolam after a meal ,when gastric emptying is prolonged and the rate of absorption is reduced.

26. Nicotine gum was developed as substitution therapy to help people stop smoking . • The preparation consists of nicotine bound to an ion exchange resin and incorporated into a gum base .The gum also contain a bicarbonate buffer to enhance the buccal absorption of nicotine . • Nicotine is well absorbed from buccal cavity during gum chewing but rather slowly

27. The absorption of methylesterone from sublingual tablets is high with the avoidance of presystemic metabolism.

28. Prolonged-Release Medication Pharmacokinetic Theory : The duration of drug effect is a function of the pharmacokinetic of the drug molecule in an individual patient. The degree of persistence of the molecule in the body is determined by clearance and apparent volume of distribution of a drug .This persistence is characterized in term of half life or mean residence time (MRT). Because the duration of drug action is related to the distribution and elimination kinetics of a drug ,the frequency of dosing must have some relation to the drug,s half life or MRT .

29. Drug absorption and duration effect. • Prolonged release medication is a dosage form containing more drug than a conventional dosage form but releasing the drug far more slowly over a period of hours or even days. • We seek a situation where the duration of drug action is determined by the duration of drug release from the dosage form rather than the drug molecule,s pharmacokinetics properties .

30. Steady State Concentration and Release Rate • Reducing the absorption rate of a drug by controlling its release rate from the dosage form can dramatically affect drug concentration at steady state . For a given dose regimen the slower the release rate of drug the smaller is the ratio of maximum to minimum drug concentration at steady state . • Under these conditions we can give larger doses at less frequent interval and still stay within the therapeutic concentration range of the drug .This is the rationale for prolonged release medication.

31. Zero Order Release The only way to achieve constant blood level is to administer the drug at a constant rate over the entire dosing interval( zero order). The concentration of drug at steady state is given by the following equation : Css= ko/cl Ko is the zero order delivery or release rate of drug Cl is the clearance of the drug . Today there are dosage forms intended for oral ,ocular , intravaginal or intramuscular administration that release the drug in zero order or near zero order fashion.

32. Oral medication The ultimate criteria for evaluating prolonged release dosage forms are : 1- The amount of the drug intended to be absorbed is indeed absorbed in a predictable and consistent manner. 2- The steady –state ratio of maximum to minimum drug concentration is no greater than or,optimally, less than that produced by more frequently administered conventional dosage form.

33. A wide variety of techniques have been used to develop prolonged release oral dosage forms. 1- the use of drug substance of decreased solubility or dissolution rate ,accomplished by : a- Increasing particle size b- the use of less soluble salt or complexes . c- Ion exchange resin to bind the drug substance. 2- Porous, non disintegrating, inert carriers as matrices for the drug . 3- Slowly eroding coatings or matrices and coatings that serve as membranes for drug diffusion.

34. Most oral prolonged release dosage forms are either subdivided or single units. • Subdivided PRD forms exemplified by Spansules. • Several kinds of beads are found in the hard gelatin capsule ,some releasing the drug rapidly, • Others releasing the drug over a period of several • Hours ,still others releasing the drug at intermediate rates. These beads of drug are slowly dissolving and releasing the drug at different rates.

35. Phenothiazine ,antihistamines,iron and many drugs are available in this kind of dosage form. The single unit prolonged release dosage form remain more or less intact throughout the GIT releasing the drug continuously during its passage down the tract. An example of this dosage form is The inert plastic matrix ,the drug is mixed with inert insoluble powdered matrix consisting of plastic resin and other ingredient and compressed .In the GIT drug particles from the surface of the matrix system dissolve and leave pores through which the drug from within the tablet leaches out .The matrix retain its shape during the leaching process and is eliminated in the feces . The release rate of drug decreases with time , and in this sense , resemble a first order process.

36. Zero Order Release: A system termed Elementary osmotic Pump (EOP) Is now available to achieve this goal. The EOP tablet contain a solid core of drug and adjuvants coated with a polymeric membrane ,permeable to water and interrupted only by a single small orifice with a diameter of 0.1 to 0.4 mm . After the tablet is swallowed the membrane selectively admits water from the GHT , drug within the membrane is gradually dissolved the internal pressure produced by entry of the water forces the drug solution out of the orifice.Since the volume of the system is fixed ,constant rate of release is achieved.

37. The depleted membrane is excreted intact .Drug release is independent of pH or motility . The duration of drug delivery is controlled by : The permeability of the membrane Composition of the core . At a given rate of drug delivery ,the duration of controlled release is determined by the amount of drug in the core.

38. Generic Osmotic Pumps : Thy are available as experimental tools for animal or clinical studies . They are useful for but not limited to oral administration . The reservoir is filled with a drug solution . The wall of the reservoir is inert ,impermeable and flexible. A sleeve of osmotically active agent is placed between the reservoir wall and the rigid semi permeable membrane .

39. Water from the surroundings is imbibed through the outer membrane into the osmotic sleeve at a rate controlled by: the permeability of membrane and the osmotic pressure difference across the membrane . The incoming water squeezes the reservoir and the drug solution is expelled at a constant volume per unit time. Delivery of drug solution continues at a constant rate until the drug reservoir is completely collapsed.

40. Limitations of Prolonged Release Medication 1- The limited residence time of the dosage form in the small intestine. 2- Drugs having a biological half life of 8 hours or more should not be used in prolonged release preparation. 3- Drugs that are efficiently absorbed only in the proximal intestine .e.g. riboflavin,as there is no release of the drug in this absorbing area. 4- The drug that is metbolised in G.I. barrier during absorption. E.g. Chlorpromazine ( extensive first pass clearance).

41. 5- Drugs administered in slow release dosage form are subjected to metabolism by bacteria in the lower intestine .This is of particular concern for drug molecules that can be biochemically reduced such as those containing nitro group . Bacterial metabolism can affect bioavailability or result in the formation of toxic metabolites. 6- Drugs whose precision (accuracy ) of dosage is important e.g. digitalis glycosides should not be administered in prolonged release D.F.

42. 7- Drugs with slow intrinsic absorption rates . 8- Drugs such as warfarin ,where pharmacological effect is delayed relative to its wood profile . 9- Low or slow solubility drug 10- Extensive first pass clearance. There are some exceptions: Nitroglycerin has a short half life ,less than 0.5 hour ,it is rapidly metabolized in the liver and is considered to be poorly absorbed, but the low circulating level of it obtained from these products appear to provide adequate prophylaxis against anginal attack.

43. Some drugs have biological half life 8 hrs and given as prolonged release .These products may reduce toxic effects by preventing the sharp peak in circulating drug levels .

44. Implants Numerous devices have been described for the diffusion through silicon rubber e.g. contraceptive devices in the form of silicon rubber capsules containing progesterone have been implanted subcutaneously. silicon rubber capsules containing ethinylestradiol have been used in the treatment of patients with prostate cancer . Certain disorders of male reproductive function can be treated with long acting implants of testosterone .

45. Sub dermal silastic implants containing levonorgestrel have been described. The capsules are implanted into a women upper or lower arm with hypodermic needle. The capsules are to be effective for 5 years . Generic osmotic pump is a useful implant for experimental drug study in animals . Commercially available pumps permit constant rate delivery over one or two weeks .

46. Refillable implant have also described .These devices have been used in patients prone to thrombophlebitis and pulmonary embolism who require heparin . One refillable implant deliver heparin solution continuously over 45days before refilling is necessary . These implants are also used to provide an intra- arterial infusion of 5- fluorouracil for the treatment of hepatoma and primary liver cancer.

47. Portable Infusion Pump(PIP): The most important application of it is the programmed delivery of insulin to provide strict control of blood glucose levels in diabetes . Recently developments of PIP provide light ,portable devices for use by out patients requiring chronic parenteral therapy but need not be hospitalized. Typically the hormones can infused S.C by a catheter leading from the portable pump.

48. There many advantages of Insulin Pump Therapy: 1- Can improve and stabilize eye and kidney function in insulin dependent diabetic patients. 2- A good and efficient glucose control is achieved by using it.

49. Ocular Medication Drug effect in the eye tend to be short lived because of the eye,s efficient mechanism to maintain homeostasis . Ocular insert (ocusert) intended to release the drug slowly in a controlled fashion ,offer the potential benefit of 1-dramatic decrease in the frequency of dosing. 2- more uniform clinical response. 3-decrease in adverse effect.

50. Ocusert containing pilocarpine is used for lowering elevated ocular pressure .The insert is placed under the eye lid where it remains seven days slowly and continuously delivering pilocarpine. Ocusert consists of the drug enclosed by a dense membrane . Pilocarpine is dissolved in the membrane and diffuses slowly to the eye . N.B the total dose delivered by a single ocusert over its 7 days lifetime is one eighth of the amount provided by the usual 2% eye drops of pilocarpine.